Nutritional Adversity, Sex and Reproduction: 30 Years of Dohad and What Have We Learned?

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Journal of P A Jazwiec and Nutritional impacts on 242:1 T51–T68 Endocrinology D M Sloboda offspring reproduction THEMATIC REVIEW Nutritional adversity, sex and reproduction: 30 years of DOHaD and what have we learned?

Patrycja A Jazwiec1,2 and Deborah M Sloboda1,2,3

1Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada 2The Farncombe Family Digestive Diseases Research Institute, McMaster University, Hamilton, Canada 3Department of Pediatrics and Obstetrics and Gynecology, McMaster University, Hamilton, Canada

Correspondence should be addressed to D M Sloboda: [email protected]

This paper is part of a thematic section on 30 Years of the Developmental Endocrinology of Health and Disease. The guest editors for this section were Sean Limesand, Kent Thornburg and Jane Harding

Abstract

It is well established that early life environmental signals, including nutrition, set the Key Words stage for long-term health and disease risk – effects that span multiple generations. This ff maternal nutrition relationship begins early, in the periconceptional period and extends into embryonic, ff developmental fetal and early infant phases of life. Now known as the Developmental Origins of programming Health and Disease (DOHaD), this concept describes the adaptations that a developing ff undernutrition organism makes in response to early life cues, resulting in adjustments in homeostatic ff obesity systems that may prove maladaptive in postnatal life, leading to an increased risk of ff reproduction chronic disease and/or the inheritance of risk factors across generations. Reproductive maturation and function is similarly influenced by early life events. This should not be surprising, since primordial germ cells are established early in life and thus vulnerable to early life adversity. A multitude of ‘modifying’ cues inducing developmental adaptations have been identified that result in changes in reproductive development and impairments in reproductive function. Many types of nutritional challenges including caloric restriction, macronutrient excess and micronutrient insufficiencies have been shown to induce early life adaptations that produce long-term reproductive dysfunction. Many pathways have been suggested to underpin these associations, including epigenetic reprogramming of germ cells. While the mechanisms still remain to be fully investigated, it is clear that a lifecourse approach to understanding lifetime reproductive function is necessary. Furthermore, investigations of the impacts of early life adversity must be extended to include the paternal environment, especially in epidemiological and Journal of Endocrinology clinical studies of offspring reproductive function. (2019) 242, T51–T68

Introduction

It is well established that our lifestyle and external evidence from epidemiological and experimental studies environment, including nutrition and physical exercise, have demonstrated that the early life environment, influences our overall health. However, seminal work including the in utero environment experienced by the completed nearly 35 years ago (Barker & Osmond embryo/fetus, also influences health and disease risk later 1986, Barker et al. 1989, 1993) as well as accumulating in life (reviewed in Chan et al. 2015b). The developing

-19-0048 Journal of P A Jazwiec and Nutritional impacts on 242:1 T52 Endocrinology D M Sloboda offspring reproduction organism is plastic, where regulation of gene expression (Stearns 1992, 2000, Speakman 2008). An example of and cell signaling pathways are sensitive to and thereby this trade-off is when an immature organism allocates adapt to, environmental cues. This plasticity is most energy resources to growth, and it is not until the time prevalent during key developmental windows, including of sexual maturity that energy resources become available the period during which gametes, germ/stem and somatic for reproduction (Stearns 2000, Sloboda et al. 2011). cells proliferate and differentiate forming organ systems Classically, this framework proposes that under postnatal (Gluckman et al. 2005). Signals received by a developing conditions of low energy or scarce resources, organisms organism from its mother (particularly in mammals) are will delay reproductive maturation until a time when used to make changes in homeostatic pathways, most resources are adequate and reproductive activities will be notably to reproductive, metabolic and stress-related successful (Tanner 1955, Ellison 1982, Garn 1987, Coall homeostasis (Gluckman & Hanson 2004), in order to & Chisholm 2010). Human and experimental evidence, maximize fitness (reproductive and metabolic in this however, shows that prenatal, early life adversity is case) in the postnatal environment (Gluckman et al. associated with early reproductive maturation (Sloboda 2005, Hanson & Gluckman 2014). It has been proposed, et al. 2011), although until recently, the focus has largely however, that when a mismatch exists between the been on female reproductive maturation and function. In developmental and predicted postnatal environments, both epidemiological and experimental studies, evidence these adaptations may negatively affect health and result exists that early life adversity results in significant changes in increased disease risk. The hypothesis that the early life in reproductive maturation and capacity. Poor nutrition, environment influences later life disease susceptibility is childhood adversity, psychosocial distress and uncertainty now recognized as the Developmental Origins of Health and poor familial relationships are associated with high and Disease (DOHaD). mortality rates, and when life expectancy is low, life histories are fast (Chisholm et al. 1993, Kramer et al. 2009, Coall & Chisholm 2010, Nettle 2010). Therefore, one Programming reproduction might argue that from this evolutionary perspective, early It is now known that non-communicable chronic diseases life adversity will lead to accelerated maturation, where that were previously associated with lifestyle and genetics the organism trades body size and longevity for earlier have their origins early in life. Of note, these disease reproduction in a ‘threatening’ environment. Indeed, we effects span multiple generations (Gluckman & Beedle and others have previously suggested that fetal growth 2007, Aiken & Ozanne 2014). Germ cells (oocytes/sperm) restriction (FGR) might reflect a life history strategy where in the developing gonads appear to be similarly vulnerable the anticipation of a shorter life and increased risk of disease to early life events and thus are likely to contribute to and mortality results in a decreased allocation of energy transgenerational disease risk. It is therefore plausible that resources into growth and increased energy investment since the gametes that will eventually give rise to grand- into reproduction to ensure reproductive fitness (Ellison offspring form during development, that the long-term et al. 1993, Gluckman & Hanson 2006, Jasienska et al. impacts of early life adversity and postnatal disease lies in 2006, Sloboda et al. 2009, 2011, Chan et al. 2015b, the gonads – within the developing germ cells and their Sharpe 2018). In this article, we review the reproductive function. literature from a DOHaD perspective. We provide a brief If one looks at programming reproduction through overview of the development of gametes in male and an evolutionary biology lens, life history theory provides female mammals, and how early life nutritional adversity a framework to understand how early life adversity impacts female and male reproductive development and results in significant shifts in reproductive capacity and function, and briefly suggest how epigenetics may be the development (Barrett et al. 2012). An organism’s success basis for the mechanism of action. is measured by the number of offspring that survive to pass on genetic information and thus relies on both reproductive capacity and survival (Barrett et al. 2012). At Brief overview of gametogenesis the basis of life history theory is the presence of trade- offs that exist between the benefits of reproducing (and In mammals, the link between early life adversity and ultimately fitness) and the price of reproduction, which reproductive impacts is not difficult to imagine, as the is costly in terms of energy requirements and may result female and male germ cells, the oocytes and spermatozoa, in resource distribution from one system to another develop from a common precursor stem cell, the primordial

Journal of P A Jazwiec and Nutritional impacts on 242:1 T53 Endocrinology D M Sloboda offspring reproduction germ cells (PGC), in the developing gonads during the mature haploid spermatozoa (sperm). Spermatogenesis early life period. After the primordial gonads differentiate occurs in the seminiferous tubules of the testis and into ovaries or testes, the PCGs develop into oocytes initiates after pubertal onset following activation through oogenesis or spermatozoa in spermatogenesis in of the HPG axis. The production of sperm through males and females, respectively. spermatogenesis is dependent on the differentiation and maturation of spermatogonial stem cells (SSCs). After Oogenesis pubertal onset, FSH and LH produced by the pituitary gland stimulate the Leydig cells of the testes to produce The mammalian adult ovary is heterogeneous in testosterone and consequently initiate spermatogenesis. composition, containing follicles at several developmental Spermatogenesis is composed of three main stages, stages. Each follicle is composed of an oocyte surrounded which include spermatocytogenesis (mitotic phase), by somatic granulosa cells (Hirshfield 1991). Follicle spermatidogenesis (meiotic phase), and spermiogenesis growth begins with a gonadotropin-independent phase. (maturation). During spermatocytogenesis, diploid Type During this phase, ovarian follicles transition through A spermatogonia undergo a round of mitosis and produce the primordial, primary and secondary stages and then two diploid spermatogonia, Type A spermatogonia and transition from the preantral to the early antral stage. d Type A spermatogonia. Type A spermatogonia undergo Subsequently, follicles grow and undergo selection and p d division to produce identical daughter cells that replenish ovulation during the gonadotropin-dependent phase and maintain the SSC population. In contrast, Type A (Sanchez & Smitz 2012). Follicle formation begins p spermatogonia form Type B spermatogonia, which serve during early embryogenesis (Mamsen et al. 2012) where to produce mature sperm. During spermatocytogenesis, oogonia enter meiosis I and arrest at the diplotene stage Type B spermatogonia divide by mitosis to produce two of prophase I forming primary oocytes. The development diploid primary spermatocytes. Primary spermatocytes of oocytes remains in meiotic arrest until pubertal onset divide and form two secondary spermatocytes by (Pepling 2012). During folliculogenesis, the primary meiosis I. During the next step of spermatogenesis, follicle develops from a primordial follicle. The presence of spermatidogenesis, the secondary spermatocytes undergo multiple layers of cuboidal granulosa cells is representative meiosis II, during which they divide and form two haploid of the secondary follicle stage. Cells derived from spermatids, half of which contain an X chromosome and surrounding stromal tissue, known as thecal cells, arise half of which contain an Y chromosome. The resulting and form a cellular layer encompassing the granulosa cells spermatids undergo the final stage of spermatogenesis, and oocyte (Young & McNeilly 2010). The formation of the known as spermiogenesis. During spermiogenesis, the granulosa and theca cell layers are essential for establishing spermatids develop into motile and mature spermatozoa. sensitivity to gonadotropins as well as for the production The key changes that occur during spermiogenesis of androgens essential in follicle maturation and ovulation include acrosomal cap and tail formation, removal of (Kumar et al. 1997). Once the secondary follicle grows excess cytoplasm, as well as histone–protamine transition to its maximum size, small cavities filled with follicular (Gilbert 2000). Following spermiogenesis, the mature fluid merge into a larger fluid-filled cavity, known as the sperm are released into the lumen of the seminiferous antrum, in the granulosa cell layer (Monniaux et al. 2014). tubules of the testis (Clermont 1966, Culty 2009). The antral follicle may then undergo apoptosis or the final steps of maturation necessary for ovulation; this process is regulated by the hypothalamic–pituitary–gonadal (HPG) Maternal nutritional impacts on axis, through the hypothalamic secretion of gonadotropin- offspring reproduction releasing hormone (GnRH), and resulting secretion of the pituitary gonadotropins follicle-stimulating hormone Impacts in female offspring (FSH) and leutinizing hormone (LH) and ovarian steroidal FGR and maternal nutritional restriction hormones estradiol (E2) and progesterone (P4) (McGee & Hsueh 2000), which occurs after the onset of puberty. Epidemiological/clinical data on growth restriction and reproduction in human females Numerous studies Spermatogenesis have shown that FGR or intrauterine growth restriction Spermatogenesis is a continuous and dynamic process (IUGR) is associated with altered development and by which immature diploid spermatogonia produce reproductive dysfunction in offspring (Cooper et al. 1996,

