Exploring aryl hydrocarbon receptor (AhR) as a target for Bisphenol-A (BPA)-induced pancreatic islet toxicity and impaired glucose homeostasis: Protective efficacy of ethanol extract of Centella asiatica

Toxicology. 2023 Dec:500:153693. doi: 10.1016/j.tox.2023.153693. Epub 2023 Nov 30.

Abstract

The estrogenic impact of Bisphenol-A (BPA), a widely recognized endocrine disruptor, causes disruption of pancreatic β-cell function through estrogen receptors (ERs). While BPA's binding affinity for ERs is significantly lower than that of its natural counterpart, estrogen, recent observations of BPA's affinity for aryl hydrocarbon receptor (AhR) in specific cellular contexts have sparked a specific question: does AhR play a role in BPA's toxicological effects within the endocrine pancreas? To explore this question, we investigated BPA's (10 and 100 μg/ kg body weight/day for 21 days) potential to activate AhR within pancreatic islets and assessed the protective role of ethanol extract of Centella asiatica (CA) (200 and 400 mg/kg body weight/day for 21 days) against BPA-mediated toxicity in mouse model. Our results indicate that BPA effectively triggers the activation of AhR and modulates its target genes within pancreatic islets. In contrast, CA activates AhR but directs downstream pathways differentially and activates Nrf2. Additionally, CA was observed to counteract the disruption caused by BPA in glucose homeostasis and insulin sensitivity. Furthermore, BPA-induced oxidative stress and exaggerated production of proinflammatory cytokines were effectively counteracted by CA supplementation. In summary, our study suggests that CA influenced AhR signaling to mitigate the disrupted pancreatic endocrine function in BPA exposed mice. By shedding light on how BPA interacts with AhR, our research provides valuable insights into the mechanisms involved in the diabetogenic actions of BPA.

Keywords: Aryl hydrocarbon receptor (AhR); Bisphenol-A (BPA); Centella asiatica; Glucose homeostasis; Insulin resistance.

MeSH terms

  • Animals
  • Benzhydryl Compounds / metabolism
  • Benzhydryl Compounds / toxicity
  • Body Weight
  • Centella* / metabolism
  • Glucose / metabolism
  • Homeostasis
  • Islets of Langerhans*
  • Mice
  • Receptors, Aryl Hydrocarbon / metabolism

Substances

  • Receptors, Aryl Hydrocarbon
  • bisphenol A
  • Benzhydryl Compounds
  • Glucose