Obesity aggravates neurotoxicity of bisphenol A in female rats via endoplasmic reticulum stress mediated death signals.

Abstract

Obesity is a chronic and multifactorial disease, in which activation of endoplasmic reticulum (ER) stress and resulting cell death have been widely implicated leading to the emergence of neurological diseases. Misfolded or unfolded proteins accumulation triggers ER stress, which modulates mitochondrial-associated death signals. Bisphenol A (BPA), an endocrine-disrupting chemical, is known to exert multiple deleterious effects on the brain. However, the influence of pre-established obesity in females on BPA-induced neurotoxicity remains poorly characterized. This study examines whether obesity aggravates the BPA toxicity in the cerebral cortex region of the brain. Rats were divided into five groups: control, HFD (high-fat diet), HFD + BPA, BPA, and thapsigargin (positive control). Obesity was induced by feeding 60% HFD (12 weeks), followed by chronic exposure to BPA (10 ppm in drinking water) for another 12 weeks. Thapsigargin (10 µg; 5 µg on either side) was given intracerebroventricularly 72 h before sacrifice. Transmission electron microscopy (TEM) revealed the deformed morphology of the ER and mitochondria. Expression levels of ER stress-associated proteins (BiP and CHOP) and genes (ATF4 and GADD34) were significantly higher (p < 0.05) in HFD + BPA rats compared to BPA alone. p-eif2α was significantly upregulated (p < 0.05) in all the treated rats as compared to the control. BPA-exposed obese rats had also shown a significantly increased ratio of apoptotic proteins Bax and Bcl2. Our findings suggest that the exacerbation of BPA toxicity through obesity can be attributed to the involvement of ER stress and the mitochondrial death signals it mediates.