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

IF 2.8 4区 医学 Q2 REPRODUCTIVE BIOLOGY
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 PGF 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 PGF 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.
在人颗粒细胞模型中,暴露于邻苯二甲酸盐混合物对排卵期间前列腺素产生的抑制作用可通过补充cAMP类似物来规避。
接触个别邻苯二甲酸盐会破坏卵巢功能;然而,接触邻苯二甲酸盐混合物对排卵的直接影响尚不清楚,特别是对女性。人类颗粒细胞被用来测试暴露于邻苯二甲酸盐混合物(PHTmix;源自女性尿中邻苯二甲酸盐水平)会破坏前列腺素(pg)的功能,而前列腺素是排卵的重要介质。此外,补充cAMP作为规避邻苯二甲酸盐毒性的方法进行了测试。体外受精妇女的颗粒细胞在培养中驯化,以恢复对人绒毛膜促性腺激素(hCG)的反应;临床黄体生成素类似物)。颗粒细胞分别加或不加hCG,加或不加PHTmix(1-500µg/ml;DMSO=载具对照),加或不加8-Br-cAMP(稳定cAMP模拟物),持续6-36小时。与hCG相比,暴露于hCG+PHTmix降低了排卵PGE2和PGF2α水平。PHTmix降低PG水平的机制是通过降低合成(降低PTGS2和PTGES水平)和增加代谢(增加AKR1C1, AKR1C3和HPGD水平)。与hCG相比,暴露于hCG+PHTmix也通过改变PG转运蛋白(ABCC4和SLCO2A1)和受体(PTGER2、PTGER3和PTGFR)的水平而损害PG功能。在hCG+PHTmix 500µg/ml组中补充cAMP可恢复PGE2和PGF2α水平,与hCG对照水平相当或超过hCG对照水平。这些发现表明,邻苯二甲酸盐通过减少合成和增加代谢来抑制人颗粒细胞中PGs的排卵增加。通过提供邻苯二甲酸盐诱导的女性排卵缺陷的潜在细胞靶点,通过补充cAMP恢复PG水平进一步建立了毒性机制。
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来源期刊
Reproductive toxicology
Reproductive toxicology 生物-毒理学
CiteScore
6.50
自引率
3.00%
发文量
131
审稿时长
45 days
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.
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