Maternal nonylphenol exposure induces offspring intestinal injury and enteric neuronal defects involving proinflammatory macrophage polarization

Nonylphenol (NP), an environmental endocrine disruptor with estrogenic activity, has been reported to exert marked neurotoxic effects. Hirschsprung's disease (HSCR) is a congenital intestinal disease characterized by the absence of enteric neurons in the gut. However, it remains unclear whether maternal exposure to NP would induce HSCR-related intestinal lesions in the offspring. Sprague Dawley rat model of maternal NP exposure during pregnancy was established to explore the effects of prenatal NP exposure on the development of enteric nervous system in offspring. In vivo and in vitro experiments and clinical samples were conducted to explore the underlying mechanisms. Results showed that prenatal NP exposure inhibited proliferation, promoted apoptosis and decreased the number of enteric neurons in offsprings. Prenatal NP exposure promoted the pro-inflammatory polarization of macrophages. NP promoted the pro-inflammatory polarization of macrophages, whereas LINC00294 overexpression attenuated the expression of pro-inflammatory cytokines in NP-treated macrophages. Conditioned medium from NP-treated macrophages inhibited the proliferation and migration of SH-SY5Y cells and promoted apoptosis. LINC00294 overexpression and NF-κB inhibitor in macrophages significantly alleviated SH-SY5Y cells damage induced by NP. In conclusion, maternal NP exposure would induce HSCR-related intestinal injury and enteric neuronal defects in offspring, potentially through NP-mediated pro-inflammatory macrophage polarization via the LINC00294-mediated modulation of NF-κB signaling pathway. These findings deepen our understanding of NP toxicity and provide a theoretical basis for developing rational strategies to reduce its adverse effects on human health.