Di(2-ethylhexyl) phthalate (DEHP) is environmental endocrine disrupting chemical that is a public health concern because it is associated with impaired fertility and reduced fecundity in women. DEHP is a plasticizer used in plastic polyvinyl chloride products to impart flexibility. The general population is continuously exposed to DEHP due to the prevalence of its use in many consumer products such as personal care products and building materials. The literature and preliminary data characterize DEHP as a reproductive toxicant in females and indicates that prenatal and ancestral exposure to DEHP accelerates folliculogenesis in ovaries through the phosphoinositide 3-kinase (PI3K) pathway. However, the specific mechanisms of prenatal and ancestral DEHP- induced ovarian toxicity are not fully characterized. Thus, the proposed work will test the hypothesis that prenatal and ancestral exposure to DEHP dysregulates the expression of various pathways critical for normal ovarian functions and disrupts epigenetic mechanisms within the ovary in the F1, F2, and F3 generations.
Aim 1 will determine if prenatal and ancestral exposure to DEHP reduces mRNA and protein expression of key ovarian regulators such as the PI3K pathway and regulators of cell proliferation and apoptosis in the F1, F2, and F3 ovaries.
Aim 2 will investigate the mechanism by which prenatal and ancestral exposure to DEHP disrupts epigenetic modifications in the ovary to induce transgenerational inheritance. Collectively, these experiments will provide a better understanding of the mechanisms by which prenatal and ancestral exposure to DEHP impact the ovary. In addition, this work will provide an opportunity for the applicant to expand her training by learning to conduct transcriptome and epigenome experiments and analyses. Overall, the completion of this study will ensure comprehensive research training under the guidance of an exceptional mentor with an expertise in reproductive physiology and toxicology.
This work will increase our understanding of the mechanism by which di(2-ethylhexyl) phthalate impacts the ovaries of current and future generations. In turn, this may lead to the development of novel methods to prevent or treat phthalate-induced reproductive problems.