An environmentally relevant phthalate mixture impairs ovulatory prostaglandin and progesterone receptor pathways in human granulosa cells in vitro

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• Phthalate mixture decreases ovulatory P4, PGR , and PG levels in human granulosa cells. • Reduced P4 levels were due to decreases in P4 steroidogenic proteins and enzymes. • Reduced PGR levels were due to decreases in cAMP/PKA and ERK1/2 levels • PG function was impaired via disrupted synthesis/metabolism, transport, and receptors. • Relevant phthalate exposure in human cells indicates ovulation may be threatened. Ovulatory defects are the leading cause of female infertility. Widespread exposure to endocrine-disrupting chemicals, such as phthalates, may contribute to the high prevalence of failed ovulation among infertile women. Using primary ovarian granulosa cells obtained from women, we tested the hypothesis that exposure to an environmentally relevant mixture of phthalate metabolites (MPTmix) impairs essential mediators of the ovulatory process, including progesterone (P4), progesterone receptor (PGR), and prostaglandins (PGs). The composition of the MPTmix was derived from urinary phthalate levels in women. Ovarian granulosa cells, obtained from in vitro fertilization patients, were acclimated in culture to regain responsiveness to hCG (human chorionic gonadotropin, clinical luteinizing hormone analogue). Following acclimation, cells were treated for 0.5-36hr with media containing DMSO (dimethyl sulfoxide, vehicle control), ± hCG (to initiate the ovulatory cascade), and ± MPTmix (1–500 µg/ml). Compared to hCG controls, treatment with hCG + MPTmix reduced active ovulatory PG levels by up to 77%, likely via decreased synthesis (lower PTGS2 and PTGES levels/activity), enhanced catabolism of PGE 2 to PGF 2α (elevated AKR1C1 and AKR1C3 levels), and increased metabolism (elevated HPGD levels/activity). MPTmix exposure further impaired PG function by altering the levels of PG transporters ( ABCC4 and SLCO2A1 ) and receptors ( PTGER1 - 4 and PTGFR ). These MPTmix-induced disruptions were accompanied by upstream defects in LH/hCG receptor signaling (cAMP/PKA, ERK1/2), P4 steroidogenesis, and PGR expression. Together, these findings demonstrate that exposure to phthalates impairs P4/PGR-driven PG production/function in human ovarian cells and advances our mechanistic understanding of how phthalate exposure may contribute to ovulatory dysfunction in women.

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