Bisphenol chemicals disturb intestinal homeostasis via Notch/Wnt signaling and induce mucosal barrier dysregulation and inflammation

• Published in: The Science of the total environment 2022-07, Vol.828, p.154444-154444, Article 154444
• Main Authors: Zhu, Min, Wei, Rongguo, Li, Yuanyuan, Li, Jinbo, Dong, Mengqi, Chen, Xuanyue, Lv, Lin, Qin, Zhanfen
• Format: Article
• Language: English
• Subjects: Animals; Benzhydryl Compounds - toxicity; Bisphenol A analogues; Cytokines; Homeostasis; Inflammation; Inflammation - chemically induced; Intestinal barrier; Intestines; Male; Mammals; Mice; Notch signaling; Phenols; Wnt signaling; Wnt Signaling Pathway
• ISSN: 0048-9697; 1879-1026
• DOI: 10.1016/j.scitotenv.2022.154444

Emerging evidence has shown that bisphenol A (BPA) can exert adverse effects on intestinal barrier in rodents, but little is known about its underlying mechanisms. We previously found BPA and its substitute bisphenol F (BPF) disrupted Notch signaling and altered intestinal histological structures in Xenopus laevis tadpoles. The present study aimed to determine whether BPA and BPF could affect intestinal homeostasis via Notch/Wnt signaling and induce intestinal barrier dysregulation in adult mammals, given the fundamental roles of the two conserved signaling pathways in intestinal homeostasis and regulation of intestinal barrier. We found that following 7-day administration with BPA or BPF through drinking water at the reference dose of 50 μg/kg/d and no observed adverse effect level of 5 mg/kg/d (NOAEL) of BPA, adult male mice displayed no alterations at histological and cellular levels in colons, but high dose of both BPA and BPF downregulated the expression of Notch- and Wnt-related genes as well as key genes responsible for intestinal homeostasis. When administration was extended to 14 days, all treatments significantly suppressed the expression of all tested Notch- and Wnt-related genes; correspondingly, administrated colons exhibited downregulated expression of key genes responsible for intestinal homeostasis and reduced cell proliferation in crypts. Importantly, all treatments suppressed secretory cell differentiation, reduced mucin protein levels and downregulated expression of tight junction markers, implicating mucosal barrier dysregulation. Furthermore, inflammatory cell infiltration and upregulated expression of inflammatory cytokine genes in colons, coupled with increased serum inflammatory cytokine levels, were observed in all treatments. All results show that both BPA and BPF at the reference dose disrupted Notch/Wnt signaling and intestinal homeostasis, thereby leading to mucosal barrier dysregulation and intestinal inflammation in mice. This is the first study revealing the adverse influences of BPF on mammal intestines and underlying mechanisms for bisphenol-caused intestinal injury. [Display omitted] •BPA and BPF disrupted Notch and Wnt signaling in mouse colons.•BPA and BPF disturbed intestinal stem cell homeostasis and inhibited cell proliferation.•BPA and BPF induced intestinal mucosal barrier dysregulation and inflammation.