Sloboda et al. 2007, Ibanez et al. 2011). Indeed low birth as exaggerated adrenarche (Ibanez et al. 1998, Veening weight (LBW) is associated with a number of morbidities et al. 2004), advanced menarche (Cooper et al. 1996, often associated with aging in women, including Veening et al. 2004, Ibanez & de Zegher 2006), reduced early reproductive aging (Alexander et al. 2014). Since rates of ovulation (Ibanez & de Zegher 2006), premature adequate nutrition during pregnancy is a key factor onset of menopause, as well as increased secretion of mediating fetal growth, it is not surprising that some adrenal androgens (Ibanez et al. 1998). However, it is of the first observations linking growth restriction and currently unknown whether earlier reproductive maturity reproductive dysfunction come from studies of famine is associated with premature follicle loss. Studies suggest in large populations. One of the first sets of observations that girls growth-restricted in utero have an increased implicating the prenatal nutritional environment to risk of infertility (Vikstrom et al. 2014); however, SGA impaired reproductive function was derived from the is not always associated with increased risk of infertility Dutch Hunger Winter Famine of 1944–1945 (Schulz 2010). in adulthood (Meas et al. 2010, Sadrzadeh-Broer et al. Women exposed to famine throughout pregnancy gave 2011), or with advanced menarche (Shim et al. 2013) or birth to children that began bearing children at a younger precocious menopause (Treloar et al. 2000). Overall, most age (Painter et al. 2008) and presented at an increased risk reports suggest that IUGR and SGA are associated with of experiencing menopause earlier in life (Elias et al. 2003, reproductive dysfunction in females. The mechanisms Yarde et al. 2013), although there is at least one report underlying these associations are unclear, but since fetal that some of these associations may not exist (Lumey nutrient supply significantly impacts fetal growth, prenatal & Stein 1997). Similarly, women that experienced acute nutritional manipulation has emerged as an important malnutrition in utero as a result of the 1959–1961 famine model, used to elucidate the relationship between fetal in China experienced an increase in the risk of sterility, growth and postnatal reproductive function. albeit a modest 1.1% increase, potentially resulting in permanent impaired fecundity (Song 2013), illustrating Experimental animal models of nutritional restriction that similar phenotypes occur in different geographical programming reproduction in females Given the locations across different populations. considerable amount of evidence from studies suggesting Data from small selected populations have suggested that reproductive function is influenced by early life events, underlying mechanisms. Ibanez and colleagues have particularly those that restrict fetal growth, animal models published an extensive set of papers showing that in of nutrient restriction and FGR have been developed utero growth restriction in girls significantly impairs to understand underlying mechanisms. Using rodents reproductive development. This groups has demonstrated models of maternal caloric restriction during pregnancy that serum levels of FSH were increased twofold in girls and/or lactation, we (Sloboda et al. 2009, Bernal et al. 2010, born small-for-gestational age (SGA) compared to girls born Chan et al. 2015a, 2018, Jazwiec et al. 2019) and others appropriate-for-gestational age (AGA) (Ibanez et al. 2002), (Caron et al. 2012, Mossa et al. 2013, Khorram et al. 2015, and FSH hypersecretion was also evident in adolescent Hoffman et al. 2018) have demonstrated that offspring females born SGA (Ibanez et al. 2000, Ibanez 2003). In born under conditions of nutrient restriction show early addition to altered gonadotropin secretion, females born puberty, reproductive cycle irregularity and reductions SGA show impaired ovarian development and reduced in follicle subpopulations; clear indicators of early ovarian size (Ibanez et al. 2000, Ibanez 2003). Similarly, ovarian aging. Although some models of maternal caloric female fetuses that experienced growth restriction in utero restriction have found that pubertal onset is delayed in show reduced ovarian size accompanied by a significant female offspring (Engelbregt et al. 2000, Sanchez-Garrido decrease in primordial follicle number (de Bruin et al. et al. 2013, Matsuzaki et al. 2018). It has been proposed 1998). Other reports contradict these findings, however, that the susceptibility of oocytes to nutritional adversity showing similar primordial follicle counts in IUGR female during development results in impairments to fetuses compared to appropriately grown fetuses (de Bruin folliculogenesis that translate to reproductive dysfunction et al. 2001). in later life. We have recently shown that these impacts Girls born SGA achieved reproductive maturity may occur very early in the development of the ovary, earlier in comparison to girls born AGA (Cooper et al. as early as day 4 of neonatal life in rats, effects that are 1996). Indeed, this relationship holds true across the associated with impaired reproductive cyclicity and normal birth weight spectrum (Sloboda et al. 2007). ovulation by young adulthood (Chan et al. 2018). We Precocious reproductive maturity in SGA girls manifested showed that neonates born to nutrient restricted mothers

Journal of P A Jazwiec and Nutritional impacts on 242:1 T55 Endocrinology D M Sloboda offspring reproduction have accelerated primordial follicle recruitment, and differential reproductive outcomes may occur. This has that beyond this stage, impaired follicle growth factor largely been explored in large animal models, since and gonadotropin responsiveness resulted in increased gestation length is long enough to explore different periods follicular atresia by apoptosis, by 65 days of age (Chan et al. of exposure. Indeed, early studies in sheep have shown 2018). We propose that accelerated follicular recruitment that an acute bout of undernutrition early in pregnancy is facilitated by an increase in the transcriptional driver impacts fetal follicular development where undernutrition FOXO3a, concomitant with a reduction in the brake on during the first 30 days (of 150-day pregnancy) impaired follicular recruitment via the AMH receptor, in neonatal growth of ovarian follicles in fetuses some 80 days later ovaries born to undernourished mothers (Chan et al. (Rae et al. 2001). Undernutrition late in pregnancy resulted 2018) (Fig. 1). We and others have shown that prenatal in smaller ovarian follicles in juvenile lambs possibly due to nutritional adversity results in ovarian oxidative lower insulin like growth factor (IGF) levels (Hoffman et al. stress (Aiken et al. 2013, Chan et al. 2015a), impaired 2018) and undernutrition throughout most of pregnancy mitochondrial function (Aiken et al. 2013) and together resulted in a diminished response to GnRH in young lambs with a loss of ovarian follicles early in life (Sloboda et al. (Deligeorgis et al. 1996). Undernutrition for the first half of 2009, Aiken et al. 2013, Chan et al. 2015a) suggests that pregnancy had no effect on FSH profiles in females, basal prenatal nutrient restriction results in early ovarian LH profiles or gonadotrophin responses to GnRH, but aging. Indeed in early sheep studies, oxidative stress was ovulation rate was significantly reduced Rae( et al. 2002a). evident even in fetal oogonia and was associated with an It is likely that some of these ovarian changes are increase in tumor suppressor/cell-cycle arrest modulator coupled with alterations in central processing and p53, suggesting that depending on the species studied, hypothalamic–pituitary drive. Coupled with changes in different windows of development may be more or less estrous cyclicity, maternal undernutrition in rats resulted vulnerable to nutritional adversity (Murdoch et al. 2003). in changes in hypothalamic gondotrophin-releasing Critical windows have been explored, suggesting that hormone (GnRH) transcript levels in 1-day-old neonatal depending on the period of exposure to undernutrition, rats, proposed to be mediated by hypothalamic leptin

Figure 1 Maternal undernutrition (UN) impacts on key signaling factors involved in primordial follicle recruitment in neonatal (P4) ovaries. Data from Chan et al. (2018). Reproduced, with permission, from Chan KA, Jazwiec PA, Gohir W, Petrik JJ & Sloboda DM; Maternal nutrient restriction impairs young adult offspring ovarian signaling resulting in reproductive dysfunction and follicle loss; Biology of Reproduction, 2018, volume 98, pages 664–682, by permission of Oxford University Press. Photographs represent the immunolocalization of phosphorylated (p)FOXO3, AMH receptor 2 (AMHR2) and AMH in P4 neonatal ovaries from either control fed (CON) or undernourished (UN) mothers. Brown color depicts protein localization. Inset circles represent the image at 20× magnification. Negative controls incubated in the absence of primary antibody showed no staining (data not shown). Scale bar represents 100 μm. Graphs represent semi- quantitative analysis of immunopositive staining for pFOXO3 (CON n = 5, UN n = 5); AMHR2 (CON; n = 5, UN; n = 5) and AMH (CON; n = 5, UN; n = 6). Data are presented as box and whiskers plots, min to max, where the center line represents the median. *P < 0.05.

https://joe.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/JOE-19-0048 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 10:08:12AM via free access Journal of P A Jazwiec and Nutritional impacts on 242:1 T56 Endocrinology D M Sloboda offspring reproduction levels (Khorram et al. 2015). Leptin is known to stimulate experienced menarche 4.1 months earlier than girls whose GnRH secretion, and it has been previously shown that mothers had a BMI of 20.0–21.9 kg/m2 (Mariansdatter et al. maternal undernutrition alters the normal neonatal 2016), and also experienced earlier onset of secondary sex leptin surge in rodents (Yura et al. 2005, Delahaye et al. characteristics (Kubo et al. 2018). These findings suggest 2008) which likely impacts neuronal regulation of both that exposure to maternal obesity, as well as maternal metabolism and reproduction (Mela et al. 2015). It is thus hyperglycemia, places girls at higher risk of earlier possible that the link between energetics and reproductive pubarche (Kubo et al. 2016). Excessive gestational weight function is dysregulated in neonatal life, and that later gain (GWG) during pregnancy is also an independent life outcomes, like ovarian follicle loss, are likely the risk factor for early menarche. Daughters whose mothers result of this disrupted interaction. Central regulation of gained greater than 40 lbs of gestational weight had a 30% behavior is also vulnerable, since hypothalamic nuclei increased risk of experiencing menarche before 11 years of appear sensitive to early nutritional adversity. Sexual age (OR 1.27; CI 1.06–1.56) (Boynton-Jarrett et al. 2011). behavior is altered by early life nutritional adversity, These findings are supported by other studies that report where receptive sexual behavior in female offspring an inverse association between maternal prepregnancy born to undernourished mothers was decreased and BMI and GWG and age of menarche of their daughters was associated with changes in transcript levels of (Shrestha et al. 2011, Deardorff et al. 2013, Jansen et al. hypothalamic progesterone receptors and oxytocin. These 2015, Lawn et al. 2018). Both maternal prepregnancy BMI changes were associated with changes in pubertal onset and GWG were inversely associated with daughter’s age and estrous cyclicity (Matsuzaki et al. 2018). at menarche and interestingly the associations remained unchanged after adjustment for many confounders, but Impacts of obesity, overweight and nutritional excess were attenuated when adjusted for daughter’s prepubertal Obesity has reached epidemic proportions, with over BMI (Lawn et al. 2018). These findings indicate that the 650 million adults obese worldwide. The prevalence of association between prepregnancy BMI and GWG may worldwide obesity has almost tripled since 1975 and the be mediated by daughters’ prepubertal BMI (Lawn et al. number of obese women of reproductive age has increased 2018), an observation that we have also found when concomitantly (Ogden et al. 2006, Vahratian 2009, Flegal considering the relationship between birth weight and et al. 2010, 2012). Maternal obesity is associated with age at menarche (Sloboda et al. 2007). obstetric complications, including gestational diabetes (GDM) and preeclampsia (Ramachenderan et al. 2008, Experimental animal models of obesity and nutritional Catalano & Shankar 2017). Beyond impairing maternal excess programming reproduction in females Animal health, maternal obesity has negative impacts on models of diet-induced obesity (DIO) provide considerable fetal and neonatal health; increased risk of stillbirth, insight into understanding the mechanisms governing preterm birth and altered fetal growth are associated maternal obesity-induced impacts on female offspring with maternal obesity (Tenenbaum-Gavish & Hod reproductive development and function. We and others 2013, Catalano & Shankar 2017). Maternal obesity also have found that adult female rat offspring exposed to predisposes her children to develop overweight and a high-fat diet (either n-6 polyunsaturated fatty acid or obesity during childhood (Catalano et al. 2009, Rooney saturated fats) in utero reach puberty earlier compared to et al. 2011, Godfrey et al. 2017) and metabolic syndrome control counterparts (Hilakivi-Clarke et al. 1997, Sloboda later in life (Drake & Reynolds 2010, Gaillard 2015, et al. 2009, Connor et al. 2012), and these offspring have Godfrey et al. 2017). increased risk of reproductive (breast) cancer (Hilakivi- Clarke et al. 1998) possibly via elevated pregnancy estrogen Epidemiological/clinical data on the impacts of levels in high-fat fed mothers. It has been proposed that maternal obesity and nutrient excess on reproduction these high levels of estrogen may alter mammary gland in human females Evidence from human cohorts morphology, increasing terminal end bud number, and suggests that maternal obesity predisposes offspring expression of fat- and/or estrogen-regulated genes in to reproductive dysfunction as adults. An overweight the offspring, thereby increasing breast cancer risk in and an obese prepregnancy body mass index (BMI) was offspring (Hilakivi-Clarke et al. 1999). Although estrogen associated with early onset of menarche (first menstrual levels were unaffected, we have demonstrated that female cycle) in daughters (OR 3.1; 95% CI 1.1–9.2) (Keim et al. rat offspring of high-fat-fed mothers experienced irregular 2009), where girls born to mothers with a BMI ≥22 kg/m2 reproductive cycles (Connor et al. 2012).

