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Sexual Epigenetic Dimorphism in the Human Placenta: Implications for Susceptibility During the Prenatal Period

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Sexual Epigenetic Dimorphism in the Human Placenta: Implications for Susceptibility During the Prenatal Period SPECIAL FOCUS y Effects of the in utero environment on the epigenome Research Article For reprint orders, please contact: [email protected] 9 Research Article 2017/02/28 Sexual epigenetic dimorphism in the human placenta: implications for susceptibility during the prenatal period Epigenomics Aim: Sex-based differences in response to adverse prenatal environments and infant Elizabeth Martin1, Lisa outcomes have been observed, yet the underlying mechanisms for this are unclear. Smeester1, Paige A The placental epigenome may be a driver of these differences. Methods: Placental Bommarito1, Matthew R 2 2 DNA methylation was assessed at more than 480,000 CpG sites from male and female Grace , Kim Boggess , Karl Kuban3, Margaret R Karagas4, infants enrolled in the extremely low gestational age newborns cohort (ELGAN) and Carmen J Marsit5, T Michael validated in a separate US-based cohort. The impact of gestational age on placental O’Shea6 & Rebecca C Fry*,1 DNA methylation was further examined using the New Hampshire Birth Cohort Study 1Department of Environmental Sciences for a total of n = 467 placentas. Results: A total of n = 2745 CpG sites, representing n & Engineering, Gillings School of Global = 587 genes, were identified as differentially methylated (p < 1 × 10-7). The majority (n Public Health, University of North = 582 or 99%) of these were conserved among the New Hampshire Birth Cohort. The Carolina, Chapel Hill, NC, USA 2Department of Obstetrics & Gynecology, identified genes encode proteins related to immune function, growth/transcription University of North Carolina School of factor signaling and transport across cell membranes. Conclusion: These data Medicine, University of North Carolina, highlight sex-dependent epigenetic patterning in the placenta and provide insight Chapel Hill, NC, USA into differences in infant outcomes and responses to the perinatal environment. 3Department of Pediatrics, Boston Medical Center, Boston, MA, USA 4 First draft submitted: 30 September 2016; Accepted for publication: 10 January 2017; Department of Epidemiology, Geisel School of Medicine at Dartmouth, Published online: 17 February 2017 Hanover, NH, USA 5Department of Environmental Health, Keywords: CpG DNA methylation • epigenetics • placenta • sexual dimorphism Rollins School of Public Health at Emory University, Atlanta, GA 30322, USA 6Department of Pediatrics, University The placenta serves as the primary organ and maternal immune status [9,17,18]. We of North Carolina School of Medicine, responsible for regulation of the prenatal hypothesize that sex-dependent health out- University of North Carolina, Chapel Hill, environment critical for optimal fetal devel- comes in infants may be associated with NC, USA opment. It is a nutrient transporter and sexual dimorphism of the placenta. In sup- *Author for correspondence: 3 Tel.: +1 919 843 6864 produces vital hormones to maintain preg- port of this hypothesis, physiologic differ- Fax: +1 919 843 9047 nancy and support the fetus [1] . In contrast ences between male and female placentas [email protected] to these essential functions, the placenta also have been observed [19] . For example, pla- serves as a source of exposure for toxic sub- centas derived from pregnancies of males 2017 stances, dysregulated hormone signaling and and females display variation in the abun- immune-related proteins [2]. Such exposures dance and type of glucocorticoid transporter including maternal stress, excess hormones, proteins, the expression of hormones and cytokines or environmental toxicants impact the production of immune-related proteins fetal health and influence later-life health including cytokines [12,19–21] . In addition, outcomes [3–11] . sex-based differences in response to prenatal An increasing body of literature supports stressors have been observed at the levels of sex-specific birth and later-life outcomes in the placental proteome, transcriptome and relation to adverse in utero environments [12] . epigenome [3,7,14,20,22–27]. Thus, the sexu- For example, sex-specific perinatal and later- ally dimorphic nature of the placenta could life outcomes have been linked to toxic sub- influence variation in toxicant transport and part of stance exposure [5,6,13–16], maternal stress [7] accumulation, hormone levels and immune 10.2217/epi-2016-0132 © 2017 Future Medicine Ltd Epigenomics (2017) 9(3), 267–278 ISSN 1750-1911 267 Research Article Martin, Smeester, Bommarito et al. response experienced by the fetus. While key physi- cental collection is as follows: delivered placentas were ological differences have been observed in male and placed in