Ovulation is Inhibited by an Environmentally Relevant Phthalate Mixture in Mouse Antral Follicles In Vitro

Phthalates are solvents and plasticizers found in consumer products including cosmetics, food/beverage containers, housing materials, etc. Phthalates are known endocrine-disrupting chemicals that can directly target the ovary, potentially causing defects in ovulation and fertility. Women are exposed to multiple different phthalates daily, therefore this study investigated the effects of an environmentally relevant phthalate mixture (PHTmix) on ovulation. Ovulation is initiated by the luteinizing hormone (LH) surge, which induces prostaglandin (PG) production, progesterone (P4)/progesterone receptor (PGR) signaling, and extracellular matrix (ECM) remodeling. We hypothesized that the PHTmix would directly inhibit ovulation by altering the levels of PGs, P4/PGR, and enzymes involved in ECM remodeling. Antral follicles from CD-1 mice were treated with vehicle control alone (dimethylsulfoxide, DMSO), hCG alone (LH analog), and hCG+PHTmix (1-500μg/ml), and samples were collected across the ovulatory period. The PHTmix decreased ovulation rates at all doses tested in a dose-dependent manner when compared to hCG. PG levels were decreased by the PHTmix when compared to hCG, which was potentially mediated by altered levels of PG synthesis (Ptgs2) and transport (Slco2a1) genes. The PHTmix altered P4 and Pgr levels when compared to hCG, leading to decreases in downstream PGR-mediated genes (Edn2, Il6, Adamts1). ECM remodeling was potentially dysregulated by altered levels of ovulatory mediators belonging to the matrix metalloproteases and plasminogen activator families. These data suggest that phthalate exposure inhibits ovulation by altering PG levels, P4/PGR action, and ECM remodeling.