Journal of P A Jazwiec and Nutritional impacts on 242:1 T57 Endocrinology D M Sloboda offspring reproduction

There is no doubt that maternal obesity affects of maternal oocytes can been seen in offspring oocytes both the mother’s own fertility (Bermejo-Alvarez et al. for at least two more generations, suggesting germline 2012, Silvestris et al. 2018) as well as development of transmission (Saben et al. 2016) (Fig. 2). Similar defects her offspring (Catalano & Shankar 2017). Obesity in in mitochondrial function have been seen in mouse women results in significant impairments in the oocyte, embryos of pregnancies complicated by diabetes including mitochondrial dysfunction (Grindler & Moley (Wang et al. 2009), although at least one study reports that 2013), lipotoxicity (Jungheim et al. 2011), elevated normal blastocyst development was observed in fertile, reactive oxygen species (ROS) (Wakefield et al. 2008, obese females (Bermejo-Alvarez et al. 2012). Igosheva et al. 2010) and ER stress (Wu et al. 2015b) Longer-term impacts of maternal obesity and high-fat damage. Weight loss, at least in mice, did not show diet (HFD) exposure on female offspring reproduction reversal of these negative defects or reverse oocyte lipid is also evident. Exposure to HFD in utero is associated accumulation, alterations in TCA cycle metabolite levels with a significant reduction in the number of primordial and mitochondrial membrane potential, or abnormalities follicles in lambs (Da Silva et al. 2001). In our work, we in mitochondrial distribution, despite reversal of the show that fetuses of mothers fed a HFD during pregnancy metabolic phenotypes of obesity (Reynolds et al. 2015). have an 11% reduction in oocyte number (Tsoulis et al. But effects can be reversed with therapies specifically 2016) – an effect that correlated significantly to maternal targeting the mitochondrial respiratory chain (Boots adiposity (Fig. 3). We proposed that maternal HFD intake et al. 2016) or ER stress, and oocyte competence has been during pregnancy resulted in an increase in primordial improved with voluntary exercise regimes (Boudoures follicle assembly, amounting to more primordial and et al. 2016). These impairments in oocytes are associated transitioning follicles early in life essentially changing with poor blastocyst and embryo development, increased the development of the primordial follicle pool in fetal ROS production as well as mitochondrial dysfunction in life, but that these follicles are then lost to atresia as embryos (Igosheva et al. 2010, Wu et al. 2010, Boudoures they transition to growing follicles (Tsoulis et al. 2016). et al. 2017). Furthermore, defects in the mitochondria Similar outcomes have been reported in rabbit offspring,

Figure 2 Saben et al. (2016) demonstrate that maternal diet-induced metabolic syndrome in an inbred mouse model results in transgenerational inheritance of aberrant mitochondria. Abnormal expression of mitochondrial electron transport chain proteins are seen in F1–F3, despite the fact that they ate a regular diet. The transmission appears to be germline and through aberrant oocytes. Reproduced, with permission, from Saben JL, Boudoures AL, Asghar Z, Thompson A, Drury A, Zhang W, Chi M, Cusumano A, Scheaffer S & Moley KH; Maternal metabolic syndrome programs mitochondrial dysfunction via germline changes across three generations; Cell Reports, 2016, volume 16, pages 1–8, with permission from Elsevier (Saben et al. 2016).

Figure 3 Maternal HF diet intake results in decreased number of oocytes in fetal ovaries in the rat at embryonic day 20. Reproduced, with permission,

– from Tsoulis MW, Chang PE, Moore CJ, Chan KA, )

3 1.2 1.3 Gohir W, Petrik JJ, Vickers MH, Connor KL & –1 )

3 Control fetuses Sloboda DM; Maternal high-fat diet-induced loss µ m 1.2 ( 1.1 of fetal oocytes is associated with compromised

( µ m 1.1 p <0.05 follicle growth in adult rat offspring;Biology of 1.0 Reproduction, 2016, volume 94, issue 4, article ID * 1.0 94, by permission of Oxford University Press 0.9 (Tsoulis et al. 2016). Maternal HF diet during 0.9 High fat pregnancy resulted in an 11% decrease in the number of oocytes at E20 in fetal offspring 0.8 0.8 fetuses

Fetal oocyte # ovaries (n = 8 CON; n = 5 HF). Maternal

Number of oocytes 0.7 0.7 retroperitoneal fat mass negatively correlated with the number of oocytes in fetal offspring Control High Fat 0510 15 ovaries (r = 0.57; P < 0.05). Solid line is the best fit, Maternal Fat mass and dotted lines are 95% confidence intervals. which had increased atretic follicle numbers without prevent advanced puberty in offspring, but returned the changes in the number of primordial, primary and number of antral follicles, follicular cysts and multi-oocyte second follicles (Leveille et al. 2014), although fertility was follicles to control values in the female offspring (Álvarez unaltered (Leveille et al. 2014). Depletion of the ovarian et al. 2018) suggesting that maternal obesity impacts on follicle reserve, also reported in other models of maternal fetal ovarian development may be a combination of both obesity, has been attributed to mitochondrial dysfunction the mother’s own metabolic dysfunction and changes in and increased lipid peroxidation (Aiken et al. 2016). the her oocyte quality. Despite numerous studies describing the impacts of maternal obesity on female reproductive function, Impacts in male offspring currently little is known about molecular mechanisms. Changes in circulating levels of sex steroids in obese FGR and maternal nutritional restriction mothers (Maliqueo et al. 2017) has generated some novel hypotheses. Maternal obesity is associated with higher Epidemiological/clinical data on growth restriction circulating androgen levels (Kallak et al. 2017), an effect and reproduction in human males Poor maternal that may be modulated by the sex of the fetus (Maliqueo periconceptional nutrition impairs fetal growth, resulting et al. 2017). Since prenatal exposure to testosterone is in IUGR and LBW infants and, accordingly, birth weight associated with higher risk of polycystic ovarian syndrome has been used as a proxy measure for intrauterine in the offspring of many species (Abbott et al. 2005, Sun nutritional adversity. One of the first studies published et al. 2012, Moore et al. 2013, Padmanabhan & Veiga- in 1953, establishing an association between fetal growth Lopez 2013), and potentially in humans (Sir-Petermann and male reproductive function was a case study of a male et al. 2002, Filippou & Homburg 2017), exposure to child born LBW that presented with, among many other high levels of androgens at vulnerable developmental complications, elevated urinary gonadotropins (Silver windows of ovarian development is a potential driver of et al. 1953). Subsequent studies show that FGR is associated offspring ovarian compromise. Changes in offspring sex with alterations in hypothalamic–pituitary–gonadal steroid concentrations may also influence ovarian follicle (HPG) activity prior to pubertal onset. Male infants born development. Offspring from HFD-fed rats demonstrated SGA have a twofold elevation in serum FSH concentrations elevated estradiol levels between day 1 and 60 of without changes in serum LH, inhibin B and free androgen postnatal life, in association with a loss of ovarian antral index (Ibanez et al. 2002). Adolescent males born SGA follicles, increased follicular cysts as well as changes in have reduced testicular size, decrease testosterone levels hepatic metabolism of estradiol (Ambrosetti et al. 2016). and increased LH levels in adolescence, suggesting that Finally, recent work suggests that improving maternal changes in HPG activity observed in infants likely persist insulin sensitivity during an obese pregnancy has positive into post-pubertal life (Cicognani et al. 2002). Reports also impacts on offspring ovarian function (Álvarez et al. 2018). exist however showing no differences in testosterone and Treating obese pregnant rats with metformin did not inhibin B levels, LH/testosterone ratio, overnight secretory

Journal of P A Jazwiec and Nutritional impacts on 242:1 T59 Endocrinology D M Sloboda offspring reproduction patterns of gonadotropins or testicular size (Jensen et al. with reduced sperm quality in male offspring. In a model 2007, Ramlau-Hansen et al. 2007) or semen quality (Olsen of placental insufficiency, prenatally growth-restricted et al. 2000, Ozturk et al. 2001, Ramlau-Hansen et al. 2007) male lambs had reduced testicular volume (Da Silva in SGA males compared to control counterparts. Despite et al. 2001). Similarly, male bovine offspring born after these apparent contradictory reports, IUGR has been prenatal nutrient restriction had an increased proportion reported to be associated with unexplained infertility of seminiferous tubules and reduced testicular blood in males in adulthood. Early studies show that 53% of vessel area (Copping et al. 2018). Maternal undernutrition men with abnormal sperm parameters are classified as was associated by reduced mean Sertoli cell numbers and having unexplained male infertility and compared to reduced seminiferous tubule diameter (Kotsampasi et al. males with a normal semen and males with unexplained 2009). In a bovine model, male offspring born to heifers subfertility had a median birth weight SD score of −0.5 fed a low-protein diet during gestation presented reduced suggesting that LBW maybe associated with unexplained sperm quality, characterized by increased proportion male infertility (Francois et al. 1997). In a cross-sectional, of sperm with non-progressive motility and abnormal population-based sibling pair study, LBW was associated morphology (Copping et al. 2018). Similarly, the number with decreased serum testosterone in adult men, of Sertoli cells were reduced by 20% in male offspring (Vanbillemont et al. 2010) and low testosterone is often born to pregnant ewes fed a low-caloric diet (Bielli et al. associated with poor reproductive outcomes (de Kretser 2001). These data have been replicated in other large 1979). Indeed, more recently, significant associations animals models; in horses, maternal undernutrition between birth weight, adult sperm DNA integrity and impaired prepubertal testicular maturation (Robles et al. total sperm count have been reported (Faure et al. 2015). 2017). Despite these many reports, contrasting studies In a relatively large cohort of men seeking infertility exist reporting that fetal testis weight and mean scrotal treatment, when compared with fertile men, infertile circumference were unaltered in adult lamb offspring men showed a lower mean birth weight and a higher undernourished in utero (Rae et al. 2002a,b, Kotsampasi proportion of LBW. These infertile LBW men had reduced et al. 2009). In rodents, in contrast, ano-genital distance, sperm motility and abnormal sperm morphology, lower a developmental marker of intrauterine testosterone total testosterone levels but higher FSH values, compared exposure, was increased by maternal protein restriction with average or high birth weight men. Interestingly, these and postnally, offspring testicular descent was delayed, LBW male patients reported a higher rate of significant testes weight was reduced as well as LH and testosterone comorbidities and reduced left testicular volume and also concentrations and fertility was reduced (Zambrano presented with higher BMI (Boeri et al. 2016). It may be et al. 2005). In other work, prenatal undernutrition that part of association between reproductive deficits and delayed sexual maturation, but did not suppress sexual LBW could be accounted for by an increased prevalence behavior, in mature male rats (Matsuzaki et al. 2018). of obesity, which occurs concomitantly with metabolic Intrauterine growth retardation (IUGR) induced by dysfunction, since LBW increases obesity risk, and obesity uterine artery ligation, delayed pubertal onset in rats in men is known to impair reproductive capacity (Palmer (Engelbregt et al. 2000). et al. 2012). Finally, maternal smoking during pregnancy (proposed to reduce fetal growth through placental Maternal obesity and nutritional excess hypoxia) significantly advances Tanner staging pubertal onset in boys (and girls) (Ernst et al. 2018). Epidemiological/clinical data on maternal obesity/ nutritional excess reproduction in human males Very Experimental animal models of nutrient restriction few studies have investigated the association between and growth restriction and reproduction in male maternal obesity and reproductive development offspring Maternal nutrient restriction-induced FGR or function in male offspring. A small pilot study has been shown to program reproductive development investigating the association between maternal BMI and in male offspring, where in lambs the adolescent offspring semen parameters found a weak association testosterone surge, a marker of pubertal onset, occurred between semen quality and reproductive hormone levels 5 weeks later in growth-restricted male lambs (Da Silva in offspring and maternal obesity, but this study was et al. 2001), and although it is unclear whether prenatal small and underpowered (Ramlau-Hansen et al. 2007). undernutrition impairs testis development, it has been In a much larger study, sons of obese mothers started consistently reported that growth restriction is associated on average to shave regularly 8.3 months earlier than

