Di(2-ethylhexyl) Phthalate (DEHP) Impairs Female Fertility and Promotes Adipogenesis in C3H/N Mice

Background: Di(2-ethylhexyl) phthalate (DEHP) and its metabolites are known to affect lipid metabolism and adipogenesis, mainly by activation of PPARs. Exposure to DEHP has been linked with testicular impairment and male subfertility. However, the effects of DEHP on female reproductive health and metabolism remain to be studied in detail. Objectives: Analysis of dietary DEHP exposure on metabolism and fertility in female mice. Methods: In two independent approaches, female C3H/N mice were exposed via their diet to DEHP [0.05, 5, 500 mg/kg bw/day] for 8 weeks. Food intake, weight gain and litter size were recorded. After exposure, liver, visceral fat, and plasma were analyzed by qRTPCR and ELISA in F0 females (Study I) and F0 dams and their F1 offspring (Study II). Results: In Study I, F0 females had a significant increase in body weight, food intake, and visceral adipose tissue in all exposure groups compared with controls. In liver tissue, PPARα and PPARγ transcripts were significantly changed in the 500mg group. In the same group, PPARγ mRNA was significantly reduced in liver but not in fat tissue. Leptin and FABP4 mRNA were increased in adipose tissue, while adiponectin was decreased. In Study II, we detected a 100% abortion rate in F0 dams in the 500mg group. F1 offspring exposed in utero and during lactation had an increase in visceral fat tissue and body weight. Conclusion: DEHP impaired fertility in high concentrations and increased body weight and visceral fat depots in female C3H/N mice in environmentally relevant dosages. Although DEHP exposure was only in utero and during lactation, metabolic changes induced by DEHP did also occur in the offspring of diet-exposed females.