Developmental Reprogramming of Reproductive and Metabolic Dysfunction in Sheep: Native Steroids Vs

international journal of andrology ISSN 0105-6263 REVIEW ARTICLE Developmental reprogramming of reproductive and metabolic dysfunction in sheep: native steroids vs. environmental steroid receptor modulators V. Padmanabhan, H. N. Sarma, M. Savabieasfahani, T. L. Steckler and A. Veiga-Lopez Department of Pediatrics and the Reproductive Sciences Program, The University of Michigan, Ann Arbor, MI, USA Summary Keywords: The inappropriate programming of developing organ systems by exposure to bisphenol A, endocrine disrupting chemicals, excess native or environmental steroids, particularly the contamination of our foetal programming, infertility, insulin environment and our food sources with synthetic endocrine disrupting chemi- resistance, metabolic programming, cals that can interact with steroid receptors, is a major concern. Studies with methoxychlor, neuroendocrine, ovary native steroids have found that in utero exposure of sheep to excess testoster- Correspondence: one, an oestrogen precursor, results in low birth weight offspring and leads to Vasantha Padmanabhan, Room 1109, 300 N. an array of adult reproductive ⁄ metabolic deficits manifested as cycle defects, Ingalls Building, University of Michigan, Ann functional hyperandrogenism, neuroendocrine ⁄ ovarian defects, insulin resis- Arbor, MI 48109, USA. tance and hypertension. Furthermore, the severity of reproductive dysfunction E-mail: [email protected] is amplified by excess postnatal weight gain. The constellation of adult reproductive and metabolic dysfunction in prenatal testosterone-treated sheep is Received 18 August 2009; revised 25 October similar to features seen in women with polycystic ovary syndrome. Prenatal 2009; accepted 27 October 2009 dihydrotestosterone treatment failed to result in similar phenotype suggesting doi:10.1111/j.1365-2605.2009.01024.x that many effects of prenatal testosterone excess are likely facilitated via aroma- tization to oestradiol. Similarly, exposure to environmental steroid imposters such as bisphenol A (BPA) and methoxychlor (MXC) from days 30 to 90 of gestation had long-term but differential effects. Exposure of sheep to BPA, which resulted in maternal levels of 30–50 ng ⁄ mL BPA, culminated in low birth weight offspring. These female offspring were hypergonadotropic during early postnatal life and characterized by severely dampened preovulatory LH surges. Prenatal MXC-treated females had normal birth weight and manifested delayed but normal amplitude LH surges. Importantly, the effects of BPA were evident at levels, which approximated twice the highest levels found in human maternal circulation of industrialized nations. These findings provide evidence in support of developmental origin of adult reproductive and metabolic diseases and highlight the risk posed by exposure to environmental endocrine disrupting chemicals. cues from the mother, underlies the developmental origin Introduction of disease or Barker hypothesis (Barker, 1994). The The developing foetus, in response to changes in the increased prevalence of some common diseases may be in utero environment develops compensatory strategies to related to exposure during development to environmental overcome insults that they experience. Such compensa- pollutants, lifestyle choices of the mother and medical tions could be adaptive, if they support survival, or interventions, all of which can adversely influence devel- disruptive, if they compromise postnatal survival. ‘Devel- opmental trajectory of target tissue differentiation. This opmental plasticity’, the ability of the developing foetus review addresses the reproductive and metabolic disrup- to change structure ⁄ function in response to physiological tions resulting from exposure to excess native steroids ª 2010 The Authors 394 Journal compilation ª 2010 European Academy of Andrology • International Journal of Andrology 33 (2010), 394–404 V. Padmanabhan et al. Developmental programming of adult function and environmental steroid receptor modulators with spe- line (gestation length: 147 days, puberty in female: cific focus on those that signal through oestrogen and approximately 28 weeks) is ideally suited for integrative androgen receptors. studies that address progression of reproductive ⁄ metabolic disruption from the initial developmental insult to manifestation of adult consequences, especially those that Developmental programming of reproductive/ involve detailed hormonal profiling or sequential moni- metabolic dysfunction with native steroids toring of ovarian follicular dynamics. Importantly, they Steroid hormones play a major role during development can be studied in natural social settings thus reducing the in setting the trajectory of developing organ systems. level of