Low doses of acetyl trihexyl citrate plasticizer promote adipogenesis in hepatocytes and mice

Accumulating epidemiological evidence underscores the association between pervasive environmental factors and an increased risk of metabolic diseases. Environmental chemicals, recognized disruptors of endocrine and metabolic processes, may contribute to the global prevalence of metabolic disorders, including obesity. Acetyl tributyl citrate (ATHC), categorized as a citric acid ester plasticizer, serves as a substitute for di-(2-ethylhexyl) phthalate (DEHP) in various everyday products. Despite its widespread use and the increasing risk of exposure in humans and animals due to its high leakage rates, information regarding the safety of exposure to environmentally relevant doses of ATHC remains limited. This study aimed to investigate the potential impact of ATHC exposure on metabolic homeostasis. Both in vivo and in vitro exposure models were used to characterize the effects induced by ATHC exposure. C57BL/6 J male mice were subjected to a diet containing ATHC for 12 weeks, and metabolism-related parameters were monitored and analyzed throughout and after the exposure period. Results indicated that sub-chronic dietary exposure to ATHC induced an increase in body fat percentage, elevated serum lipid levels, and increased lipid content in the liver tissue of mice. Furthermore, the effect of ATHC exposure on murine hepatocytes were examined and results indicated that ATHC significantly augmented lipid levels in AML12 hepatocytes, disrupting energy homeostasis and altering the expression of genes associated with fatty acid synthesis, uptake, oxidation, and secretion pathways. Conclusively, both in vivo and in vitro results suggest that exposure to low levels of ATHC may be linked to an elevated risk of obesity and fatty liver in mice. The potential implications of ATHC on human health warrant comprehensive evaluation in future studies.