https://joe.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/JOE-19-0048 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 10:08:12AM via free access Journal of P A Jazwiec and Nutritional impacts on 242:1 T60 Endocrinology D M Sloboda offspring reproduction sons of normal weight mothers (Hounsgaard et al. 2014) Paternal nutritional impacts on suggesting that pubertal onset is earlier in sons of obese offspring reproduction mothers. Maternal diabetes, in contrast, did not show a strong association between maternal GDM or type Much of the work on programming of offspring 2 diabetes with pubertal milestones (Lauridsen et al. reproductive function has focused on the mother and the 2018), although in a sub-analysis, after adjusting for maternal environment, while paternal impacts have been potential confounders, daughters and sons of mothers largely overlooked and understudied. To our knowledge, with BMI >25 kg/m2 and GDM entered puberty earlier there have been no epidemiological studies that have than daughters and sons of mothers with BMI <25 kg/m2 investigated the impacts of paternal nutrition on their without GDM, suggesting that both GDM and BMI may children’s reproductive outcomes. However, despite the together play a role in modulating pubertal onset in boys. lack of epidemiological evidence, experimental studies have recently begun exploring the contribution of Experimental animal models of maternal obesity paternal nutrition, specifically obesity, on reproductive and nutrient excess and reproduction in male outcomes in female and male offspring using rodent offspring Despite the fact that few human studies models of paternal DIO. exist investigating the linking prenatal exposure to an obesogenic environment and reproductive compromise in Impacts in female offspring males, many animal models suggest that maternal obesity affects reproductive function in male offspring. Adult Impacts of obesity, overweight and male offspring born to pregnant rats consuming a high- nutritional excess calorie cafeteria diet throughout pregnancy and lactation had reduced plasma levels of LH, FSH and testosterone, Experimental animal models of obesity and as well as altered sexual behavior compared to control nutritional excess programming reproduction male offspring (Jacobs et al. 2014). Male rat offspring in females Rodent models of paternal DIO report were deficient in testosterone, and this was accompanied detrimental effects on reproductive health in female by an overall reduced sperm count, with reductions offspring and grand-offspring. F1 females fathered in round and elongated spermatids, which may be by HFD-fed males presented with impaired oocyte mediated by testosterone deficiency, fueling the impaired quality, evident as reduced meiotic progression and formation and/or survival of spermatids and contributed altered mitochondrial function (Fullston et al. 2012). to reduced sperm count (Navya & Yajurvedi 2017). The In addition to altered mitochondrial function, oocytes early neonatal window may also be a vulnerable time from F2 females had increased oxidative stress (Fullston for sperm programming. Daily sperm production was et al. 2012). Whether impairments in these oocytes reduced in adult male rats born to mothers exposed to affected embryo quality is unknown. Females fathered HFD during pregnancy and lactation (Reame et al. 2014) by HF-fed males have delayed embryo development, but only when mothers were exposed to HFD during both reduced compaction rates and reduced proportion pregnancy and lactation and not pregnancy alone (Reame of embryos achieving blastocyst stage (Binder et al. et al. 2014, Rodriguez-Gonzalez et al. 2015). In addition 2012). Similarly, female offspring sired by HF-fed males to reducing sperm counts, sperm quality is also affected generated embryos with delayed development and by prenatal adversity. In offspring born to obese mothers, altered proportions of trophectoderm and inner cell mass sperm viability and motility was reduced and the number cells in developing blastocyst (Fullston et al. 2015b). of sperm presenting with impaired oxidative stress Collectively, the findings from these studies suggest that management was increased; malondialdehyde (MDA) paternal HFD reduces oocyte quality in female offspring. levels were increased, superoxide dismutase (SOD) was In contrast, one report shows that paternal obesity did decreased and glutathione peroxidase (GPx) activity was not significantly alter gonadotropin levels in the female increased in sperm and testes of males offspring, resulting offspring fed HFD, although these females displayed in decreased fertility rates (Rodriguez-Gonzalez et al. 2015, reduced LH responses to kisspeptin-10 (Fernandois et al. Bautista et al. 2017). Collectively, suggesting that maternal 2017). Given that changes in oocyte and embryo quality obesity during pregnancy impairs the antioxidant defense are observed in female offspring and grand-offspring in system in testes, contributing to reduced reproductive rodent models of paternal obesity, investigations using capacity in adulthood. data from human cohorts are warranted.

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Impacts in male offspring mediate gene expression very early life. Parental lifestyle factors, notably maternal and paternal diet/nutrition Impacts of obesity, overweight and (as reviewed in Jiménez-Chillarón et al. 2012), have been nutritional excess shown to alter the epigenome and changes to epigenetic Experimental animal models of obesity and nutritional processes and signaling pathways, are associated with excess programming reproduction in males Evidence increased disease risk in offspring later in life and many from rodent models indicates that paternal obesity is also studies now suggest that epigenetic mechanisms underpin detrimental to the reproductive health of male offspring programming of disease. The epigenome is a collection and grand-offspring. HF-fed males generated male offspring of heritable chemical modifications and proteins that whose sperm had reduced progressive motility, increased regulate gene expression through transcription without ROS and DNA damage, as well as reduced binding and changes to the DNA sequence (Skinner et al. 2010), fertilization rates. Indeed, grand-offspring also presented modifications that may include DNA methylation, a similar phenotype, where their sperm also had decreased histone modifications, regulatory RNAs and transcription progressive motility and increased ROS (Fullston et al. factors. Particularly relevant to the investigation of 2012). Male offspring born to F1 females, who displayed reproductive development and function is the fact decreased oocyte quality, had decreased testis weights, that the epigenome is reprogrammed several times decreased serum testosterone, as well reduced progressive throughout the lifespan and thus likely plays a key role motility and increased ROS in sperm (Fullston et al. in modulating reproductive outcomes in circumstances 2012). These findings are supported by a follow-up of early life adversity. As there are many reports that study showing that paternal obesity results in offspring review epigenetic reprogramming (Messerschmidt et al. with reduced sperm motility, elevated intracellular ROS 2014, Stuppia et al. 2015, Xu et al. 2015, Fraser & Lin and decreased sperm–oocyte binding (Fullston et al. 2016), this topic will not be extensively reviewed here 2015a). Paternal obesity caused a decrease in LH levels and we will simply identify some of the processes that and exacerbated the drop in circulating testosterone and could underlie the link between nutritional adversity and gene expression of its key biosynthetic enzymes caused offspring reproductive compromise. by HFD in the male offspring (Fernandois et al. 2017). The epigenome is first reprogrammed during Furthermore, central regulation of the HPG axis also gametogenesis. As PGCs proliferate and migrate to the appeared compromised where LH responses to central genital ridges, methylation patterns are erased by active kisspeptin-10 administration were suppressed in HFD global demethylation. This loss of DNA methylation males from obese fathers (Fernandois et al. 2017). Efforts patterns enables establishment of sex-specific imprints in to mitigate these outcomes with dietary intervention female and male germ cell precursor cells. Following sex in founders improved offspring sperm motility and determination, DNA remethylation occurs in germ cell mitochondrial markers of sperm health (decreased ROS precursors in female and male embryos. Specifically, in and mitochondrial membrane potential) and improving male embryos, de novo methylation initiates in mitotically sperm binding. Sperm binding and capacitation was arrested prospermatogonia and is completed prior to also improved in F1 males born to a combined diet and birth. In female embryos, however, DNA methylation exercise intervention in founders (McPherson et al. 2014). initiates after birth when ovarian follicles are growing. Other forms of epigenetic reprogramming occur in PCGs concomitantly, such as histone deacetylation and histone Epigenetic mechanisms underlying variant H2A.Z replacement (Wu et al. 2015a). In males, reproductive programming epigenetic reprogramming continues into postnatal life. After birth, spermatogonia undergo rapid expansion and As reviewed earlier, it is well established that exposure remain dormant until puberty. Spermatogenesis initiates to adverse parental nutritional environments programs after pubertal onset following activation of the HPG impairments in reproductive health of offspring. There axis. Final DNA methylation patterns are established is now overwhelming evidence showing that the germ in spermatogonia during spermatocytogenesis. cells that will eventually give rise to grand-offspring are Subsequently, during the initial stages of spermiogenesis, vulnerable to nutritional adversity, and while the exact histone–protamine exchange occurs and results in cellular signaling pathways remain to be fully investigated, extensive chromatin remodeling (Wu et al. 2015a). At this many have turned their research focus to processes that point in development, both the paternal and maternal

Figure 4 Perturbations at vulnerable windows of development, particularly in germ cells, have impacts that span multiple generations. Since primordial germ cells (PGCs) that eventually give rise to grand-offspring form during development, and are vulnerable to nutritional adversity through epigenetics mechanisms, the link between early life adversity and postnatal disease likely lies within the developing gonads and their function. These PGCs give rise to alterations in numerous organ systems, and in the control of reproductive development and function – ultimately resulting in not only impairments in the first generations, but many generations thereafter. genomes of the oocyte and sperm are hypermethylated Conclusions and future directions and transcriptionally silent. Shortly after fertilization the paternal and maternal genomes are actively and There is now overwhelming evidence that health and disease passively demethylated, respectively, and generate a has its origins early in life and perturbations at vulnerable transcriptionally active totipotent zygote. However, windows of development, particularly in germ cells, have methylation patterns are maintained at imprinted impacts that span multiple generations (Gluckman & Beedle genes during this phase of reprogramming. Following 2007, Aiken & Ozanne 2014, Pembrey et al. 2014). Evidence implantation, a new methylation pattern is established in suggests that since germ cells that eventually give rise to the embryo by de novo methylation (Wu et al. 2015a). grand-offspring form during development and are vulnerable Given the above described epigenetic landscape, it is to nutritional adversity through epigenetics mechanisms not surprising that adversity early in life is hypothesized and that the link between early life adversity and postnatal to operate through epigenetic mechanisms that can disease lies within the developing germ cells and their have long-term impacts on offspring. Environments function. These germ cells give rise to alterations in numerous during pregnancy have been shown to perturb epigenetic organ systems, none the least, in the control of reproductive remodeling in PGCs and embryos and result in lasting development and function – ultimately resulting in not only impacts on male and female offspring. In a similar impairments in the first generations, but many generations manner, exposure to adverse paternal nutrition post- thereafter (Fig. 4). New approaches to understanding puberty, when epigenetic reprogramming is occurring paternal and offspring health and disease have recently in maturing sperm, can alter the sperm epigenome highlighted mechanisms other than epigenetics that need and program impairments in reproductive function in to be considered, including immune factors (Schjenken & offspring (Lambrot et al. 2013, Desai et al. 2015, Gu et al. Robertson 2015, Evans et al. 2019). While the mechanisms 2015, Ly et al. 2015, Siklenka et al. 2015, Whidden et al. still remain to be fully investigated, it is clear that a lifecourse 2016, Ly et al. 2017, Morgan et al. 2019). Although there approach to understanding reproductive development and is much work to be done in understanding the drivers lifetime reproductive function is necessary. Furthermore, of epigenetic modifications due to early life nutritional investigations of the impacts of early life adversity must be adversity, it seems that this will likely be a fruitful path of extended to include the paternal environment, especially investigation linking early life adversity to reproductive in epidemiological studies and clinical studies of offspring impairments in offspring. reproductive function.

