Gestational exposure to short-chain chlorinated paraffins induces sex-specific hepatic steatosis in adult mouse offspring.

Short-chain chlorinated paraffins (SCCPs), ubiquitous persistent organic pollutants, have been increasingly implicated in metabolic disorders; however, their developmental effects on hepatic lipid metabolism in offspring remain poorly understood. This study aimed to investigate whether gestational SCCPs exposure induces hepatic lipid accumulation in adult offspring and elucidate the underlying mechanisms. Pregnant C57BL/6J mice were orally administered SCCPs (0, 1, 10, or 100 mg/kg) from gestational day 0 (GD0) to GD18. At 12 weeks of age, male offspring exposed to the medium dose of SCCPs developed pronounced hepatic steatosis, as evidenced by increased hepatic and serum triglyceride levels and excessive lipid droplet accumulation, whereas female offspring exhibited no significant alterations, indicating a sex-specific and non-monotonic dose-response pattern. Mechanistically, gestational SCCPs exposure markedly upregulated key regulators involved in fatty acid uptake and triglyceride synthesis, including CD36, GPAT4, and DGAT2. In vitro, serum from medium-dose SCCPs-exposed adult male offspring induced lipid accumulation in AML12 hepatocytes, which was significantly attenuated by pharmacological inhibition of CD36. Furthermore, gestational SCCPs exposure was associated with increased PPAR-γ/CD36 pathway in vivo and in vitro, whereas pharmacological inhibition of PPAR-γ suppressed CD36 expression and alleviated lipid accumulation in hepatocytes. Collectively, these findings suggest that gestational SCCPs exposure promotes male-specific hepatic steatosis in adult offspring potentially through PPAR-γ-mediated enhancement of fatty acid uptake and triglyceride synthesis, providing new evidence that early-life SCCPs exposure can developmentally program long-term hepatic metabolic dysfunction.