Short-chain chlorinated paraffins at environmentally relevant doses disrupt glucose homeostasis and insulin signaling by macrophage-mediated inflammation

Short-chain chlorinated paraffins (SCCPs) are ubiquitously distributed in environmental matrices and have been detected in diverse human biospecimens. While high-dose SCCP exposure can induce liver, kidney, and thyroid toxicity, the health risks of SCCPs at environmentally relevant doses remain poorly characterized. This study systematically investigated the impacts of SCCPs at environmentally relevant doses on glucose homeostasis and insulin signaling and explored the underlying mechanisms. It was found that subacute SCCP exposure (1-50 mg/kg bw) compromised insulin and glucose tolerance, increased serum insulin levels, and impaired insulin signaling activity in mouse liver and adipose tissues. The homeostasis model assessment of insulin resistance (HOMA-IR) was increased from 2.53 in control group to 2.98, 3.22, 3.86, and 4.85 in 1, 5, 10, and 50 mg/kg bw SCCP groups, respectively. SCCP exposure triggered inflammation in these tissues, evidenced by macrophage infiltration, nuclear factor kappa B (NF-κB) activation, and upregulated Il6, Il1b, and Tnfa mRNA expression. In vitro experiments employing a hepatocyte-macrophage co-culture system revealed that SCCPs (100 μg/L) -induced insulin resistance in hepatocytes was mediated by activated macrophages. Notably, pharmacological NF-κB inhibitor (JSH-23) and cytokine neutralization (IL6 and IL1β) significantly ameliorated SCCP-induced insulin resistance in hepatocytes. These findings reveal insulin signaling as a previously unrecognized sensitive target of SCCP exposure at environmentally relevant doses and identify macrophage-mediated inflammation as a pivotal mechanism. This study only addressed the subacute effects of SCCP exposure on insulin signaling in male mice. The effects of chronic SCCP exposure on insulin signaling and potential gender differences warrant further investigation.