Effects of in utero and lactational exposure to phthalates on reproductive development and glycemic homeostasis in rats

Prenatal exposure to phthalates is associated with reproductive and metabolic systems alterations. We investigated the effects of in utero and lactational exposure to Di-(2-ethyl-hexyl) phthalate (DEHP) and Di-n-butyl phthalate (DBP) on the reproductive system and glycemic homeostasis in male and female offspring of rats. Pregnant rats were exposed to equimolar doses (0.018, 0.18 and 1.8 mmol/kg/day) of DEHP or DBP corresponding to 7, 70, and 700 mg/kg/day for DEHP and 5, 50, and 500 mg/kg/day for DBP, respectively, by oral gavage from gestation day 13 to postnatal day 21, and using canola oil as vehicle control. Male and female offspring were examined for body weight development, external markers of prenatal androgenization and puberty onset, plasma concentrations of glucose and insulin, insulin tolerance (ITT), glucose-stimulated insulin secretion (GSIS), and the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and pancreatic and duodenal homeobox 1 protein (PDX-1). Male and female rats exposed to the highest doses of DEHP and DBP exhibited increased fasting glucose levels. In rats exposed to DEHP 700 mg/kg/day we also observed a reduced glucose decay rate (Kitt) following insulin administration and decreased insulin secretion in the GSIS assay. Male offspring exposed to DEHP 700 mg/kg/day had reduced anogenital distance (AGD) on PDN 4 and delayed preputial separation at puberty, while female offspring exposed to DEHP 70 and 700 mg/kg/day and to the highest DBP dose had delayed vaginal opening. Our results suggest that maternal treatment with DEHP and DBP can induce a wide range of metabolic and reproductive alterations in offspring rats, with more pronounced effects following DEHP exposure.