O-090 Endocrine disruptors

Abstract

Abstract Female mammals, including women, are exposed to endocrine disrupting chemicals (EDCs) on a daily basis. This is of concern because many EDCs inhibit ovarian follicle growth and steroidogenesis, processes that are critical for maintaining female fertility. Our research focuses on the effects of EDCs known as phthalates on female fertility. Phthalates are of interest because they are ubiquitous synthetic chemicals used as plasticizers and stabilizers in a myriad of consumer products, including everything from shower curtains to children’s toys to cosmetics and personal care products such as perfumes, nail polish, deodorants, and lotions. Phthalates are also used in pesticides, wood finishes, adhesives, solvents, lubricants, defoaming agents, and in medical devices including tubing, blood bags, surgical gloves, and dialysis equipment. Despite the widespread use of phthalates and ubiquitous human exposure, limited information is available about the effects of environmentally relevant phthalate mixtures on female reproduction. Thus, we tested the hypothesis that prenatal exposure to an environmentally relevant phthalate mixture affects female reproduction in the F1, F2, and F3 generations of mice. To test this hypothesis, pregnant CD-1 mice were orally dosed with vehicle control (corn oil) or a phthalate mixture (20µg/kg/day-500mg/kg/day) daily from gestational day 10 to birth. The mixture was based on urinary phthalate metabolite levels measured pregnant women in the United States, and consisted of 35% diethyl phthalate, 21% di(2-ethylhexyl) phthalate, 15% dibutyl phthalate, 15% di-isononyl phthalate, 8% diisobutyl phthalate, and 5% benzylbutyl phthalate. Adult F1 females born to these dams were used to create the F2 generation by mating them with unexposed males and F2 females were used to create the F3 generation by mating them with unexposed males. At selected times, estrous cyclicity and fertility indices were monitored and ovaries and sera were collected for analysis. Our data indicate that prenatal exposure to the phthalate mixture significantly decreases anogenital distance, testosterone levels, and litter size, but it significantly increases abnormal estrous cyclicity, uterine weight, the number of cystic ovaries, follicle-stimulating hormone levels, and luteinizing hormone levels compared to control in the F1 generation. Further, our data indicate that prenatal exposure to the phthalate mixture increases body weight, uterine weight, the number of cystic ovaries, and time to pregnancy and it decreases testosterone levels compared to control in the F2 generation. In addition, our data indicate that prenatal exposure to the phthalate mixture increases body weight, uterine weight, the number of cystic ovaries, and abnormal cyclicity and it decreases anogenital distance and the number of live pups compared to control in the F3 generation. Collectively, these data suggest that prenatal exposure to an environmentally relevant mixture of phthalates adversely affects reproductive function in a multi- and transgenerational manner in female mice. These findings have increased our understanding of the mechanisms by which EDCs cause female reproductive toxicity. This information eventually may lead to the development of novel targets for the prevention or treatment of infertility induced by EDCs.