基于氧化应激与细胞凋亡探究双酚A慢性暴露致小鼠肾毒性作用机制

Mechanism of nephrotoxicity induced by chronic exposure of bisphenol A in mice based on oxidative stress and cell apoptosis

摘要:

双酚A (bisphenol A, BPA)被广泛应用于生产环氧树脂和聚碳酸酯塑料等制品，在强酸、强碱或高温条件下，BPA被释放出来，然后渗入环境中。在大多数生物液体中都检测到了不同浓度的BPA，BPA的存在已被证明与许多慢性疾病密切相关，包括慢性肾病(chronic kidney disease, CKD)。然而，关于BPA的有害作用及其对CKD的不良影响知之甚少。为了探讨BPA对动物肾毒性的作用机制，本研究通过向饮水中加入0.01、0.1和1 mg/L的BPA，暴露于雌性小鼠4周后，交配和怀孕的雌性小鼠持续接触BPA，直到断奶；F1代3周龄雄性仔鼠继续口服相同剂量的BPA，持续10周。结果表明，0.1 mg/L和1mg/L BPA处理组小鼠的肾脏损伤严重，血清中肾脏功能指标尿素氮(urea nitrogen, UN)、肌酐(creatinine, CR)和尿酸(uric acid, UA)的含量均发生显著升高(P＜0.05)；肾脏组织形态结构被损害；肾脏抗氧化相关基因在mRNA和蛋白水平上的表达显著降低(P＜0.05)，包括谷胱甘肽硫转移酶(glutathione-S-transferase, GST)、超氧化物歧化酶(superoxide dismutase, SOD)和过氧化氢酶(catalase, CAT)；硫代巴比妥酸反应物(thiobarbituric acid reactive substances, TBARS)的含量和凋亡指数(Caspase-3和Bax/Bcl-1的比值)相关基因和蛋白的表达显著增强。以上研究结果证实，氧化应激和细胞凋亡在BPA慢性暴露诱导的动物肾毒性中起着重要作用。

Abstract:

Bisphenol A (BPA) is widely used to produce epoxy resin and polycarbonate plastic products. In severe cases, these plastics may release BPA, which then infiltrates into the environment. Various concentrations of BPA have been found in most biological fluid. Its presence has been well shown to be closely related to many chronic diseases, including chronic kidney disease (CKD). However, little is known regarding the adverse effects of BPA exposure and its succedent cellular events on CKD. Hence, in the current in vivo study, we aimed to assess the effects of chronic exposure to BPA on animal nephrotoxicity through investigating oxidative stress and apoptosis. Upon exposure to BPA at 0.01, 0.1, and 1 mg/L via drinking water for four weeks, the mated and pregnant females were continuously exposed to BPA until weaning. Subsequently, three weeks old F1-male neonates were also orally challenged with the same three doses of BPA for ten weeks. The results showed that the kidneys of 0.1 and 1 mg/L BPA-treated mice were seriously damaged; the contents of serum renal function indexes and lipid peroxidation products were significantly increased, including urea nitrogen, creatinine, uric acid, and thiobarbituric acid reactive substances; the morphological structure of mouse kidneys was impaired; the expressions of antioxidant-related genes at mRNA and protein levels from mouse kidneys were markedly diminished, including glutathione-S-transferase, superoxide dismutase, and catalase; the expressions of genes and proteins related to apoptosis index (ratio of Bax/Bcl-1 and Caspase-3) were significantly enhanced. The data manifested that cumulative oxidative stress and apoptosis might play an essential role in the animal nephrotoxicity induced by chronic exposure to BPA.