Co-exposure to bisphenol a and arsenic enhance hepatotoxicity in zebrafish by targeting the hypothalamic-pituitary-thyroid axis and PPAR pathway.

The worldwide production of bisphenol A (BPA) has doubled over the last two decades, reaching around 6.2 million tons in 2020, with a continuing rise. In contrast, arsenic (As) persists as a prevalent geogenic and anthropogenic contaminant in both global drinking water and surface water. Both substances are recognized as metabolic disruptors, targeting the liver with overlapping effects. Nonetheless, the combined hepatotoxic impacts of these substances and the molecular mechanisms involved remain inadequately understood. In this study, zebrafish, a widely acknowledged vertebrate model sharing significant genetic similarities with humans, was utilized to explore the separate and combined hepatotoxic effects of BPA and As, as well as the associated molecular mechanisms. Following a 28-day exposure, BPA and/or As induced marked hepatic damage, characterized by histopathological alterations, impaired liver function, oxidative stress, and dysregulated lipid metabolism. Notably, co-exposure to BPA and As amplified oxidative stress and lipid metabolic dysfunction, indicating enhanced toxicity under the combined treatment. Additionally, BPA and/or As exposure perturbed the hypothalamic‒pituitary‒thyroid (HPT) axis, as demonstrated by significantly decreased levels of thyrotropin-releasing hormone (TRH), thyroid‒stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4), accompanied by dysregulated expression of HPT axis-related genes (e.g., trα and trβ). Transcriptomic profiling of the liver implicated disruption of the peroxisome proliferator-activated receptor (PPAR) signaling pathway as a key contributor to oxidative stress and lipid metabolism dysregulation. Collectively, these findings reveal that BPA and As promote hepatotoxicity in zebrafish, likely through concurrent disruption of the HPT axis and the PPAR signaling pathway. This study provides novel mechanistic insights into the combined hepatotoxic effects of BPA and As, underscoring the importance of evaluating co-exposure risks in environmental and toxicological assessments.