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. 2025 Sep:136:108968.
doi: 10.1016/j.reprotox.2025.108968. Epub 2025 May 31.

The inhibition of prostaglandin production during ovulation by exposure to a phthalate mixture is circumvented by cAMP analogue supplementation in a human granulosa cell model

Patrick R Hannon  1 , Katie L Land  2 , Hong Xu  3 , James W Akin  4 , Thomas E Curry  5
Affiliations

The inhibition of prostaglandin production during ovulation by exposure to a phthalate mixture is circumvented by cAMP analogue supplementation in a human granulosa cell model

Patrick R Hannon et al. Reprod Toxicol. 2025 Sep.

Abstract

Exposure to individual phthalates disrupts ovarian function; however, the direct effects of phthalate mixture exposure on ovulation is unknown, especially in women. Human granulosa cells were used to test the hypothesis that exposure to a phthalate mixture (PHTmix; derived from women's urinary phthalate levels) disrupts the function of prostaglandins (PGs), which are vital mediators of ovulation. Additionally, cAMP supplementation was tested as a method 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, with or without PHTmix (1-500 µg/ml; DMSO=vehicle control), and with or without 8-Br-cAMP (stable cAMP analogue) for 6-36 hr. Exposure to hCG+PHTmix decreased ovulatory PGE2 and PGF2α levels when compared to hCG. The mechanism by which the PHTmix decreased PG levels was via decreased synthesis (decreased PTGS2 and PTGES levels) and increased metabolism (increased AKR1C1, AKR1C3, and HPGD levels). Exposure to hCG+PHTmix also impaired PG function by altering levels of PG transporters (ABCC4 and SLCO2A1) and receptors (PTGER2, PTGER3, and PTGFR) when compared to hCG. Supplementation with cAMP in the hCG+PHTmix 500 µg/ml group restored PGE2 and PGF2α levels comparable to and beyond hCG control levels. These findings suggest that phthalates inhibit the ovulatory increase in PGs in human granulosa cells via decreased synthesis and increased metabolism. Restored PG levels with cAMP supplementation further establishes a mechanism of toxicity by providing demonstration of a potential cellular target of phthalate-induced ovulatory defects in women.

Keywords: Fertility; Granulosa cells; Mixture; Ovary; Ovulation; Phthalates; Prostaglandin.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Patrick Hannon reports financial support was provided by National Institute of Environmental Health Sciences. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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