a sterile exam basin and transported to a female placentas, the underlying mechanisms are not sampling room, where they were biopsied under ster- well established. ile conditions. At the midpoint of the longest distance Epigenetic regulation may underlie the physiologic between the cord insertion and the edge of the pla- differences observed between male and female pla- cental disk, the amnion was pulled back using sterile centas [12] . For instance, key differences in chromatin technique to expose the chorion. Traction was applied structure have been observed between male and female to the chorion and the underlying trophoblast tissue placentas, suggesting that there is a role for epigen- and a piece of tissue was removed by cutting at the etic regulation in placental sexual dimorphism [12,21] . base of the section. The tissue was placed into a cryo Understanding epigenetic regulation in the placenta vial and immediately immersed in the liquid nitro- is important given the modifiability of its epigenome gen. Specimens were stored at -80°C until laboratory in response to prenatal stressors, and its role as a processing [38]. mediator of the developmental origins of health and The replication cohort included 40 subjects of disease [2,20,21,28]. Additionally, because certain epig- women receiving obstetric care at UNC hospitals who enomic markers are stable over time [29], it is possible consented to collection of placental samples at the time that changes to the fetal placenta methylome explain of birth. Subjects gave written informed consent prior the sex-based differences in later-life disease risks. to enrollment and participation in this study. A full- To our knowledge, this study is among the first to thickness placental biopsy was obtained after delivery, address the gap in knowledge related to sexual dimor- avoiding the periphery and areas of obvious infarction. phism of the placental DNA methylome. Here, we Samples were flash frozen in liquid nitrogen, and stored investigated whether DNA (CpG) methylation pat- at -70°C until analysis. This research was approved by terns in the placenta differed based on the sex of the the Institutional Review Board at the University of fetus. Sex-based differences within the placenta were North Carolina (#11–2054). identified in a subset of subjects from the extremely low Data from a third cohort comprising 343 placenta gestational age newborns (ELGAN) cohort [30–35], and samples obtained from women and children involved validated in a replication cohort comprised of women in the New Hampshire Birth Cohort, an ongoing pro- recruited at the University of North Carolina (UNC) spective pregnancy and birth cohort, were utilized as a hospitals [36]. To confirm that gestational age was not contrast and validation of the results in a cohort with a major driver of the differences in DNA methylation, a more generalizable spread of gestational age. This all data were subsequently compared with CpG meth- cohort and the placental DNA methylation array data ylation assessed in the New Hampshire Birth Cohort. have been previously described [39]. Briefly, pregnant The goal of these analyses is to provide key insights women whose primary source of residential water is a into whether sexual dimorphism of the placental meth- private well and who obtained their prenatal care at ylome may explain differential susceptibility to adverse clinics in New Hampshire, were recruited into the prenatal environmental conditions. study. Eligibility criteria were that women were cur- rently pregnant; 18–45 years old; received routine pre- Methods natal care at one of the study clinics; used a private well ELGAN study subject recruitment & sample that serves <15 households or 25 individuals at their collection residence; resided in the sample place since their last ELGAN study recruitment has been previously menstrual period; and did not plan to move prior to described in detail [37]. In short, from 2002 to 2004, delivery. Like the replication cohort, a full-thickness women giving birth at one of the 14 participating sites placental biopsy was obtained after delivery, avoid- before 28 weeks gestation were asked to enroll in the ing the periphery and areas of obvious infarction, and ELGAN study. Their consent was provided either upon placed immediately in RNA later for at least 48 h, then hospital admission prior to or shortly after delivery. All removed from the fixative and stored at -80°C until procedures were approved by the Institutional Review laboratory processing. Board at each of the 14 participating study sites. A total of 1506 infants and 1249 mothers enrolled DNA extraction & assessment of DNA in the ELGAN study. A subcohort of 84 mother-infant methylation pairs, representative of the larger cohort, were selected DNA extraction and assessment of DNA methylation for this analysis. As part of participation in ELGAN, was performed
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