Functional and epigenetic effects of preconceptional EDCs on the female HPG axis

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ABSTRACT Exposures to environmental endocrine-disrupting chemicals (EDCs), especially during early life, are strongly linked to adverse reproductive outcomes. Polychlorinated biphenyls (PCBs) are a well-established family of EDCs, used for decades in industrial applications. While banned decades ago, humans are exposed to PCBs today primarily through the food chain. In both humans and animals, higher PCB body burdens are associated with endocrine and reproductive dysfunctions. However, there are several important gaps in knowledge in this field that we propose to fill. First, while PCBs perturb each level of the hypothalamic-pituitary-gonadal (HPG) axis when assessed individually, the cross-talk among these levels has not been explored. Second, while early development (fetus, infant) is recognized as a period of vulnerability to EDCs, the preconceptional period is another critical window that has not been studied for PCB actions on HPG systems, especially in females, something we propose to redress. Third, the vast majority of phenotyping following EDC exposures is conducted at a single life stage, typically in the adult. Yet, the reproductive system undergoes enormous dynamic change in structure and function throughout life, underscoring the need for a lifecycle approach to phenotyping. The fourth and perhaps largest gap is whether and how preconceptional exposures reprogram the germline epigenome, and if that leads to somatic effects. In this proposal, we will develop and utilize a novel intergenerational model of preconceptional exposure to PCBs. We will feed pregnant Sprague-Dawley rat dams (F0 grandmothers) human-relevant levels of a PCB mixture, or vehicle, from E8-18, when germ cell epigenetic marks are being erased in the gonads of the F1 fetuses; and/or during lactation when F1 pups are P1-21 and when germ cell epigenetic marks are re-established. The F1 females are bred with untreated male rats to generate the F2 generation. The F2 female offspring (grandchildren) will be phenotyped at 3 reproductive life stages: neonatal, pubertal, and adult. Physiological outcomes, expression of key HPG genes and proteins involved in the control of reproductive competence, and underlying molecular epigenetic marks (DNA and histone methylation) will be assessed. In addition, we will use a novel method to isolate primordial germ cells (PGCs) of newborn F1 and F2 females rats of the PCB and vehicle lineage, to quantify gene expression and methylation marks. This allows us to relate HPG phenotypes to prior germ cell programming. Thus, this proposal is anticipated to provide novel insights into the effects of preconceptional PCB exposures on female HPG physiology, function, and underlying epigenetic mechanisms of regulation, results of which are directly relevant to women’s environmental health.