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Barker DJ, Osmond C, Simmonds SJ & Wield GA 1993 The relation Declaration of interest of small head circumference and thinness at birth to death from The authors declare that there is no conflict of interest that could be cardiovascular disease in adult life. BMJ 306 422–426. (https://doi. perceived as prejudicing the impartiality of this review. org/10.1136/bmj.306.6875.422) Barrett L, Dunbar R & Lummaa V 2012 Life-History Theory, Reproduction and Longevity in Humans. Oxford, UK: Oxford University Press. Bautista CJ, Rodriguez-Gonzalez GL, Morales A, Lomas-Soria C, Cruz- Perez F, Reyes-Castro LA & Zambrano E 2017 Maternal obesity in the Funding rat impairs male offspring aging of the testicular antioxidant defence D M S is supported by the Canada Research Chairs Program and P A J system. Reproduction, Fertility, and Development 29 1950–1957. (https:// is supported by the Natural Sciences and Engineering Research Council doi.org/10.1071/RD16277) of Canada. Bermejo-Alvarez P, Rosenfeld CS & Roberts RM 2012 Effect of maternal obesity on estrous cyclicity, embryo development and blastocyst gene expression in a mouse model. Human Reproduction 27 3513–3522. (https://doi.org/10.1093/humrep/des327) Author contribution statement Bernal AB, Vickers MH, Hampton MB, Poynton RA & Sloboda DM 2010 P A J wrote the manuscript, D M S edited and wrote the manuscript and Maternal undernutrition significantly impacts ovarian follicle number compiled the figures. and increases ovarian oxidative stress in adult rat offspring. PLoS ONE 5 e15558. (https://doi.org/10.1371/journal.pone.0015558) Bielli A, Katz H, Pedrana G, Gastel MT, Morana A, Castrillejo A, Lundeheim N, Forsberg M & Rodriguez-Martinez H 2001 Nutritional management during fetal and postnatal life, and the infuence on Acknowledgements testicular stereology and Sertoli cell numbers in Corriedale ram lambs. The authors would like to thank Katharine Kennedy for her assistance in Small Ruminant Research 40 63–71. (https://doi.org/10.1016/S0921- generating Figure 4. 4488(00)00213-3) Binder NK, Mitchell M & Gardner DK 2012 Parental diet-induced obesity leads to retarded early mouse embryo development and altered carbohydrate utilisation by the blastocyst. Reproduction, Fertility and Development 24 804–812. (https://doi.org/10.1071/RD11256) References Boeri L, Ventimiglia E, Capogrosso P, Ippolito S, Pecoraro A, Paciotti M, Abbott DH, Barnett DK, Bruns CM & Dumesic DA 2005 Androgen excess Scano R, Galdini A, Valsecchi L, Papaleo E, et al. 2016 Low birth fetal programming of female reproduction: a developmental aetiology weight is associated with a decreased overall adult health status and for polycystic ovary syndrome? Human Reproduction Update 11 reproductive capability – results of a cross-sectional study in primary 357–374. (https://doi.org/10.1093/humupd/dmi013) infertile patients. PLoS ONE 11 e0166728. (https://doi.org/10.1371/ Aiken CE & Ozanne SE 2014 Transgenerational developmental journal.pone.0166728) programming. Human Reproduction Update 20 63–75. (https://doi. Boots CE, Boudoures A, Zhang W, Drury A & Moley KH 2016 Obesity- org/10.1093/humupd/dmt043) induced oocyte mitochondrial defects are partially prevented and Aiken CE, Tarry-Adkins JL & Ozanne SE 2013 Suboptimal nutrition rescued by supplementation with co-enzyme Q10 in a mouse model. in utero causes DNA damage and accelerated aging of the female Human Reproduction 31 2090–2097. (https://doi.org/10.1093/ reproductive tract. FASEB Journal 27 3959–3965. (https://doi. humrep/dew181) org/10.1096/fj.13-234484) Boudoures AL, Chi M, Thompson A, Zhang W & Moley KH 2016 The Aiken CE, Tarry-Adkins JL, Penfold NC, Dearden L & Ozanne SE 2016 effects of voluntary exercise on oocyte quality in a diet-induced obese Decreased ovarian reserve, dysregulation of mitochondrial biogenesis, murine model. Reproduction 151 261–270. (https://doi.org/10.1530/ and increased lipid peroxidation in female mouse offspring exposed REP-15-0419) to an obesogenic maternal diet. FASEB Journal 30 1548–1556. (https:// Boudoures AL, Saben J, Drury A, Scheaffer S, Modi Z, Zhang W & doi.org/10.1096/fj.15-280800) Moley KH 2017 Obesity-exposed oocytes accumulate and transmit Alexander BT, Henry Dasinger J & Intapad S 2014 Effect of low birth damaged mitochondria due to an inability to activate mitophagy. weight on women’s health. Clinical Therapeutics 36 1913–1923. Developmental Biology 426 126–138. (https://doi.org/10.1016/j. (https://doi.org/10.1016/j.clinthera.2014.06.026) ydbio.2017.04.005) Álvarez D, Ceballo K, Olguin S, Martinez-Pinto J, Maliqueo M, Boynton-Jarrett R, Rich-Edwards J, Fredman L, Hibert EL, Michels KB, Fernandois D, Sotomayor-Zarate R & Cruz G 2018 Prenatal metformin Forman MR & Wright RJ 2011 Gestational weight gain and daughter’s treatment improves ovarian function in offspring of obese rats. age at menarche. Journal of Women’s Health 20 1193–1200. (https:// Journal of Endocrinology 239 325–338. (https://doi.org/10.1530/ doi.org/10.1089/jwh.2010.2517) JOE-18-0352) Caron E, Ciofi P, Prevot V & Bouret SG 2012 Alteration in neonatal Ambrosetti V, Guerra M, Ramirez LA, Reyes A, Alvarez D, Olguin S, nutrition causes perturbations in hypothalamic neural circuits Gonzalez-Manan D, Fernandois D, Sotomayor-Zarate R & Cruz G controlling reproductive function. Journal of Neuroscience 32 2016 Increase in endogenous estradiol in the progeny of obese rats is 11486–11494. (https://doi.org/10.1523/JNEUROSCI.6074-11.2012) associated with precocious puberty and altered follicular development Catalano PM & Shankar K 2017 Obesity and pregnancy: mechanisms of in adulthood. Endocrine 53 258–270. (https://doi.org/10.1007/s12020- short term and long term adverse consequences for mother and child. 016-0858-0) BMJ 356 j1. (https://doi.org/10.1136/bmj.j1) Barker DJ & Osmond C 1986 Infant mortality, childhood nutrition, and Catalano PM, Farrell K, Thomas A, Huston-Presley L, Mencin P, de ischaemic heart disease in England and Wales. Lancet 1 1077–1081. Mouzon SH & Amini SB 2009 Perinatal risk factors for childhood (https://doi.org/10.1016/S0140-6736(86)91340-1) obesity and metabolic dysregulation. American Journal of Clinical Barker DJ, Winter PD, Osmond C, Margetts B & Simmonds SJ 1989 Nutrition 90 1303–1313. (https://doi.org/10.3945/ajcn.2008.27416) Weight in infancy and death from ischaemic heart disease. Lancet 2 Chan KA, Bernal AB, Vickers MH, Gohir W, Petrik JJ & Sloboda DM 2015a 577–580. (https://doi.org/10.1016/S0140-6736(89)90710-1) Early life exposure to undernutrition induces ER stress, apoptosis, and

reduced vascularization in ovaries of adult rat offspring. Biology of Desai M, Jellyman JK & Ross MG 2015 Epigenomics, gestational Reproduction 92 110. programming and risk of metabolic syndrome. International Journal of Chan KA, Tsoulis MW & Sloboda DM 2015b Early-life nutritional effects Obesity 39 633–641. (https://doi.org/10.1038/ijo.2015.13) on the female reproductive system. Journal of Endocrinology 224 Drake AJ & Reynolds RM 2010 Impact of maternal obesity on offspring R45–R62. (https://doi.org/10.1530/JOE-14-0469) obesity and cardiometabolic disease risk. Reproduction 140 387–398. Chan KA, Jazwiec PA, Gohir W, Petrik JJ & Sloboda DM 2018 Maternal (https://doi.org/10.1530/REP-10-0077) nutrient restriction impairs young adult offspring ovarian signaling Elias SG, van Noord PAH, Peeters PHM, den Tonkelaar I & Grobbee DE resulting in reproductive dysfunction and follicle loss. Biology of 2003 Caloric restriction reduces age at menopause: the effect of Reproduction 98 664–682. (https://doi.org/10.1093/biolre/ioy008) the 1944–1945 Dutch famine. Menopause 10 399–405. (https://doi. Chisholm JS, Ellison PT, Evans J, Lee PC, Lieberman LS, Pavlik Z, Ryan AS, org/10.1097/01.GME.0000059862.93639.C1) Salter EM, Stini WA & Worthman CM 1993 Death, hope, and sex: Ellison PT 1982 Skeletal growth, fatness and menarcheal age: a life-history theory and the development of reproductive strategies. comparison of two hypotheses. Human Biology 54 269–281. Current Anthropology 34 1–24. (https://doi.org/10.1086/204131) Ellison PT, Panter-Brick C, Lipson SF & O’Rourke MT 1993 The ecological Cicognani A, Alessandroni R, Pasini A, Pirazzoli P, Cassio A, Barbieri E & context of human ovarian function. Human Reproduction 8 Cacciari E 2002 Low birth weight for gestational age and subsequent 2248–2258. (https://doi.org/10.1093/oxfordjournals.humrep. male gonadal function. Journal of Pediatrics 141 376–380. (https://doi. a138015) org/10.1067/mpd.2002.126300) Engelbregt MJT, Houdijk ME, Popp-Snijders C & Delemarre-van de Clermont Y 1966 Renewal of spermatogonia in man. American Journal of Waal HA 2000 The effects of intra-uterine growth retardation and Anatomy 118 509–524. (https://doi.org/10.1002/aja.1001180211) postnatal undernutrition on onset of puberty in male and female rats. Coall DA & Chisholm JS 2010 Reproductive development and parental Pediatric Research 48 803–807. (https://doi.org/10.1203/00006450- investment during pregnancy: moderating influence of mother’s early 200012000-00017) environment. American Journal of Human Biology 22 143–153. Ernst A, Ramlau-Hansen CH, Lauridsen LLB, Brix N, Parner ET, Olsen J & Connor KL, Vickers MH, Beltrand J, Meaney MJ & Sloboda DM 2012 Henriksen TB 2018 Maternal smoking During pregnancy and timing Nature, nurture or nutrition? Impact of maternal nutrition on of puberty in sons and daughters: A population-based cohort study. maternal care, offspring development and reproductive function. American Journal of Epidemiology 188 47–56. Journal of Physiology 590 2167–2180. (https://doi.org/10.1113/ Evans JP, Wilson AJ, Pilastro A & Garcia-Gonzalez F 2019 Ejaculate- jphysiol.2011.223305) mediated paternal effects: evidence, mechanisms and evolutionary Cooper C, Kuh D, Egger P, Wadsworth M & Barker D 1996 Childhood implications. Reproduction 157 R109–R126. (https://doi.org/10.1530/ growth and age at menarche. British Journal of Obstetrics and REP-18-0524) Gynaecology 103 814–817. (https://doi.org/10.1111/j.1471-0528.1996. Faure C, Dupont C, Chavatte-Palmer P, Gautier B & Levy R 2015 Are tb09879.x) semen parameters related to birth weight? Fertility and Sterility 103 Copping KJ, Ruiz-Diaz MD, Rutland CS, Mongan NP, Callaghan MJ, 6–10. (https://doi.org/10.1016/j.fertnstert.2014.11.027) McMillen IC, Rodgers RJ & Perry VEA 2018 Peri-conception and first Fernandois D, Velasco I, Manfredi-Lozano M, Sanchez-Garrido MA, trimester diet modifies reproductive development in bulls.Reproduction, Heras V, Ruiz-Pino F, Roa J, Pinilla L, Tena-Sempere M, Barroso A, et al. Fertility and Development 30. (https://doi.org/10.1071/RD17102) 2017 Intergenerational influence of paternal obesity on metabolic Culty M 2009 Gonocytes, the forgotten cells of the germ cell lineage. and reproductive health parameters of the offspring: male-preferential Birth Defects Research Part C 87 1–26. (https://doi.org/10.1002/ impact and involvement of Kiss1-mediated pathways. Endocrinology bdrc.20142) 159 1005–1018. Da Silva P, Aitken RP, Rhind SM, Racey PA & Wallace JM 2001 Influence Filippou P & Homburg R 2017 Is foetal hyperexposure to androgens a of placentally mediated fetal growth restriction on the onset of cause of PCOS? Human Reproduction Update 23 421–432. (https://doi. puberty in male and female lambs. Reproduction 122 375–383. org/10.1093/humupd/dmx013) (https://doi.org/10.1530/rep.0.1220375) Flegal KM, Carroll MD, Ogden CL & Curtin LR 2010 Prevalence and de Bruin JP, Dorland M, Bruinse HW, Spliet W, Nikkels PGJ & te Velde ER trends in obesity Among US adults, 1999–2008. JAMA 303 235–241. 1998 Fetal growth retardation as a cause of impaired ovarian (https://doi.org/10.1001/jama.2009.2014) development. Early Human Development 51 39–46. (https://doi. Flegal KM, Carroll MD, Kit BK & Ogden CL 2012 Prevalence of obesity org/10.1016/S0378-3782(97)00073-X) and trends in the distribution of body mass index among US adults, de Bruin JP, Nikkels PGJ, Bruinse HW, van Haaften M, Looman CWN 1999–2010. JAMA 307 491. (https://doi.org/10.1001/jama.2012.39) & te Velde ER 2001 Morphometry of human ovaries in normal and Francois I, De Zegher F, Spiessens C, D’hooghe T & Vandershueren D growth-restricted fetuses. Early Human Development 60 179–192. 1997 Low birth weight and subsequent male subfertility. Pediatric (https://doi.org/10.1016/S0378-3782(00)00118-3) Research 42 899–901. (https://doi.org/10.1203/00006450-199712000- de Kretser DM 1979 Endocrinology of male infertility. British Medical 00029) Bulletin 35 187–192. (https://doi.org/10.1093/oxfordjournals. Fraser R & Lin C-J 2016 Epigenetic reprogramming of the zygote in mice bmb.a071568) and men: on your marks, get set, go! Reproduction 152 R211–R222. Deardorff J, Berry-Millett R, Rehkopf D, Luecke E, Lahiff M & Abrams B (https://doi.org/10.1530/REP-16-0376) 2013 Maternal pre-pregnancy BMI, gestational weight gain, and Fullston T, PalmerNO, Owens JA, Mitchell M, Bakos HW & Lane M 2012 age at menarche in daughters. Maternal and Child Health Journal 17 Diet-induced paternal obesity in the absence of diabetes diminishes 1391–1398. (https://doi.org/10.1007/s10995-012-1139-z) the reproductive health of two subsequent generations of mice. Delahaye F, Breton C, Risold P-Y, Enache M, Dutriez-Casteloot I, Human Reproduction 27 1391–1400. (https://doi.org/10.1093/humrep/ Laborie C, Lesage J & Vieau D 2008 Maternal perinatal des030) undernutrition drastically reduces postnatal leptin surge and Fullston T, McPherson NO, Owens JA, Kang WX, Sandeman LY & Lane M affects the development of arcuate nucleus proopiomelanocortin 2015a Paternal obesity induces metabolic and sperm disturbances neurons in neonatal male rat pups. Endocrinology 149 470–475. in male offspring that are exacerbated by their exposure to an (https://doi.org/10.1210/en.2007-1263) “obesogenic” diet. Physiological Reports 3 e12336. (https://doi. Deligeorgis SG, Chadio S & Menegatos J 1996 Pituitary responsiveness to org/10.14814/phy2.12336) GnRH in lambs undernourished during fetal life. Animal Reproduction Fullston T, Shehadeh H, Sandeman LY, Kang WX, Wu LL, Robker RL, Science 43 113–121. (https://doi.org/10.1016/0378-4320(96)01471-6) McPherson NO & Lane M 2015b Female offspring sired by diet

