Health Risks of Low-Dose Dietary Exposure to Triphenyl Phosphate and Diphenyl Phosphate in Mice: Insights from the Gut–Liver Axis

Abstract

Aryl phosphate esters have been detected throughout the natural environment and in human blood samples, making it important to determine the health risks associated with exposure to triphenyl phosphate (TPHP) and its metabolite diphenyl phosphate (DPHP). Here, C57BL/6J male mice were exposed to TPHP or DPHP for 12 weeks at estimated daily intake doses of 0.1 and 7 μg/kg bw/day. TPHP intake affected the levels of short-chain fatty acids and bile acids in the gut, enhancing the production of 29 medium- and long-chain fatty acids in the liver by 3.72-fold and significantly increasing hepatic lipid and cholesterol levels. Metabolomic and molecular analysis confirmed that elevated liver cholesterol levels persisted after an 8 week recovery period. Gut microbiota-dependent cholesterol alterations were the toxic end points observed in TPHP-fed mice, as supported by the results of fecal microbiota transplantation. In DPHP-fed mice, serotonergic and glutamatergic synapses were simultaneously altered in the liver and intestine, corresponding to the reduction of five brain neurotransmitters (15.4–60.8%). Decreased liver carbohydrate levels and insulin resistance were observed in the DPHP-fed mice. These results suggest that TPHP and DPHP affect metabolism via different toxic modes, mediated through the gut–liver axis, providing novel insights into the mechanisms of organophosphate-ester-mediated metabolic disruption.