Environmental di-(2-ethylhexyl) phthalate exposure accelerates lipid metabolism disorders via the gut-fat axis in male SAMP8 mice: role of gut microbiota and thyroid hormone signaling

Di-(2-ethylhexyl) phthalate (DEHP) is a widely used environmental endocrine disruptor and a potential obesogen. Its pervasive presence in pharmaceutical and personal care products (PPCPs), along with the associated ecological and health risks, has attracted growing scientific concern. Building on our previous findings linking DEHP exposure to an increased risk of obesity in elderly humans, this study investigated the effects of DEHP on lipid metabolism in adipose tissue during aging. Male senescence-accelerated prone (SAMP8) mice were orally administered DEHP (0, 0.2, or 200 mg/kg/day) for five weeks. DEHP exposure significantly increased body weight and induced adipocyte hypertrophy, particularly at the lower dose. It also suppressed systemic energy metabolism and impaired thermogenic function in brown adipose tissue (BAT). In epididymal white adipose tissue (eWAT), DEHP promoted lipid accumulation and disrupted lipidomic profiles. Moreover, DEHP altered gut microbiota composition, reducing α- and β-diversity, and notably increasing the abundance of Prevotellaceae_UCG-001, which was positively correlated with elevated triglyceride levels in eWAT. Concurrently, DEHP exposure downregulated the mRNA and protein expression of deiodinases and thyroid hormone receptors in adipose tissues, indicating suppression of local thyroid hormone signaling. Taken together, these findings demonstrate that DEHP exposure disrupts lipid metabolism via alterations in the gut-fat axis, mediated by gut microbiota dysbiosis and impaired thyroid hormone signaling, ultimately contributing to obesity development in aging SAMP8 mice.