Sex-Specific Alterations in the Steroidogenic Pathway Following DEHP Exposure in CD1 Mice

Infertility is defined by the World Health Organization (WHO) as the inability of the reproductive system to achieve a clinical pregnancy after one year or more of unprotected sexual intercourse. Di-(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer found in a variety of consumer products, raising concerns due to its widespread presence. Reproductive effects linked to phthalates have been observed in both human and animal studies. In women, phthalate exposure has been associated with an increased risk of pregnancy loss, reduced oocyte yield in IVF patients, and infertility. In men, phthalates have been linked to decreased sperm motility, abnormal sperm morphology, altered reproductive hormones, and infertility. This study investigates whether DEHP exposure affects the steroidogenic pathway in adult female and male CD1 mice, with a focus on sex differences under identical exposure dosages. Adult CD1 mice (60 days post-partum) were exposed to corn oil (control) or varying concentrations of DEHP via oral administration for 10-14 days in females (to account for the estrous cycle) and 12 days in males. The mice were divided into four groups: vehicle control (N=5), 20μg/kg/day (N=5), 200μg/kg/day (N=5), and 1000mg/kg/day (N=5). These doses were selected to reflect general population exposure, workplace exposure, and high-dose exposure. After the final dose, the mice were euthanized (females in the proestrus/estrus stages), and their gonads were collected and snap-frozen for analysis. RNA was extracted from the gonads, followed by cDNA synthesis and qPCR to examine the effects of DEHP on genes involved in the steroidogenic pathway in both the ovaries and testes. Notably, DEHP exposure led to a significant decrease in the expression of Cyp11a1 in the 1000mg/kg/day group (p=0.024), Lhcgr (p=0.028), and Cyp17a1 (p=0.029) in the 200μg/kg/day group, Hsd17b in the 20μg/kg/day (p=0.037) and 1000mg/kg/day (p=0.037) groups, and Hsd3b expression in the 20μg/kg/day group (p=0.014) in female ovaries, compared to controls. However, no significant changes were observed in the testes of male mice treated with DEHP. These results suggest that environmentally relevant DEHP exposure alters the expression of steroidogenic genes differently in males and females, highlighting sex-specific effects in response to the same doses of phthalate exposure. This study advances our knowledge of how endocrine disruptors, such as phthalates, influence human health, specifically by emphasizing the sex-specific differences in their effects. Supported by Midwestern University Biomedical Sciences Program (VR) and Physiology Start-up Funds (EJ) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.