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Abstracts 2019 Focus Sessions 52nd ANNUAL CONFERENCE Beyond Possible: Remarkable Transformation of Reproductive Biology Abstracts 2019 Focus Sessions S1.1 - The maternal lactocrine continuum programming uterine capacity. Frank Bartol, Jeffrey Vallet, Carol Bagnell Lactocrine signaling describes a mechanism by which milk-borne bioactive factors (MbFs) are communicated from mother to offspring by consequence of nursing. Lactocrine communication is an element of the maternal environmental continuum of factors that define pre- and postnatal developmental conditions and, therefore, the trajectory of mammalian development and offspring phenotype. Lactocrine-active factors can include MbFs of maternal origin, as well as factors of environmental origin to which the lactating female is exposed. Ideally, lactocrine signals communicated to nursing offspring insure a smooth transition and adaptation to extrauterine life. Disruption of lactocrine communication occurs when the quality or quantity of colostrum (first milk) is compromised. This can have lasting consequences for the health and fitness of nursing young. In the pig (Sus domesticus), imposition of a lactocrine-null state from birth (postnatal day = PND 0) by feeding milk replacer altered global patterns of uterine gene expression by PND 2, and inhibited endometrial development by PND 14. Similarly, lactocrine deficiency, reflecting minimal colostrum consumption from birth, retarded endometrial development in neonates, altered endometrial gene expression on pregnancy day (PxD) 13, and reduced live litter size in adult, neonatally lactocrine-deficient gilts. Elements of the lactocrine-sensitive, adult endometrial transcriptome at PxD 13 included factors affecting conceptus-endometrial interactions. A window for lactocrine programming of porcine endometrial function and uterine capacity was defined during the first 24 h of postnatal life. Lactocrine effects on the neonatal uterine miRNA-mRNA interactome at PND 2 implicated miRNAs as elements of the maternal lactocrine programming mechanism. In addition to molecular signals, maternally-derived somatic cells delivered to nursing young may affect the trajectory of postnatal development. Lactocrine targets in other species include pituitary mammotropes, immune system, and brain. Observations reinforce the importance of defining lactocrine mechanisms driving maternal programming of postnatal development and offspring phenotype. [Support: USDA-NIFA-2013-67016-20523] S1.2 - Maternal programming of fetal development via endocrine disruptors. Almudena Veiga-Lopez The burden of endocrine disruptor chemicals (EDCs) has risen in the past decades. Bisphenol A, S, and F (BPA, BPS, and BPF) are among the most common bisphenolic EDCs use in the manufacture of consumer products. Because exposure to bisphenols during pregnancy occurs in >90% of pregnancies, there is a growing interest to understand the risk that these chemicals may pose to human health. The goal of our research is to investigate the effect that bisphenol chemicals may have on the developing fetus, as well as the placenta. Because BPA has been demonstrated to lead to insulin resistance and obesity, we were particularly interested in evaluating if adipogenesis was altered as early as the fetal stage and if so, the mechanism by which BPA could program an adipogenic phenotype. Our work using sheep as an animal model shows that BPA, but not BPS, increases the adipogenic ability in fetal-derived preadipocytes and that this effect is accompanied by alterations in the uncoupled protein response in female fetuses. Because chemical exposure effects on the fetus are highly driven by effective crossing of the placental barrier, we also focused our attention in delineating pregnancy bisphenol toxicokinetics and their ability to persist in fetal circulation. We have demonstrated significant differences in bisphenol kinetics between mother and fetus as well as among bisphenols. We have also explored the potential effects of bisphenols on placental function and demonstrated deleterious effects of the emerging chemical BPS on placental endocrine capacity and maintenance of the trophoblast layer. Taken together, these studies show novel effects from bisphenol chemicals on fetal and placental development suggesting that pregnancy is a vulnerable window for chemical exposures. S1.3 - Ovarian Metabolism of an Environmentally Relevant Phthalate Mixture. Genoa Warner, Zhong Li, Madeline Houde, Cassandra Atkinson, Daryl Meling, Catheryne Chiang, Jodi Flaws Phthalates are synthetic chemicals with widespread human exposure that are commonly used as additives in consumer products. Evidence suggests that metabolites mediate the toxic effects of phthalates and that intravenous medical exposure can lead to significant