The regulatory function of the non-classical estrogen receptor GPR30 in porcine respiratory immunotoxicity induced by environmental exposure level of zearalenone.

BACKGROUND: Co-exposure to zearalenone (ZEA) and pathogenic microorganisms can accelerate the progression of diseases, and the estrogenic activity of ZEA is potentially implicated in immune-related signal transduction mechanisms. The aim of this study is to clarify the respiratory immunotoxicity and estrogen receptor targets of environmentally relevant doses of ZEA. METHODS: We predicted the respiratory immunotoxicity of ZEA using a computer - based toxicology platform and verified these results through in vitro experiments. By integrating molecular docking simulations, transcriptomic data, and protein expression analyses, we assessed the expression, distribution, and binding activity of different types of estrogen receptors in porcine alveolar macrophages. Subsequently, we carried out targeted pharmacological interventions on these receptors and established a porcine model infected with Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) under ZEA exposure conditions to clarify the specific mechanism by which ZEA exerts immunotoxic effects through interaction with estrogen receptors. RESULTS: Under physiological conditions, ZEA induces cellular oxidative stress and inflammatory responses via GPR30. Conversely, in the pulmonary microenvironment established by PRRSV infection, blocking the binding of ZEA to GPR30 leads to excessive activation of the PERK signaling pathway-mediated endoplasmic reticulum stress and subsequent apoptosis, thereby exacerbating viral lung injury. CONCLUSION: This research challenges the traditional view that "ZEA directly generates toxic signals upon binding to estrogen receptors". We have demonstrated the mechanism of the functional modulation of estrogen receptors in the impact of ZEA on respiratory immune toxicity under various pulmonary microenvironments.