Individual and combined antagonism of aryl hydrocarbon receptor (AhR) and estrogen receptors (ERs) offers distinct level of protection against Bisphenol A (BPA)-induced pancreatic islet cell toxicity in mice

Bisphenol A (BPA), a pervasive endocrine-disrupting chemical, is known to convey harmful impact on pancreatic islets through estrogen receptors (ERs). Conversely, BPA can activate Aryl Hydrocarbon Receptor (AhR) in certain contexts and has raised concerns about potential toxicological effects. However, BPA-AhR interaction in the context of pancreatic islet toxicity is yet to be reported. We demonstrated the specific role of AhR and its interaction with ERs to mediate BPA toxicity in pancreatic islets. In vitro, isolated islet cells treated with BPA (1 nM), with or without CH22319 (10 mM) and ICI182780 (1 mM) and Insulin release, glucose-stimulated Insulin secretion (GSIS), cell viability, and pERK1/2 and pAkt expression were measured. In vivo, mice were treated with BPA (10 and 100 µg/kg body weight/day for 21 days) with or without intraperitonial co-treatment of CH22319 (AhR antagonist, 10mg/kg), and ICI182780 (ER antagonist, 500 µg/kg). Glucose homeostasis, Insulin resistance, oxidative stress, and inflammatory markers were measured. In vitro data revealed the involvement of AhR in the BPA-mediated alteration in Insulin secretion, GSIS, and pERK1/2 and pAkt expression which were counteracted by CH223191 (AhR antagonist) alone or with ICI182780 (ER antagonist). Further, CH223191 alone or with ICI182780 modulated BPA-induced oxidative stress and pro-inflammatory cytokines and alleviated islet cell dysfunction and impaired Insulin secretion. In conclusion, therapeutic targeting of AhR and ER combined might be a promising target against diabetogenic action of BPA.

Bisphenol A; Estrogen receptor; Insulin resistance aryl hydrocarbon receptor; Islet cell; Oxidative stress.