Perinatal exposure to 2-Ethylhexyl Diphenyl Phosphate (EHDPHP) affected the metabolic homeostasis of male mouse offspring: Unexpected findings help to explain dose- and diet- specific phenomena

Abstract The environmental health risks of a new type of organophosphate flame retardant, 2-ethylhexyl diphenyl phosphate (EHDPHP), which is present in large quantities in various Nordic foods, have attracted the attention of scientists recently. In this study, the metabolic homeostasis of low-fat diet (LFD) and high-fat diet (HFD) fed male mice offspring was assessed after perinatal exposure to two doses (30 μg/kg bw/day and 300 μg/kg bw/day) of EHDPHP. Perinatal exposure to EHDPHP resulted in weight changes in male mice offspring, altered glucose tolerance and induced liver damage, and surprisingly these changes were dose- and diet- specific. Then the 1H NMR-based metabolomics, 16S rRNA sequencing, and qRT-PCR techniques were used to explore the mechanisms of these specific changes. The results indicate that the increase in short-chain fatty acids and the increase in Clostridium in the high-dose group may be responsible for the dose-specificity, while the attenuation of the purine metabolic pathway and the decrease in glutamine levels in the HFD group are accountable for the diet-specificity. In addition, down-regulation of PPARG (peroxisome proliferator-activated receptor gamma) gene expression levels might have caused the decrease in body weight in the H + HFD (high dose exposure with HFD feeding) group. Over all, these results elucidated the effects of dosage and diet on the toxicology of EHDPHP.