Systematic transcriptome-wide analysis and validation of tributyltin-induced differential changes in the liver with sex-specific effects

Tributyltin (TBT), a prevalent environmental antiseptic, contaminates seafood, fish, and drinking water, posing health risks. While TBT's hepatic toxicity is well-known, its sex-specific effects on liver function remain poorly understood.

To address this gap, a comprehensive analysis was conducted utilizing the Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription (TaRGET) dataset. Chromatin accessibility changes and transcriptomic alterations were analyzed via ATAC-seq and RNA-seq in liver tissues from TBT-exposed male and female mice. In vitro experiments were performed to validate the key bioinformatic findings.

TBT exposure induced significant chromatin accessibility changes and transcriptomic alterations in male liver compared to female counterparts. Notably, Signal transducer and activator of transcription 3 (STAT3) was identified as a central regulator among differentially expressed genes (DEGs) in male liver cells. Functional validation experiments confirmed that TBT-mediated downregulation of STAT3 impaired liver cell function and contributed to increased hepatotoxicity in males.

Our study highlights significant sex-dependent differences in TBT-induced hepatotoxicity and identifies STAT3 as a critical mediator in male liver cells, providing a novel perspective on the toxicology of TBT.