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

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.

Shorter version abstract

The environmental health risks of a new type of organophosphate flame retardant, 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 LFD and 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 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.