Gender and sex differences in phthalate-induced toxicity in the reproductive system

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Phthalates are ubiquitous synthetic chemicals used as plasticizers and stabilizers in a myriad of consumer products. People are ubiquitously exposed to phthalates on a daily basis, and gender- and sex-specific differences exist in phthalate exposures and toxicity. However, few studies have examined the gender- and sex-specific effects of prenatal exposure to phthalates on the reproductive health of the offspring. The reproductive system is complex and requires a timeline of normal development and function of the reproductive tissues (i.e., brain, pituitary, ovary, testes, and uterus), key reproductive hormones (i.e., estrogens, androgens, progesterone, luteinizing hormone, and follicle-stimulating hormone), and reproductive sex behaviors (i.e., male and female sexual interest, behavioral responsiveness, and partner preference), which may differ by gender and sex. Therefore, the proposed studies will test the hypothesis that exposure to an environmentally relevant phthalate mixture causes earlier subfertility in female offspring than male offspring through mechanisms that involve gender- and sex-specific effects on the brain, pituitary, gonads, uterus, key hormone pathways, and reproductive behaviors. To test this hypothesis, the proposed studies will determine: 1) the effects of prenatal exposure to an environmentally relevant phthalate mixture on the morphology of key reproductive tissues, 2) the effects of prenatal exposure to an environmentally relevant phthalate mixture on hormone production and responsiveness, and 3) the impact of prenatal exposure to an environmentally relevant phthalate mixture on reproductive behaviors and sexual attractiveness. Collectively, the proposed work will determine the mechanisms by which prenatal phthalate exposure causes sex-specific and gender-specific subfertility and reproductive behavior in the offspring. A better understanding of the mechanisms of action of phthalates may lead to the development of novel targets for the treatment of phthalate-induced diseases. It also may lead to the identification of factors that cause sex-specific and gender-specific adverse reproductive outcomes. This could have a major impact on improving the health of women and men, particularly because it currently is not possible to eliminate phthalate exposure.