Hepatic peroxisome proliferator-activated receptor a may have an important role in the toxic effects of di(2-ethylhexyl)phthalate on offspring of mice

Maternal exposure to di(2-ethylhexyl)phthalate (DEHP) is associated with adverse effects on offspring, and the metabolites are agonists of peroxisome proliferator-activated receptor (PPAR) alpha, which exhibits species differences in expression and function. This study aimed to clarify the mechanism of DEHP-induced adverse effects on offspring in relation to maternal mouse and human PPAR alpha. Male and female Sv/129 wild-type (mPPAR alpha), Ppar alpha-null and humanized PPAR alpha (hPPAR alpha) mice were treated with diets containing 0%, 0.01%, 0.05% (medium) or 0.1% (high) DEHP. After 4 weeks, males and females were mated. Dams were killed on gestational day 18 and postnatal day (PND) 2. High-dose DEHP decreased the number of total and live fetuses, and increased resorptions in mPPAR alpha mice. In hPPAR alpha mice, resorptions were increased above the medium dose, and the number of births was decreased at the high dose. The number of live pups on PND2 was decreased over the medium dose in mPPAR alpha and at the high dose in hPPAR alpha mice. No such findings were observed in Ppar alpha-null mice. High-dose DEHP decreased plasma triglyceride in pregnant mPPAR alpha mice, but not in Ppar alpha-null and hPPAR alpha ones. Above the medium dose in mPPAR alpha mice significantly reduced hepatic microsomal triglyceride transfer protein (MTP) expression. Medium-and/or high-dose DEHP increased the levels of maternal PPAR alpha target genes in mPPAR alpha and hPPAR alpha mice. Taken together, PPAR alpha expression is required for the toxicity of DEHP in fetuses and pups and altered plasma triglyceride levels, through regulation of MTP may be important in mPPAR alpha mice and not in hPPAR alpha mice. (C) 2011 Elsevier Ireland Ltd. All rights reserved.