Bisphenol A Promotes Cell Survival Following Oxidative DNA Damage in Mouse Fibroblasts

Bisphenol A (BPA) is a biologically active industrial chemical used in production of consumer products. BPA has become a target of intense public scrutiny following concerns about its association with human diseases such as obesity, diabetes, reproductive disorders, and cancer. Recent studies link BPA with the generation of reactive oxygen species, and base excision repair (BER) is responsible for removing oxidatively induced DNA lesions. Yet, the relationship between BPA and BER has yet to be examined. Further, the ubiquitous nature of BPA allows continuous exposure of the human genome concurrent with the normal endogenous and exogenous insults to the genome, and this co-exposure may impact the DNA damage response and repair. To determine the effect of BPA exposure on base excision repair of oxidatively induced DNA damage, cells compromised in double-strand break repair were treated with BPA alone or co-exposed with either potassium bromate (KBrO3) or laser irradiation as oxidative damaging agents. In experiments with KBrO3, co-treatment with BPA partially reversed the KBrO3-induced cytotoxicity observed in these cells, and this was coincident with an increase in guanine base lesions in genomic DNA. The improvement in cell survival and the increase in oxidatively induced DNA base lesions were reminiscent of previous results with alkyl adenine DNA glycosylase-deficient cells, suggesting that BPA may prevent initiation of repair of oxidized base lesions. With laser irradiation-induced DNA damage, treatment with BPA suppressed DNA repair as revealed by several indicators. These results are consistent with the hypothesis that BPA can induce a suppression of oxidized base lesion DNA repair by the base excision repair pathway.双酚A（Bisphenol A, BPA）是一种具有生物活性的工业化学品，广泛应用于消费品生产。自公众担忧其与肥胖、糖尿病、生殖系统紊乱及癌症等人类疾病存在关联以来，BPA已成为公众密切关注的焦点。近期研究表明，BPA可诱导活性氧（reactive oxygen species）生成，而碱基切除修复（base excision repair, BER）负责清除氧化诱导的DNA损伤。然而，目前尚未有研究探讨BPA与碱基切除修复之间的关联。此外，BPA在环境中无处不在，使得人类基因组持续暴露于BPA之中，同时还会遭遇正常的内源性与外源性基因组损伤刺激，这种联合暴露可能会影响DNA损伤应答与修复过程。为探究BPA暴露对氧化诱导DNA损伤的碱基切除修复的影响，研究人员对双链断裂修复（double-strand break repair）功能受损的细胞分别进行单独BPA处理，或与作为氧化损伤诱导剂的溴酸钾（potassium bromate, KBrO3）联合处理，亦或是与激光照射联合处理。在溴酸钾处理实验中，与BPA联合处理可部分逆转此类细胞中溴酸钾诱导的细胞毒性，这一变化与基因组DNA中鸟嘌呤碱基损伤的增加相吻合。细胞存活率的提升与氧化诱导DNA碱基损伤的增加，与此前针对烷基腺嘌呤DNA糖苷酶（alkyl adenine DNA glycosylase）缺陷细胞的研究结果高度相似，这提示BPA可能会抑制氧化碱基损伤的修复启动过程。在激光照射诱导的DNA损伤实验中，BPA处理经多项检测指标证实可抑制DNA修复。上述研究结果与“BPA可通过碱基切除修复通路抑制氧化碱基损伤的DNA修复”这一假说相一致。