Exposure to triphenyl phosphate during pregnancy: The role of gut-bile acids-liver axis on lipid metabolism in male offspring

Abstract

The widespread use of Triphenyl phosphate (TPhP) as a substitute flame retardant in various commercial products has raised global concerns for its health risks. Previously, we found that gestational and lactational TPhP exposure disturbed lipid metabolism and gut microbiota in offspring sex-dependently. In this study, we further explored the prenatal TPhP exposure on lipid metabolism in male offspring, and the role of gut-bile acids-liver axis in it. The results showed that gestational TPhP exposure would induce hyperlipidemia in male offspring, it dose-dependently increased the weight of body and liver, levels of serum lipid, and enlarged lipid droplets in white adipose tissue. The expression of lipid metabolism-related genes was significantly changed in the liver and adipose tissue. The gut microbiome of male offspring was also altered, with different profiles between the low and high dose treatment group. Target bile acids (BAs) metabolites analysis revealed a significant increased levels of primary BAs cholic acid (CA), but decreased levels of chenodeoxycholic acid (CDCA), and decreased levels of the secondary BAs deoxycholic acid (DCA), hyodeoxycholic acid (HDCA), ursodeoxycholic acid (UDCA), and lithocholic acid (LCA) in TPhP treatment group. Measurements of gene expression along the gut-BAs-liver axis showed that the TPhP treatment group had an increase in cholesterol-7alpha-hydroxylase (CYP7A1) and a decrease in apical sodium-dependent bile acid transporter (ASBT), with only the low-dose group exhibiting an increase in carbohydrate response element binding protein (ChREBP). Correlation and mediation analysis highlighted associations of Burkholderiaceae in low-dose treatment group and Erysipelotrichaceae in high dose group with lipid metabolism and BAs metabolites. No consistent correlations were observed in two treatment group. Additionally, Mantel tests did not reveal a consistent correlation between the microbiome network community and lipid metabolism or the gut-bile acids-liver axis. Overall, our findings indicate that gestational TPhP exposure induces hyperlipidemia in male offspring, and while the gut-BAs-liver axis plays a role, other mechanisms warrant further investigation.

Keywords

• Flame retardants
• Gut microbiota
• Gut-bile acids-liver axis
• Lipid metabolism