Journal of P A Jazwiec and Nutritional impacts on 242:1 T65 Endocrinology D M Sloboda offspring reproduction

induced obese male mice display impaired blastocyst development Ibanez L & de Zegher F 2006 Puberty and prenatal growth. Molecular and with molecular alterations to their ovaries, oocytes and cumulus cells. Cellular Endocrinology 254–255 22–25. (https://doi.org/10.1016/j. Journal of Assisted Reproduction and Genetics 32 725–735. (https://doi. mce.2006.04.010) org/10.1007/s10815-015-0470-x) Ibanez L, Potau N, Francois I & De Zegher F 1998 Precocious pubarche, Gaillard R 2015 Maternal obesity during pregnancy and cardiovascular hyperinsulinism, and ovarian hyperandrogenism in girls- relation to development and disease in the offspring. European Journal of reduced fetal growth. Journal of Clinical Endocrinology and Metabolism Epidemiology 30 1141–1152. (https://doi.org/10.1007/s10654- 83 3558–3562. 015-0085-7) Ibanez L, Potau N, Enriquez G & De Zegher F 2000 Reduced uterine and Garn SM 1987 The secular trend in size and maturational timing and ovarian size in adolescent girls born small for gestational age. Pediatric its implications for nutritional assessment. Journal of Nutrition 117 Research 47 575–577. (https://doi.org/10.1203/00006450-200005000- 817–823. (https://doi.org/10.1093/jn/117.5.817) 00003) Gilbert SF 2000 Developmental Biology. Sunderland, MA, USA: Sinauer Ibanez L, Valls C, Cols M, Ferrer A, Marcos MV & De Zegher F 2002 Associates. Hypersecretion of FSH in infant boys and girls born small for Gluckman PD & Beedle AS 2007 Migrating ovaries: early life influences gestational age. Journal of Clinical Endocrinology and Metabolism 87 on later gonadal function. PLOS Medicine 4 e190. 1986–1988. Gluckman PD & Hanson MA 2004 The developmental origins of the Ibanez L, Lopez-Bermejo A, Diaz M & Marcos MV 2011 metabolic syndrome. Trends in Endocrinology and Metabolism 15 Endocrinology and gynecology of girls and women with low 183–187. (https://doi.org/10.1016/j.tem.2004.03.002) birth weight. Fetal Diagnosis and Therapy 30 243–249. (https://doi. Gluckman PD & Hanson MA 2006 Evolution, development and timing of org/10.1159/000330366) puberty. Trends in Endocrinology and Metabolism 17 7–12. (https://doi. Igosheva N, Abramov AY, Poston L, Eckert JJ, Fleming TP, Duchen MR & org/10.1016/j.tem.2005.11.006) McConnell J 2010 Maternal diet-induced obesity alters mitochondrial Gluckman PD, Hanson MA & Pinal C 2005 The developmental origins activity and redox status in mouse oocytes and zygotes. PLoS ONE 5 of adult disease. Maternal and Child Nutrition 1 130–141. (https://doi. e10074. (https://doi.org/10.1371/journal.pone.0010074) org/10.1111/j.1740-8709.2005.00020.x) Jacobs S, Teixeira DS, Guilherme C, da Rocha CFK, Aranda BCC, Godfrey KM, Reynolds RM, Prescott SL, Nyirenda M, Jaddoe VWV, Reis AR, de Souza MA, Franci CR & Sanvitto GL 2014 The impact of Eriksson JG & Broekman BFP 2017 Influence of maternal obesity on maternal consumption of cafeteria diet on reproductive function the long-term health of offspring. Lancet Diabetes and Endocrinology 5 in the offspring. Physiology and Behavior 129 280–286. (https://doi. 53–64. (https://doi.org/10.1016/S2213-8587(16)30107-3) org/10.1016/j.physbeh.2014.03.003) Grindler NM & Moley KH 2013 Maternal obesity, infertility and Jansen EC, Herran OF & Villamor E 2015 Trends and correlates of age mitochondrial dysfunction: potential mechanisms emerging from at menarche in Colombia: results from a nationally representative mouse model systems. Molecular Human Reproduction 19 486–494. survey. Economics and Human Biology 19 138–144. (https://doi. (https://doi.org/10.1093/molehr/gat026) org/10.1016/j.ehb.2015.09.001) Gu L, Liu H, Gu X, Boots C, Moley KH & Wang Q 2015 Metabolic control Jasienska G, Thune I & Ellison PT 2006 Fatness at birth predicts adult of oocyte development: linking maternal nutrition and reproductive susceptibility to ovarian suppression: an empirical test of the outcomes. Cellular and Molecular Life Sciences 72 251–271. (https://doi. Predictive Adaptive Response hypothesis. PNAS 103 12759–12762. org/10.1007/s00018-014-1739-4) (https://doi.org/10.1073/pnas.0605488103) Hanson MA & Gluckman PD 2014 Early developmental conditioning of Jazwiec P, Li X, Matushewski B, Richardson B & Sloboda DM 2019 later health and disease: physiology or pathophysiology? Physiological Fetal growth restriction is associated with decreased number of Reviews 94 1027–1076. (https://doi.org/10.1152/physrev.00029.2013) ovarian follicles and impaired follicle growth in young adult Hilakivi-Clarke L, Clarke R, Onojafe I, Raygada M, Cho E & Lippman M guinea pig offspring. Reproductive Sciences [epub]. (https://doi. 1997 A maternal diet high in n-6 polyunsaturated fats alters org/10.1177/1933719119828041) mammary gland development, puberty onset, and breast cancer Jensen RB, Vielwerth S, Larsen T, Greisen G, Veldhuis J & Juul A 2007 risk among female rat offspring. PNAS 94 9372–9377. (https://doi. Pituitary-gonadal function in adolescent males born appropriate org/10.1073/pnas.94.17.9372) or small for gestational age with or without intrauterine growth Hilakivi-Clarke L, Stoica A, Raygada M & Martin M 1998 Consumption restriction. Journal of Clinical Endocrinology and Metabolism 92 of a high-fat diet alters estrogen receptor content, protein kinase C 1353–1357. (https://doi.org/10.1210/jc.2006-2348) activity, and mammary gland morphology in virgin and pregnant Jiménez-Chillarón JC, Díaz R, Martínez D, Pentinat T, Ramón-Krauel M, mice and female offspring. Cancer Research 58 654–660. Ribó S & Plösch T 2012 The role of nutrition on epigenetic Hilakivi-Clarke L, Clarke R & Lippman M 1999 The influence of maternal modifications and their implications on health.Biochimie 94 diet on breast cancer risk among female offspring. Nutrition 15 2242–2263. (https://doi.org/10.1016/j.biochi.2012.06.012) 392–401. (https://doi.org/10.1016/S0899-9007(99)00029-5) Jungheim ES, Macones GA, Odem RR, Patterson BW, Lanzendorf SE, Hirshfield AN 1991 Development of follicles in the mammlian ovary. Ratts VS & Moley KH 2011 Associations between free fatty acids, International Review of Cytology 124 43–101. cumulus oocyte complex morphology and ovarian function during Hoffman F, Boretto E, Vitale S, Gonzalez V, Vidal G, Pardo MF, Flores MF, in vitro fertilization. Fertility and Sterility 95 1970–1974. (https://doi. Garcia F, Bagnis G, Queiroz OCM, et al. 2018 Maternal nutritional org/10.1016/j.fertnstert.2011.01.154) restriction during late gestation impairs development of the Kallak TK, Hellgren C, Skalkidou A, Sandelin-Francke L, reproductive organs in both male and female lambs. Theriogenology Ubhayasekhera K, Bergquist J, Axelsson O, Comasco E, 108 331–338. (https://doi.org/10.1016/j.theriogenology.2017.12.023) Campbell RE & Poromaa S 2017 Maternal and female fetal Hounsgaard ML, Håkonsen LB, Vested A, Thulstrup AM, Olsen J, testosterone levels are associated with maternal age and gestational Bonde JP, Nohr EA & Ramlau-Hansen CH 2014 Maternal pre- weight gain. European Journal of Endocrinology 177 379–388. pregnancy body mass index and pubertal development among (https://doi.org/10.1530/EJE-17-0207) sons. Andrology 2 198–204. (https://doi.org/10.1111/j.2047- Keim SA, Branum AM, Klebanoff MA & Zemel BS 2009 Maternal body 2927.2013.00171.x) mass index and daughters’ age at menarche. Epidemiology 20 677–681. Ibanez L 2003 Hypergonadotrophinaemia with reduced uterine and (https://doi.org/10.1097/EDE.0b013e3181b093ce) ovarian size in women born small-for-gestational-age. Human Khorram O, Keen-Rinehart E, Chuang TD, Ross MG & Desai M 2015 Reproduction 18 1565–1569. (https://doi.org/10.1093/humrep/deg351) Maternal undernutrition induces premature reproductive senescence

