Exposure to bisphenol A and sodium nitrate found in processed meat induces endocrine disruption and dyslipidemia through PI3K/AKT/SREBP pathway in zebrafish larvae

Abstract

Meat is a staple in many cultural diets, and the consumption of processed meats has increased significantly worldwide. The widespread use of sodium nitrate (NaNO₃) as a preservative and the unintentional leaching of bisphenol A (BPA) from packaging into meats have raised health concerns. This study evaluates the combined toxicity of BPA and NaNO₃ despite their individual safety assessments. Our findings reveal that coexposure to BPA and NaNO₃ at levels found in processed meats induces mortality and malformations in zebrafish larvae. The combined exposure triggers oxidative stress, lipid peroxidation, dyslipidemia, inflammation, and apoptosis. Network toxicology analysis elucidates the molecular mechanisms underlying metabolic dysfunction caused by these substances. Dysregulation of genes related to thyroid function (tsh-β, dio-1, thr-b) and inflammation (tnf-α, il-1β, il-6, nfκb) was observed in the co-exposure group. Additionally, this group exhibited increased lipid accumulation, elevated cholesterol and triglyceride levels, and dysregulation of essential lipid metabolism genes (srebp2, pcsk9). Co-exposure also impaired larval motility and behavior, evidenced by hypolocomotion and reduced acetylcholinesterase levels. Further gene expression analysis showed increased levels of pi3k and akt, two major signaling molecules. Ultimately, the simultaneous exposure to BPA and NaNO₃ leads to disruptions in the endocrine system and abnormal lipid levels via activating the PI3K/AKT/SREBP pathway.