Mechanism of DNA damaging by photo- and metabolic products of carcinogenic ethylbenzene

乙苯是一种在环境中经常检测到的空气污染物。乙苯是一种非致突变致癌物质，其致癌机制尚未阐明。在这项研究中，我们证明了乙苯通过光照或代谢转化为遗传毒性。其潜在机制涉及过氧乙苯和乙基儿茶酚/对苯二酚，它们在与铜的氧化还原反应中产生活性氧物种，并对DNA造成损伤，特别是在5‘连续鸟嘌呤处。我们将这一机制扩展到随后的其他几种环境化学品。1)政府认证的内分泌干扰物--壬基酚在光照射下具有遗传毒性。2)对羟基苯甲酸甲酯是一种广泛使用的防腐剂，在光和新陈代谢的共同作用下被激活。3)增加一个官能团可抑制邻苯二酚对DNA的损伤。这种结构-活性关系对预测化学物质的风险是有用的。DNA损伤活性的关键结构是芳香族羟基化，这对内分泌干扰等其他活动也很重要。4)在阳光照射下，增塑剂表现出潜在的雌激素活性。5)防晒剂在太阳光照射下产生羟基自由基并被激活。6)特殊的羟化作用使黄酮类化合物具有高度的抗雌激素活性。如上所述，这项研究为环境化学品的风险评估提供了许多重要的发现。

Ethylbenzene is an air pollutant detected often in the environment. Ethylbenzene is a non-mutagenic carcinogen and its carcinogenesis mechanism is not elucidated. In this research, we showed that ethylbenzene transformed into genotoxic by light exposure or metabolism. Its underlying mechanism involves peroxiethylbenzene and ethyl catechol/hydroquinone, which generates reactive oxygen species in their redox reaction with Cu and damages DNA especially at 5' of consecutive guanine. We expanded this mechanism to other several environmental chemicals that follows. 1)Nonylphenol, a government-certified endocrine disruptor turned to be genotoxic by light irradiation. 2)Methyl paraben, a widely used preservative, was activated by the combination of light and metabolism. 3)An additional functional group suppressed DNA damage of catechol. This structure-activity relationship is useful to predict the risk of chemicals. The key structure for DNA damaging activity is aromatic hydroxylation and this is important for other activities such as endocrine disruption. 4)Plasticizers revealed its potential estrogenic activity after sunlight exposure. 5)Sunscreens generated hydroxyl radical and activated themselves by sunlight irradiation. 6)A specific hydroxylation made flavonoides highly anti-estrogenic. As stated above, this study provided many important findings for risk assessment of environmental chemicals.