in adult female rat offspring. Fertility and Sterility 103 291.e2–298.e2. of Developmental Biology 56 771–778. (https://doi.org/10.1387/ (https://doi.org/10.1016/j.fertnstert.2014.09.026) ijdb.120202lm) Kotsampasi B, Balaskas C, Papadomichelakis G & Chadio SE 2009 Mariansdatter SE, Ernst A, Toft G, Olsen SF, Vested A, Kristensen SL, Reduced Sertoli cell number and altered pituitary responsiveness in Hansen ML & Ramlau-Hansen CH 2016 Maternal pre-pregnancy BMI male lambs undernourished in utero. Animal Reproduction Science 114 and reproductive health of daughters in young adulthood. Maternal 135–147. (https://doi.org/10.1016/j.anireprosci.2008.08.017) and Child Health Journal 20 2150–2159. (https://doi.org/10.1007/ Kramer KL, Greaves RD & Ellison PT 2009 Early reproductive maturity s10995-016-2062-5) among Pumé foragers: implications of a pooled energy model to fast Matsuzaki T, Munkhzaya M, Iwasa T, Tungalagsuvd A, Yano K, Mayila Y, life histories. American Journal of Human Biology 21 430–437. (https:// Yanagihara R, Tokui T, Kato T, Kuwahara A, et al. 2018 Prenatal doi.org/10.1002/ajhb.20930) undernutrition suppresses sexual behavior in female rats. General Kubo A, Ferrara A, Laurent CA, Windham GC, Greenspan LC, Deardorff J, and Comparative Endocrinology 269 46–52. (https://doi.org/10.1016/j. Hiatt RA, Quesenberry CP & Kushi LH 2016 Associations Between ygcen.2018.08.013) maternal Pregravid obesity and gestational diabetes and the timing McGee EA & Hsueh AJ 2000 Initial and cyclic recruitment of ovarian of pubarche in daughters. American Journal of Epidemiology 184 7–14. follicles. Endocrine Reviews 21 200–214. (https://doi.org/10.1093/aje/kww006) McPherson NO, Fullston T, Bakos HW, Setchell BP & Lane M 2014 Kubo A, Deardorff J, Laurent CA, Ferrara A, Greenspan LC, Obese father’s metabolic state, adiposity, and reproductive capacity Quesenberry CP & Kushi LH 2018 Associations Between maternal indicate son’s reproductive health. Fertility and Sterility 101 865. obesity and pregnancy hyperglycemia and timing of puberty onset e861–873.e861. in adolescent girls: A population-based study. American Journal of Meas T, Deghmoun S, Levy-Marchal C & Bouyer J 2010 Fertility is Epidemiology 187 1362–1369. (https://doi.org/10.1093/aje/kwy040) not altered in young adults born small for gestational age. Human Kumar TR, Wang Y, Lu N & Matzuk MM 1997 Follicle stimulating Reproduction 25 2354–2359. (https://doi.org/10.1093/humrep/deq184) hormone is required for ovarian follicle maturation but not male Mela V, Díaz F, Lopez-Rodriguez AB, Vázquez MJ, Gertler A, Argente J, fertility. Nature Genetics 15 201–204. (https://doi.org/10.1038/ng0297- Tena-Sempere M, Viveros M-P & Chowen JA 2015 Blockage of 201) the neonatal leptin surge affects the gene expression of growth Lambrot R, Xu C, Saint-Phar S, Chountalos G, Cohen T, Paquet M, factors, glial proteins, and neuropeptides involved in the control of Suderman M, Hallett M & Kimmins S 2013 Low paternal dietary metabolism and reproduction in peripubertal male and female rats. folate alters the mouse sperm epigenome and is associated with Endocrinology 156 2571–2581. (https://doi.org/10.1210/en.2014-1981) negative pregnancy outcomes. Nature Communications 4 2889–2889. Messerschmidt DM, Knowles BB & Solter D 2014 DNA methylation (https://doi.org/10.1038/ncomms3889) dynamics during epigenetic reprogramming in the germline and Lauridsen LLB, Arendt LH, Ernst A, Brix N, Parner ET, Olsen J & preimplantation embryos. Genes and Development 28 812–828. Ramlau-Hansen CH 2018 Maternal diabetes mellitus and timing of (https://doi.org/10.1101/gad.234294.113) pubertal development in daughters and sons: a nationwide cohort Monniaux D, Clement F, Dalbies-Tran R, Estienne A, Fabre S, Mansanet C study. Fertility and Sterility 110 35–44. (https://doi.org/10.1016/j. & Monget P 2014 The ovarian reserve of primordial follicles and the fertnstert.2018.03.014) dynamic reserve of antral growing follicles: what is the link? Biology of Lawn RB, Lawlor DA & Fraser A 2018 Associations between maternal Reproduction 90 85. (https://doi.org/10.1095/biolreprod.113.117077) prepregnancy body mass index and gestational weight gain and Moore AM, Prescott M & Campbell RE 2013 Estradiol negative and daughter’s age at menarche: the Avon longitudinal study of parents positive feedback in a prenatal androgen-induced mouse model of and children. American Journal of Epidemiology 187 677–686. (https:// polycystic ovarian syndrome. Endocrinology 154 796–806. (https://doi. doi.org/10.1093/aje/kwx308) org/10.1210/en.2012-1954) Leveille P, Tarrade A, Dupont C, Larcher T, Dahirel M, Poumerol E, Morgan CP, Chan JC & Bale TL 2019 Driving the next generation: Cordier AG, Picone O, Mandon-Pepin B, Jolivet G, et al. 2014 paternal lifetime experiences transmitted via extracellular vesicles and Maternal high-fat diet induces follicular atresia but does not their small RNA cargo. Biological Psychiatry 85 164–171. (https://doi. affect fertility in adult rabbit offspring. Journal of Developmental org/10.1016/j.biopsych.2018.09.007) Origins of Health and Disease 5 88–97. (https://doi.org/10.1017/ Mossa F, Carter F, Walsh SW, Kenny DA, Smith GW, Ireland JL, S2040174414000014) Hildebrandt TB, Lonergan P, Ireland JJ & Evans AC 2013 Maternal Lumey LH & Stein AD 1997 In utero exposure to famine and undernutrition in cows impairs ovarian and cardiovascular systems in subsequent fertility: the Dutch Famine Birth Cohort Study. American their offspring. Biology of Reproduction 88 92. Journal of Public Health 87 1962–1966. (https://doi.org/10.2105/ Murdoch WJ, Van Kirk EA, Vonnahme KA & Ford SP 2003 Ovarian AJPH.87.12.1962) responses to undernutrition in pregnant ewes, USA. Reproductive Ly L, Chan D & Trasler JM 2015 Developmental windows of susceptibility Biology and Endocrinology 1 6. (https://doi.org/10.1186/ for epigenetic inheritance through the male germline. Seminars in 1477-7827-1-6) Cell and Developmental Biology 43 96–105. (https://doi.org/10.1016/j. Navya H & Yajurvedi HN 2017 Obesity causes weight increases in semcdb.2015.07.006) prepubertal and pubertal male offspring and is related to changes in Ly L, Chan D, Aarabi M, Landry M, Behan NA, MacFarlane AJ & spermatogenesis and sperm production in rats. Reproduction, Fertility Trasler J 2017 Intergenerational impact of paternal lifetime and Development 29 815–823. (https://doi.org/10.1071/RD15480) exposures to both folic acid deficiency and supplementation on Nettle D 2010 Dying young and living fast: variation in life history across reproductive outcomes and imprinted gene methylation. English neighborhoods. Behavioral Ecology 21 387–395. (https://doi. Molecular Human Reproduction 23 461–477. (https://doi.org/ org/10.1093/beheco/arp202) 10.1093/molehr/gax029) Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ & Flegal KM Maliqueo M, Cruz G, Espina C, Contreras I, García M, Echiburú B 2006 Prevalence of overweight and obesity in the United States, & Crisosto N 2017 Obesity during pregnancy affects sex steroid 1999–2004. JAMA 295 1549–1555. (https://doi.org/10.1001/ concentrations depending on fetal gender. International Journal of jama.295.13.1549) Obesity 41 1636–1645. (https://doi.org/10.1038/ijo.2017.159) Olsen J, Bonde JP, Basso O, Hjollund NHI, Sorensen HT & Abell A Mamsen LS, Brochner CB, Byskov AG & Mollgard K 2012 The migration 2000 Birthweight and semen characteristics. International Journal and loss of human primordial germ stem cells from the hind of Andrology 23 230–235. (https://doi.org/10.1046/j.1365- gut epithelium towards the gonadal ridge. International Journal 2605.2000.00239.x)

Journal of P A Jazwiec and Nutritional impacts on 242:1 T67 Endocrinology D M Sloboda offspring reproduction

