非经典雌激素受体GPR30在玉米赤霉素环境暴露诱导的猪呼吸道免疫毒性中的调控作用

Abstract

ZEA induces mild oxidative stress in PAMs under physiological conditions. • The estrogen receptor target of ZEA in PAMs is GPR30 rather than ERα. • Blocking the signal transmission between ZEA and GPR30 aggravates PRRSV infection. • Excessive endoplasmic reticulum stress aggravates PRRSV infection. • GPR30 has a functional regulatory effect in ZEA-induced respiratory immunotoxicity. 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 bind