Effectiveness of N-Acetylcysteine in the Treatment of Renal Deterioration Caused by Long-Term Exposure to Bisphenol A

Abstract

Human health hazards caused by bisphenol A (BPA), a precursor for epoxy resins and polycarbonate-based plastics, are well documented and are closely associated with mitochondrial impairment and oxidative imbalance. This study aimed to assess the therapeutic efficacy of N-acetylcysteine (NAC) on renal deterioration caused by long-term BPA exposure and examine the signaling transduction pathway involved. Male Wistar rats were given vehicle or BPA orally for 12 weeks then the BPA-treated group was subdivided to receive vehicle or NAC concurrently with BPA for a further 4 weeks, while the vehicle-treated normal control group continued to receive vehicle through to the end of experiment. Proteinuria, azotemia, glomerular filtration reduction and histopathological abnormalities caused by chronic BPA exposure were significantly reduced following NAC therapy. NAC also diminished nitric oxide and lipid peroxidation but enhanced renal glutathione levels, and counteracted BPA-induced mitochondrial swelling, increased mitochondrial reactive oxygen species production, and the loss of mitochondrial membrane potential. The benefit of NAC was related to the modulation of signaling proteins in the AMPK-SIRT3-SOD2 axis. The present study shows the potential of NAC to restore mitochondrial integrity and oxidative balance after long-term BPA exposure, and suggests that NAC therapy is an effective approach to tackle renal deterioration in this condition.

Keywords: N-acetylcysteine; bisphenol A; kidney; long-term exposure; mitochondria; oxidative stress.

Figure 1

Effects of long-term BPA exposure and NAC treatment on (a) blood urea nitrogen; (b) serum creatinine; (c) creatinine clearance; (d) urine protein excretion; (e) urine protein-to-creatinine ratio. Values are mean ± SEM (n = 6 each). Veh: vehicle-treated group; BPA: BPA-treated group; BPA + NAC: BPA plus NAC-treated group. * p < 0.05 vs. their respective values in week 0. ^# p < 0.05 vs. their respective values in week 12.

Figure 2

Histopathological changes following long-term BPA exposure and NAC treatment. The first and second panels show kidney sections stained with hematoxylin and eosin (H&E, 10× and 40×, respectively). The third and last panels show transmission electron micrographs of glomerulus and renal tubules, respectively (Original magnification: 3000×). Veh: vehicle-treated group; BPA: BPA-treated group; BPA + NAC: BPA plus NAC-treated group. Arrows and arrowheads show abnormal glomerulus and apoptotic cells, respectively. The inserted frame is enlarged from the dashed area. The squares within the third panel highlight the morphology of the podocytes, especially the podocyte effacement in the BPA-treated group.

Figure 3

Effects of long-term BPA exposure and NAC treatment on renal oxidative stress. (a) nitric oxide; (b) malondialdehyde; (c) reduced glutathione; (d) superoxide dismutase. Values are mean ± SEM (n = 6). Veh: vehicle-treated group; BPA: BPA-treated group; BPA + NAC: BPA plus NAC-treated group. * p < 0.05 vs. Veh, ^# p < 0.05 vs. BPA.

Figure 4

Effects of long-term BPA exposure and NAC treatment on renal mitochondrial function. (a) ROS production; (b) membrane potential change; (c) mitochondrial swelling. Values are mean ± SEM (n = 6). Veh: vehicle-treated group; BPA: BPA-treated group; BPA + NAC: BPA plus NAC-treated group. * p < 0.05 vs. Veh, ^# p < 0.05 vs. BPA.

Figure 5

Effects of long-term BPA exposure and NAC treatment on renal cortical expressions of apoptotic markers. (a) Bax/Bcl-2; (b) Cleaved/Pro-caspase-3. Values are mean ± SEM (n = 4). Veh: vehicle-treated group; BPA: BPA-treated group; BPA + NAC: BPA plus NAC-treated group. * p < 0.05 vs. Veh, ^# p < 0.05 vs. BPA.

Figure 6

Effects of long-term BPA exposure and NAC treatment on renal cortical expressions of signaling proteins involved in the AMPK-SIRT3-SOD2 axis. (a) pAMPK/AMPK; (b) PGC-1α/β-actin; (c) SIRT3/β-actin; (d) Ac-SOD2/SOD2. Values are mean ± SEM (n = 4). Veh: vehicle-treated group; BPA: BPA-treated group; BPA + NAC: BPA plus NAC-treated group. * p < 0.05 vs. Veh, ^# p < 0.05 vs. BPA.