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However, limited studies have investigated the effects of phthalate mixtures on ovulation, especially in women. Human granulosa cells were used to test the hypothesis that exposure to a phthalate mixture (PHTmix) disrupts progesterone (P4)\/progesterone receptor (PGR) signaling, which is a crucial pathway for ovulation. In addition, progestin and cyclic adenosine 3\u2032, 5\u2032-monophosphate (cAMP) supplementation were tested as methods to circumvent phthalate toxicity. Granulosa cells from women undergoing in vitro fertilization were acclimated in culture to regain responsiveness to human chorionic gonadotropin (hCG; clinical luteinizing hormone analogue). Granulosa cells were treated with or without hCG, and with or without PHTmix (1\u2013500\u00a0\u03bcg\/ml; dimethylsulfoxide\u2009=\u2009vehicle control) for 0.5\u201336\u00a0h. In the supplementation experiments, cells were treated with or without R5020 (stable progestin), and with or without 8-Br-cAMP (stable cAMP analogue). Exposure to hCG\u2009+\u2009PHTmix decreased P4 levels and mRNA levels of steroidogenic factors when compared to hCG. This was accompanied by decreased mRNA levels of PGR and downstream P4\/PGR ovulatory mediators (ADAM metallopeptidase with thrombospondin type 1 motif 1 (ADAMTS1), C-X-C motif chemokine receptor 4 (CXCR4), pentraxin 3 (PTX3), and regulator of G protein signaling 2 (RGS2)) in the hCG\u2009+\u2009PHTmix groups compared to hCG. Exposure to hCG\u2009+\u2009PHTmix 500\u00a0\u03bcg\/ml decreased cAMP levels and protein kinase A activity compared to hCG. Supplementation with progestin in the hCG\u2009+\u2009PHTmix 500\u00a0\u03bcg\/ml group did not rescue toxicity, while supplementation with cAMP restored PGR levels and downstream P4\/PGR mediator levels to hCG levels. These findings suggest that phthalate mixture exposure inhibits P4\/PGR signaling in human granulosa cells via decreased steroidogenesis, cAMP levels, and protein kinase A activity. Restored P4\/PGR signaling with cAMP supplementation provides a potential cellular target for intervention of phthalate-induced ovulatory dysfunction in women.<\/jats:p>","DOI":"10.1093\/biolre\/ioad091","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T13:44:59Z","timestamp":1691502299000},"page":"552-565","source":"Crossref","is-referenced-by-count":15,"title":["Exposure to a phthalate mixture disrupts ovulatory progesterone receptor signaling in human granulosa cells in vitro"],"prefix":"10.1093","volume":"109","author":[{"given":"Patrick R","family":"Hannon","sequence":"first","affiliation":[{"name":"Department of Obstetrics & Gynecology , College of Medicine, , Lexington, KY , USA"},{"name":"University of Kentucky , College of Medicine, , Lexington, KY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W","family":"Akin","sequence":"additional","affiliation":[{"name":"Bluegrass Fertility Center , Lexington, KY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas E","family":"Curry Jr","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynecology , College of Medicine, , Lexington, KY , USA"},{"name":"University of Kentucky , College of Medicine, , Lexington, KY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,8,8]]},"reference":[{"key":"2023101605092640400_ref1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.3389\/fendo.2015.00008","article-title":"The effects of phthalates on the ovary","volume":"6","author":"Hannon","year":"2015","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2023101605092640400_ref2","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.envres.2011.01.013","article-title":"Phthalates in cosmetic and personal care products: concentrations and possible dermal 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