Short-term exposure to 2,3,6,7-tetrachlorocarbazole induces early serum metabolic disturbance and hepatic lipid remodeling in mice.

Abstract

Polyhalogenated carbazoles (PHCZs), particularly 2,3,6,7-tetrachlorocarbazole (2367-CCZ), are emerging dioxin-like contaminants with bioaccumulation potential, but their early mammalian metabolic effects remain insufficiently understood. Here, male mice were orally exposed to 2367-CCZ for 7 days, and early molecular responses were examined using serum metabolomics followed by liver lipidomics. Untargeted serum metabolomics was first applied to capture systemic metabolic signatures, including lipid-associated metabolic changes. To further resolve hepatic lipid remodeling, a DDA-derived and manually curated liver lipid annotation library was constructed and then used to support high-throughput DIA(HDMSE) lipidomics across exposure groups. No overt changes in body or organ weights were observed, whereas serum metabolomics revealed glutamate/glutathione-related and lipid-associated metabolic responses, with glutathione metabolism showing the strongest nominal serum pathway-level signal. The DDA library-assisted liver lipidomics workflow identified 60 candidate differential lipids and highlighted glycerophospholipid-centered hepatic lipid remodeling as the primary liver response. Additional changes in sphingolipid-related lipids, neutral lipids, oxidized fatty acids, and authentic-standard-confirmed decreases in alpha-linolenic acid and eicosapentaenoic acid further indicated hepatic lipid remodeling and impaired fatty acid homeostasis. Together, these serum and liver omics data indicate early hepatometabolic perturbation and hepatic lipid remodeling in the absence of detectable changes in body or organ weights.

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