Ozturk O, Armstrong K, Bhattacharya S & Templeton A 2001 Fetal and Child Health Journal 15 1166–1175. (https://doi.org/10.1007/ antecedents of male factor sub-fertility- how important is s10995-010-0689-1) birthweight? Human Reproduction 16 2238–2241. (https://doi. Saben JL, Boudoures AL, Asghar Z, Thompson A, Drury A, Zhang W, org/10.1093/humrep/16.10.2238) Chi M, Cusumano A, Scheaffer S & Moley KH 2016 Maternal Padmanabhan V & Veiga-Lopez A 2013 Sheep models of polycystic ovary metabolic syndrome programs mitochondrial dysfunction via syndrome phenotype. Molecular and Cellular Endocrinology 373 8–20. germline changes across three generations. Cell Reports 16 1–8. (https://doi.org/10.1016/j.mce.2012.10.005) (https://doi.org/10.1016/j.celrep.2016.05.065) Painter RC, Westendorp RGJ, de Rooij SR, Osmond C, Barker DJP & Sadrzadeh-Broer S, Kuijper EAM, Van Weissenbruch MM & Lambalk CB Roseboom TJ 2008 Increased reproductive success of women after 2011 Ovarian reserve in young women with low birth weight prenatal undernutrition. Human Reproduction 23 2591–2595. (https:// and normal puberty: a pilot case-control study. Gynecological doi.org/10.1093/humrep/den274) Endocrinology 27 641–644. (https://doi.org/10.3109/09513590.201 Palmer NO, Bakos HW, Fullston T & Lane M 2012 Impact of obesity 0.508544) on male fertility, sperm function and molecular composition. Sanchez F & Smitz J 2012 Molecular control of oogenesis. Biochimica Spermatogenesis 2 253–263. (https://doi.org/10.4161/spmg.21362) and Biophysica Acta 1822 1896–1912. (https://doi.org/10.1016/j. Pembrey M, Saffery R, Bygren LO, Network in Epigenetic E & Network bbadis.2012.05.013) in Epigenetic E 2014 Human transgenerational responses to early-life Sanchez-Garrido MA, Castellano JM, Ruiz-Pino F, Garcia-Galiano D, experience: potential impact on development, health and biomedical Manfredi-Lozano M, Leon S, Romero-Ruiz A, Dieguez C, research. Journal of Medical Genetics 51 563–572. (https://doi. Pinilla L & Tena-Sempere M 2013 Metabolic programming org/10.1136/jmedgenet-2014-102577) of puberty: sexually dimorphic responses to early nutritional Pepling ME 2012 Follicular assembly: mechanisms of action. Reproduction challenges. Endocrinology 154 3387–3400. (https://doi.org/ 143 139–149. (https://doi.org/10.1530/REP-11-0299) 10.1210/en.2012-2157) Rae MT, Palassio S, Kyle CE, Brooks AN, Lea RG, Miller DW & Rhind SM Schjenken JE & Robertson AR 2015 Seminal fluid signalling in the female 2001 Effect of maternal undernutrition during pregnancy on early reproductive tract: implications for reproductive success and offspring ovarian development and subsequent follicular development in health. In The Male Role in Pregnancy Loss and Embryo Implantation sheep fetuses. Reproduction 122 915–922. (https://doi.org/10.1530/ Failure. Advances in Experimental Medicine and Biology. pp127–158. Ed. rep.0.1220915) R Bronson. Berlin, Germany: Springer. Rae MT, Kyle CE, Miller DW, Hammond AJ, Brooks AN & Rhind SM Schulz LC 2010 The Dutch Hunger winter and the developmental 2002a The effects of undernutrition, in utero, on reproductive origins of health and disease. PNAS 107 16757–16758. (https://doi. function in adult male and female sheep. Animal Reproduction Science org/10.1073/pnas.1012911107) 72 63–71. (https://doi.org/10.1016/S0378-4320(02)00068-4) Sharpe RM 2018 Programmed for sex: nutrition-reproduction Rae MT, Rhind SM, Fowler PA, Miller DW, Kyle CE & Brooks AN 2002b relationships from an inter-generational perspective. Reproduction 155 Effect of maternal undernutrition on fetal testicular steroidogenesis S1–S16. (https://doi.org/10.1530/REP-17-0537) during the CNS androgen-responsive period in male sheep fetuses. Shim YS, Park HK, Yang S & Hwang IT 2013 Age at menarche and adult Reproduction 124 33–39. (https://doi.org/10.1530/rep.0.1240033) height in girls born small for gestational age. Annals of Pediatric Ramachenderan J, Bradford J & McLean M 2008 Maternal obesity and Endocrinology and Metabolism 18 76–80. pregnancy complications: a review. Australian and New Zealand Journal Shrestha A, Olsen J, Ramlau-Hansen CH, Bech BH & Nohr EA 2011 of Obstetrics and Gynaecology 48 228–235. (https://doi.org/10.1111/ Obesity and age at menarche. Fertility and Sterility 95 2732–2734. j.1479-828X.2008.00860.x) (https://doi.org/10.1016/j.fertnstert.2011.02.020) Ramlau-Hansen CH, Nohr EA, Thulstrup AM, Bonde JP, Storgaard L & Siklenka K, Erkek S, Godmann M, Lambrot R, McGraw S, Lafleur C, Olsen J 2007 Is maternal obesity related to semen quality in the male Cohen T, Xia J, Suderman M, Hallett M, et al. 2015 Disruption of offspring? A pilot study. Human Reproduction 22 2758–2762. (https:// histone methylation in developing sperm impairs offspring health doi.org/10.1093/humrep/dem219) transgenerationally. Science 350 aab2006. (https://doi.org/10.1126/ Reame V, Pytlowanciv EZ, Ribeiro DL, Pissolato TF, Taboga SR, Goes RM science.aab2006) & Pinto-Fochi ME 2014 Obesogenic environment by excess of dietary Silver HK, Kiyasu W, George J & Deamer WC 1953 Syndrome of fats in different phases of development reduces spermatic efficiency congenital hemihypertrophy, shortness of stature, and elevated of wistar rats at adulthood: correlations with metabolic status. Biology urinary gonadotropin. Pediatrics 12 368–376. of Reproduction 91 151. Silvestris E, de Pergola G, Rosania R & Loverro G 2018 Obesity as Reynolds KA, Boudoures AL, Chi MM-Y, Wang Q & Moley KH 2015 disruptor of the female fertility. Reproductive Biology and Endocrinology Adverse effects of obesity and/or high-fat diet on oocyte quality and 16 22–22. (https://doi.org/10.1186/s12958-018-0336-z) metabolism are not reversible with resumption of regular diet in Sir-Petermann T, Maliqueo M, Angel B, Lara HE, Perez-Bravo F & mice. Reproduction, Fertility and Development 27 716–724. (https://doi. Recabarren SE 2002 Maternal serum androgens in pregnant women org/10.1071/RD14251) with polycystic ovarian syndrome: possible implications in prenatal Robles M, Gautier C, Mendoza L, Peugnet P, Dubois C, Dahirel M, androgenization. Human Reproduction 17 2573–2579. (https://doi. Lejeune J-P, Caudron I, Guenon I, Camous S, et al. 2017 Maternal org/10.1093/humrep/17.10.2573) nutrition during pregnancy affects testicular and bone development, Skinner MK, Manikkam M & Guerrero-Bosagna C 2010 Epigenetic glucose metabolism and response to overnutrition in weaned horses transgenerational actions of environmental factors in disease etiology. up to two years. PLoS One 12 e0169295. (https://doi.org/10.1371/ Trends in Endocrinology and Metabolism 21 214–222. (https://doi. journal.pone.0169295) org/10.1016/j.tem.2009.12.007) Rodriguez-Gonzalez GL, Vega CC, Boeck L, Vazquez M, Bautista CJ, Sloboda DM, Hart R, Doherty DA, Pennell CE & Hickey M 2007 Age Reyes-Castro LA, Saldana O, Lovera D, Nathanielsz PW & at menarche: influences of prenatal and postnatal growth.Journal Zambrano E 2015 Maternal obesity and overnutrition increase of Clinical Endocrinology and Metabolism 92 46–50. (https://doi. oxidative stress in male rat offspring reproductive system and org/10.1210/jc.2006-1378) decrease fertility. International Journal of Obesity 39 549–556. (https:// Sloboda DM, Howie GJ, Pleasants A, Gluckman PD & Vickers MH 2009 doi.org/10.1038/ijo.2014.209) Pre- and postnatal nutritional histories influence reproductive Rooney BL, Mathiason MA & Schauberger CW 2011 Predictors of obesity maturation and ovarian function in the rat. PLoS ONE 4 e6744. in childhood, adolescence, and adulthood in a birth cohort. Maternal (https://doi.org/10.1371/journal.pone.0006744)

Sloboda DM, Hickey M & Hart R 2011 Reproduction in females: the role Vikstrom J, Hammar M, Josefsson A, Bladh M & Sydsjo G 2014 Birth of the early life environment. Human Reproduction Update 17 210–227. characteristics in a clinical sample of women seeking infertility (https://doi.org/10.1093/humupd/dmq048) treatment: a case-control study. BMJ Open 4 e004197. (https://doi. Song S 2013 Assessing the impact of in utero exposure to famine on org/10.1136/bmjopen-2013-004197) fecundity: evidence from the 1959–61 famine in China. Population Wakefield SL, Lane M, Schulz SJ, Hebart ML, Thompson JG & Mitchell M Studies 67 293–308. (https://doi.org/10.1080/00324728.2013.774045) 2008 Maternal supply of omega-3 polyunsaturated fatty acids alter Speakman JR 2008 The physiological costs of reproduction in small mechanisms involved in oocyte and early embryo development in the mammals. Philosophical Transactions of the Royal Society of London mouse. American Journal of Physiology: Endocrinology and Metabolism Series B: Biological Sciences 363 375–398. (https://doi.org/10.1098/ 294 E425–E434. (https://doi.org/10.1152/ajpendo.00409.2007) rstb.2007.2145) Wang Q, Ratchford AM, Chi MM-Y, Schoeller E, Frolova A, Schedl T & Stearns SC 1992 The Evoluation of Life Histories: New York, NY, USA: Moley KH 2009 Maternal diabetes causes mitochondrial dysfunction Oxford University Press. and meiotic defects in murine oocytes. Molecular Endocrinology 23 Stearns SC 2000 Life history evolution: successes, limitations, and 1603–1612. (https://doi.org/10.1210/me.2009-0033) prospects. Naturwissenschaften 87 476–486. (https://doi.org/10.1007/ Whidden L, Martel J, Rahimi S, Chaillet JR, Chan D & Trasler JM 2016 s001140050763) Compromised oocyte quality and assisted reproduction contribute to Stuppia L, Franzago M, Ballerini P, Gatta V & Antonucci I 2015 sex-specific effects on offspring outcomes and epigenetic patterning. Epigenetics and male reproduction: the consequences of paternal Human Molecular Genetics 25 4649–4660. (https://doi.org/10.1093/ lifestyle on fertility, embryo development, and children lifetime hmg/ddw293) health. Clinical Epigenetics 7 120. (https://doi.org/10.1186/s13148- Wu LL-Y, Dunning KR, Yang X, Russell DL, Lane M, Norman RJ & 015-0155-4) Robker RL 2010 High-fat diet causes lipotoxicity responses in Sun M, Maliqueo M, Benrick A, Johansson J, Shao R, Hou L, Jansson T, cumulus–oocyte complexes and decreased fertilization rates. Wu X & Stener-Victorin E 2012 Maternal androgen excess reduces Endocrinology 151 5438–5445. (https://doi.org/10.1210/ placental and fetal weights, increases placental steroidogenesis, and en.2010-0551) leads to long-term health effects in their female offspring. American Wu H, Hauser R, Krawetz SA & Pilsner JR 2015a Environmental Journal of Physiology: Endocrinology and Metabolism 303 E1373–E1385. susceptibility of the sperm epigenome During Windows of male germ (https://doi.org/10.1152/ajpendo.00421.2012) cell development. Current Environmental Health Reports 2 356–366. Tanner JM 1955 Relation between age at puberty and adult physique in (https://doi.org/10.1007/s40572-015-0067-7) man. Journal of Physiology 127 17p. Wu LL, Russell DL, Wong SL, Chen M, Tsai T-S, St John JC, Norman RJ, Tenenbaum-Gavish K & Hod M 2013 Impact of maternal obesity Febbraio MA, Carroll J & Robker RL 2015b Mitochondrial dysfunction on fetal health. Fetal Diagnosis and Therapy 34 1–7. (https://doi. in oocytes of obese mothers: transmission to offspring and reversal by org/10.1159/000350170) pharmacological endoplasmic reticulum stress inhibitors. Development Treloar SA, Sadrzadeh S, Do K, Martin NG & Lambalk CB 2000 Birth 142 681–691. (https://doi.org/10.1242/dev.114850) weight and age at menopause in Australian female twin pairs: Xu J, Du Y & Deng H 2015 Direct lineage reprogramming: strategies, exploration of the fetal origin hypothesis. Human Reproduction 15 mechanisms, and applications. Cell Stem Cell 16 119–134. (https:// 55–59. (https://doi.org/10.1093/humrep/15.1.55) doi.org/10.1016/j.stem.2015.01.013) Tsoulis MW, Chang PE, Moore CJ, Chan KA, Gohir W, Petrik JJ, Yarde F, Broekmans FJM, van der Pal-de Bruin KM, Schonbeck Y, te Vickers MH, Connor KL & Sloboda DM 2016 Maternal high-fat diet- Velde ER, Stein AD & Lumey LH 2013 Prenatal famine, birthweight, induced loss of fetal oocytes is associated with compromised follicle reproductive performance and age at menopause: the Dutch hunger growth in adult rat offspring. Biology of Reproduction 94 94. (https:// winter families study. Human Reproduction 28 3328–3336. (https://doi. doi.org/10.1095/biolreprod.115.135004) org/10.1093/humrep/det331) Vahratian A 2009 Prevalence of overweight and obesity among women Young JM & McNeilly AS 2010 Theca: the forgotten cell of the ovarian of childbearing age: results from the 2002 National Survey of Family follicle. Reproduction 140 489–504. (https://doi.org/10.1530/ Growth. Maternal and Child Health Journal 13 268–273. (https://doi. REP-10-0094) org/10.1007/s10995-008-0340-6) Yura S, Itoh H, Sagawa N, Yamamoto H, Masuzaki H, Nakao K, Vanbillemont G, Lapauw B, Bogaert V, De Naeyer H, De Bacquer D, Kawamura M, Takemura M, Kakui K, Ogawa Y, et al. 2005 Role Ruige J, Kaufman JM & Taes YEC 2010 Birth weight in relation to sex of premature leptin surge in obesity resulting from intrauterine steroid status and body composition in young healthy male siblings. undernutrition. Cell Metabolism 1 371–378. (https://doi.org/10.1016/j. Journal of Clinical Endocrinology and Metabolism 95 1587–1594. cmet.2005.05.005) (https://doi.org/10.1210/jc.2009-2149) Zambrano E, Rodríguez-González GL, Guzmán C, García-Becerra R, Veening MA, van Weissenbruch MM, Roord JJ & Delemarre-van de Boeck L, Díaz L, Menjivar M, Larrea F & Nathanielsz PW 2005 A Waal HA 2004 Pubertal development in children born small for maternal low protein diet during pregnancy and lactation in the rat gestational age. Journal of Pediatric Endocrinology and Metabolism 17 impairs male reproductive development. Journal of Physiology 563 1487–1505. (https://doi.org/10.1515/JPEM.2004.17.11.1497) 275–284. (https://doi.org/10.1113/jphysiol.2004.078543)

Received in final form 15 March 2019 Accepted 25 March 2019