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 , Katie L. Land , Hong Xu , James W. Akin , Thomas E. Curry
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引用次数: 0
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.
期刊介绍:
Drawing from a large number of disciplines, Reproductive Toxicology publishes timely, original research on the influence of chemical and physical agents on reproduction. Written by and for obstetricians, pediatricians, embryologists, teratologists, geneticists, toxicologists, andrologists, and others interested in detecting potential reproductive hazards, the journal is a forum for communication among researchers and practitioners. Articles focus on the application of in vitro, animal and clinical research to the practice of clinical medicine.
All aspects of reproduction are within the scope of Reproductive Toxicology, including the formation and maturation of male and female gametes, sexual function, the events surrounding the fusion of gametes and the development of the fertilized ovum, nourishment and transport of the conceptus within the genital tract, implantation, embryogenesis, intrauterine growth, placentation and placental function, parturition, lactation and neonatal survival. Adverse reproductive effects in males will be considered as significant as adverse effects occurring in females. To provide a balanced presentation of approaches, equal emphasis will be given to clinical and animal or in vitro work. Typical end points that will be studied by contributors include infertility, sexual dysfunction, spontaneous abortion, malformations, abnormal histogenesis, stillbirth, intrauterine growth retardation, prematurity, behavioral abnormalities, and perinatal mortality.