concentrations of unmetabolized phthalates reaching organs such as the ovary. Thus, the ovary may be bioactivating phthalates in-house, increasing the local concentration of toxic metabolites in one of the most sensitive organs for endocrine disruption. This study investigated the ability of neonatal and adult mouse ovaries to metabolize an environmentally relevant phthalate mixture. Whole neonatal ovaries (postnatal day 4) and adult antral follicles from CD-1 mice were cultured in media treated with dimethyl sulfoxide (DMSO; vehicle control) or phthalate mixture (0.1–100 µg/mL) composed of 35% diethyl phthalate (DEP), 21% di(2-ethylhexyl) phthalate (DEHP), 15% dibutyl phthalate (DBP), 15% diisononyl phthalate (DiNP), 8% diisobutyl phthalate (DiBP), and 5% benzylbutyl phthalate (BBzP), which is representative of exposure of pregnant women in Illinois. After four days of culture, media were subjected to liquid chromatography mass spectrometry (LCMS) to measure the amounts of monoester metabolites. Metabolites for all phthalates except DiNP were detected in the media for both culture types. The long-chain phthalates BBzP, DEHP, and DiNP were metabolized less than the short-chain phthalates DEP, DBP, and DiBP, with neonatal ovaries showing preferential metabolism of short-chain phthalates. Ovaries and follicles were collected to measure gene and protein expression of enzymes required for phthalate metabolism, lipoprotein lipase (LPL) and aldehyde dehydrogenase family 1, subfamily A1 (ALDH1A1). Neonatal ovaries predominantly expressed LPL, whereas adult follicles expressed high levels of ALDH1A1. These data demonstrate that neonatal and adult ovaries are capable of metabolizing low doses of phthalates and suggest that metabolic capacity differs for follicles at different stages of development. Supported by NIH R56ES025147, NIH R01ES028661, and NIH T32ES007326. S1.4 - Worldwide pollution by persistent organic pollutants impacts the sperm DNA methylation of Inuit men in a dose-dependent manner. Marie-Charlotte Dumargne, Xiaojian Shao, Mathieu Dalvai, Gunnar Toft, Jens Peter Bonde, Marie-Michelle Simon, Tony Kwan, Vanessa Dumeaux, Donovan Chan, Guillaume Bourque, Tomi Pastinen, Sarah Kimmins, Jacquetta Trasler, Janice Bailey Persistent organic pollutants (POPs), either used as pesticides (e.g. DDT and its principal metabolite DDE) or industrial by-products (e.g. polychlorinated biphenyls), bio-accumulate in organisms. At the top of the Arctic food chain, Inuit populations have been exposed to POPs for generations in orders of magnitude higher than the safety threshold. We hypothesize that the sperm DNA methylome from Inuit men may be altered in response to exposure to POPs. We collected blood and sperm from 47 Inuit men from Greenland (with a serum DDE ranging from 39.4 ng/g to 5000 ng/g lipids). The sperm DNA methylome was examined using a custom human sperm-specific 5mC-Capture-sequencing approach. The quantitative association between sperm DNA methylation and an increasing environmental exposure to DDE was assessed using a binomial regression, adjusted for potential confounders (smoking, age and body mass index). We identified 8506 dose-dependent differentially methylated regions (DMRs), of which the majority were hypermethylated (74%). Genomic annotation indicated a positive enrichment at CpG islands, exons, CpG shores, sub-telomeres, transfer-RNAs and promoters (permutation test, p<0.001). Gene ontology analysis revealed enrichment for genes with roles in biological processes such as axon guidance, neurotransmitter secretion, cardiac and osteoblast development, retinoic acid receptor signaling, and histone lysine methylation (p<0.01). We report a dose-dependent association between an environmental exposure to DDE and the sperm DNA methylome. The extensive epigenetic changes detected in the most variable regions strongly suggest an alteration by environmental toxicants. This study is the first to accurately assess the genome-wide DNA methylation of sensitive sites in sperm from Inuit menand pave the way to the identification of environmental stressors which could inform on the sperm epigenetic integrityand may be predictive of fertility status and/or embryonic outcomes. S2.2 - Engineering Reproduction. Jennifer Woodruff Infertility is a major health concern, affecting more than 50 million couples. In the Western world most infertile couples resort to assisted reproduction technology (ART) to try to conceive a child. Despite undeniable successes, near half the couples who seek medical assistance for infertility fail to achieve a pregnancy. ART, as it is currently proposed, is mainly palliative, with little effort made to understand and specifically address the dysfunctions responsible for couple infertility. In these couples,
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