Gassman Natalie R, Coskun Erdem, Jaruga Pawel, Dizdaroglu Miral, Wilson Samuel H
Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
Environ Health Perspect. 2016 Aug;124(8):1241-52. doi: 10.1289/EHP237. Epub 2016 Apr 15.
Exposure to bisphenol A (BPA) has been reported to alter global gene expression, induce epigenetic modifications, and interfere with complex regulatory networks of cells. In addition to these reprogramming events, we have demonstrated that BPA exposure generates reactive oxygen species and promotes cellular survival when co-exposed with the oxidizing agent potassium bromate (KBrO3).
We determined the cellular microenvironment changes induced by co-exposure of BPA and KBrO3 versus either agent alone.
Ku70-deficient cells were exposed to 150 μM BPA, 20 mM KBrO3, or co-exposed to both agents. Four and 24 hr post-damage initiation by KBrO3, with BPA-only samples timed to coincide with these designated time points, we performed whole-genome microarray analysis and evaluated chromatin structure, DNA lesion load, glutathione content, and intracellular pH.
We found that 4 hr post-damage initiation, BPA exposure and co-exposure transiently condensed chromatin compared with untreated and KBrO3-only treated cells; the transcription of DNA repair proteins was also reduced. At this time point, BPA exposure and co-exposure also reduced the change in intracellular pH observed after treatment with KBrO3 alone. Twenty-four hours post-damage initiation, BPA-exposed cells showed less condensed chromatin than cells treated with KBrO3 alone; the intracellular pH of the co-exposed cells was significantly reduced compared with untreated and KBrO3-treated cells; and significant up-regulation of DNA repair proteins was observed after co-exposure.
These results support the induction of an adaptive response by BPA co-exposure that alters the microcellular environment and modulates DNA repair. Further work is required to determine whether BPA induces similar DNA lesions in vivo at environmentally relevant doses; however, in the Ku70-deficient mouse embryonic fibroblasts, exposure to a high dose of BPA was associated with changes in the cellular microenvironment that may promote survival.
Gassman NR, Coskun E, Jaruga P, Dizdaroglu M, Wilson SH. 2016. Combined effects of high-dose bisphenol A and oxidizing agent (KBrO3) on cellular microenvironment, gene expression, and chromatin structure of Ku70-deficient mouse embryonic fibroblasts. Environ Health Perspect 124:1241-1252; http://dx.doi.org/10.1289/EHP237.
据报道，双酚A（BPA）暴露会改变整体基因表达、诱导表观遗传修饰并干扰细胞的复杂调控网络。除了这些重编程事件外，我们还证明，BPA暴露会产生活性氧，并在与氧化剂溴酸钾（KBrO₃）共同暴露时促进细胞存活。
我们确定了BPA与KBrO₃共同暴露相对于单独暴露于任何一种试剂所诱导的细胞微环境变化。
将Ku70缺陷细胞暴露于150μM BPA、20mM KBrO₃或两种试剂共同暴露。在KBrO₃引发损伤后的4小时和24小时，仅BPA处理的样本时间与这些指定时间点一致，我们进行了全基因组微阵列分析，并评估了染色质结构、DNA损伤负荷、谷胱甘肽含量和细胞内pH值。
我们发现，在损伤引发后4小时，与未处理和仅用KBrO₃处理的细胞相比，BPA暴露和共同暴露使染色质短暂浓缩；DNA修复蛋白的转录也减少。在这个时间点，BPA暴露和共同暴露还减少了仅用KBrO₃处理后观察到的细胞内pH值变化。在损伤引发后24小时，暴露于BPA的细胞比仅用KBrO₃处理的细胞染色质浓缩程度更低；共同暴露细胞的细胞内pH值与未处理和用KBrO₃处理的细胞相比显著降低；共同暴露后观察到DNA修复蛋白显著上调。
这些结果支持BPA共同暴露诱导适应性反应，改变微细胞环境并调节DNA修复。需要进一步的研究来确定BPA在环境相关剂量下是否在体内诱导类似的DNA损伤；然而，在Ku70缺陷的小鼠胚胎成纤维细胞中，高剂量BPA暴露与可能促进存活的细胞微环境变化有关。
Gassman NR, Coskun E, Jaruga P, Dizdaroglu M, Wilson SH. 2016. 高剂量双酚A和氧化剂（KBrO₃）对Ku70缺陷小鼠胚胎成纤维细胞的细胞微环境、基因表达和染色质结构的联合作用。环境健康展望124:1241 - 1252；http://dx.doi.org/10.1289/EHP237。
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