University of Kentucky

Exposure to an Environmentally Relevant Phthalate Mixture Inhibits Ovulation By Impairing Prostaglandin Function in the Mouse Ovary

Grade Level at Time of Presentation

Senior

Major

Agricultural and Medical Biotechnology

Institution 24-25

University of Kentucky

KY House District #

79

KY Senate District #

13

Department

Department of Obstetrics and Gynecology

Abstract

Phthalates are solvents and plasticizers found in cosmetics, food/beverage containers, and medical supplies; therefore, human exposure is ubiquitous. Phthalates are known endocrine disruptors that target the ovary, meaning exposure could disrupt ovarian processes like ovulation. Prostaglandins (PGs) are vital mediators of ovulation due to their involvement in angiogenesis and cumulus-oocyte complex (COC) expansion. PGs are synthesized by various cell types within the ovulating follicle (granulosa and cumulus cells) and bind to their receptors on endothelial and cumulus cells to facilitate angiogenesis and COC expansion, respectively. Levels of active PGs, inactive PG metabolites, expression of PG synthases, expression of PG receptors, and ovulation rates were measured via various ovulatory experimental mouse models using cultured whole ovarian follicles (WF), COCs, and ovarian endothelial cells. Culture media contained vehicle control (dimethylsulfoxide, DMSO) ± a mixture of 6 phthalates (MPTmix, 1-500μg/mL) derived from urinary phthalate levels in pregnant women to best mimic human exposure. In WFs, exposure to MPTmix decreased active PG levels (PGE2 and PGF)and increased PG metabolite levels. The levels of PGE2 were also decreased in COCs exposed to MPTmix. These decreases were largely attributed to decreased expression of PG synthase (Ptgs2) in WFs and COCs exposed to MPTmix. MPTmix exposure increased expression of PGE2 receptor 4 in ovarian endothelial cells and altered expression of PGE2 receptor 1 and 3 in WFs. Most notably, exposure to MPTmix in WF cultures decreased ovulation rates. Across these ovulatory models, MPTmix exposure likely disrupted the function of PGs by decreasing PG levels and synthases, increasing metabolite levels, and altering PG receptor levels. These MPTmix-induced changes may be why ovulation was inhibited in the WFs. Thus, exposure to phthalates may disrupt the ovulatory process and may ultimately contribute to the prevalence of infertility in women. Supported by R01ES033767.

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Exposure to an Environmentally Relevant Phthalate Mixture Inhibits Ovulation By Impairing Prostaglandin Function in the Mouse Ovary

Phthalates are solvents and plasticizers found in cosmetics, food/beverage containers, and medical supplies; therefore, human exposure is ubiquitous. Phthalates are known endocrine disruptors that target the ovary, meaning exposure could disrupt ovarian processes like ovulation. Prostaglandins (PGs) are vital mediators of ovulation due to their involvement in angiogenesis and cumulus-oocyte complex (COC) expansion. PGs are synthesized by various cell types within the ovulating follicle (granulosa and cumulus cells) and bind to their receptors on endothelial and cumulus cells to facilitate angiogenesis and COC expansion, respectively. Levels of active PGs, inactive PG metabolites, expression of PG synthases, expression of PG receptors, and ovulation rates were measured via various ovulatory experimental mouse models using cultured whole ovarian follicles (WF), COCs, and ovarian endothelial cells. Culture media contained vehicle control (dimethylsulfoxide, DMSO) ± a mixture of 6 phthalates (MPTmix, 1-500μg/mL) derived from urinary phthalate levels in pregnant women to best mimic human exposure. In WFs, exposure to MPTmix decreased active PG levels (PGE2 and PGF)and increased PG metabolite levels. The levels of PGE2 were also decreased in COCs exposed to MPTmix. These decreases were largely attributed to decreased expression of PG synthase (Ptgs2) in WFs and COCs exposed to MPTmix. MPTmix exposure increased expression of PGE2 receptor 4 in ovarian endothelial cells and altered expression of PGE2 receptor 1 and 3 in WFs. Most notably, exposure to MPTmix in WF cultures decreased ovulation rates. Across these ovulatory models, MPTmix exposure likely disrupted the function of PGs by decreasing PG levels and synthases, increasing metabolite levels, and altering PG receptor levels. These MPTmix-induced changes may be why ovulation was inhibited in the WFs. Thus, exposure to phthalates may disrupt the ovulatory process and may ultimately contribute to the prevalence of infertility in women. Supported by R01ES033767.