stress. From a reproductive perspective, ovarian Because, differentiation of organ systems depend upon differentiation in sheep is similar to humans with full precise exposure to steroid hormones at specific times follicular differentiation occurring by birth (Fig. 1A) during development, exposure to low doses of endocrine (Padmanabhan et al., 2007). Neuroendocrine aspects disrupting compounds (EDCs) that can signal through of reproductive cyclicity are also similar to human steroid receptors during these hormone sensitive, critical (McNeilly, 1991; Goodman & Inskeep, 2006). periods of development can lead to long-term deleterious Comparison of sheep treated with T (aromatizable effects on the adult organism. It is well established that androgen) from days 30 to 90 of gestation (T30–90 inappropriate exposure to excess testosterone (T) during females) with those treated from days 60 to 90 of gesta- foetal life leads to phenotypic virilization and behaviour- tion (T60–90 females) has helped address critical period al masculinization in the female offspring (Jost et al., of programming of reproductive and metabolic disrup- 1973; Gorski, 1986; Wood & Foster, 1998). The amount tions. Comparison of prenatal T, prenatal dihydrotestos- as well as the timing of T exposure dictates the degree terone (non-aromatizable androgen, DHT) and T plus of masculinization of external genitalia in the female flutamide (an androgen antagonist) treatments has helped (Wood & Foster, 1998). Inappropriate perinatal exposure address the quality of steroid (androgen or oestrogen) to excess T during early development also disrupts responsible for programming adult dysfunctions (Fig. 1B). reproductive cyclicity in several species (Abbott et al., Earlier studies with the Dorset breed of sheep found that 2006). T30–90 females showed progressive deterioration of For the remainder of the review, focus is on the repro- cyclicity culminating in absent cycles during the second ductive and metabolic disruptions resulting from inap- breeding season (Fig. 2A) (Birch et al., 2003). Studies propriate developmental exposure of sheep to native with other breeds of sheep also found progressive loss of steroids or environmental steroid mimics. Sheep are cyclicity (Clarke et al., 1977; Manikkam et al., 2006), the exceptionally well suited for investigating developmental severity of which differing between breeds. In contrast, programming of adult disorders. They have long been majority of the T60–90 females cycled during the second used as model systems to study foetal physiology breeding season (Birch et al., 2003; Savabieasfahani et al., (Harding & Bloomfield, 2004). Their developmental time 2005). A B Control Conception T Implantation Gonadal differentiation T Ovary clearly distinguishable with mitotically active oogonia DHT Development of hypophyseal portal vasculature T + Flutamide LH and FSH in circulation and pituitary BPA FSH in pituitary MXC Primordial follicle differentiation complete Appearance of primary F 0 30 60 90 147 Appearance of FSH R & antral F Days of gestation Birth (full complement of F) 30–90 vs. 60–90: Critical period T/DHT/T + Flutamide: Quality of steroid (androgenic vs. estrogenic) 0 1430 40 5055 75 90 100 110 135 147 Gestation day BPA/MXC: Environmental endocrine disruptors Figure 1 (A) Schematic showing the time of appearance of different classes of follicles (F) in sheep, timing of establishment of hypophyseal portal vasculature to pituitary and timing of appearance of LH and FSH in circulation and pituitary during foetal life in sheep. (B) Schematic showing the timing and duration of the various steroid ⁄ EDC treatments used in studies discussed in this review. ª 2010 The Authors Journal compilation ª 2010 European Academy of Andrology • International Journal of Andrology 33 (2010), 394–404 395 Developmental programming of adult function V. Padmanabhan et al. A Progesterone profiles (ng/mL) Percentage of ewes cycling 10 100 Control 5 100 100 0 0 10 100 T60–90 5 86 71 0 0 10 100 T30–90 5 71 0 0 0 Aug DecApr Aug Dec Apr Apr Aug DecApr Aug Dec Apr 1998 1999 2000 19981999 2000 B 300 6 200 4 100 2 0 0 200 4 LH (ng/mL) 100 2 Oestradiol (pg/mL) 0 0 200 4 Figure 2 (A) Plasma progesterone profiles 100 2 from representative control, T60–90, and 0 0 T30–90 females during the first and second –100 0 100 breeding seasons are shown on the left. On Time relative to LH surge peak in controls (h) the right are shown percentages of sheep cycling during the first and second breeding C Oestrus- Oestrus- Breeding seasons (modified from Birch et al., 2003). synchronized synchronized herd (B) Patterns of LH (closed circles) and oestradiol (E) (open circles) from control (top), T30–90 (middle), and DHT30–90 (bottom) 80 80 80 following oestrous synchronization with PGF2a (Veiga-Lopez

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