National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA.
Environ Health Perspect. 2009 Nov;117(11):1664-72. doi: 10.1289/ehp.0900758. Epub 2009 May 15.
Diverse environmental contaminants, including the plasticizer di(2-ethylhexyl)phthalate (DEHP), are hepatocarcinogenic peroxisome proliferators in rodents. Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activation and its sequelae have been proposed to constitute a mode of action (MOA) for hepatocarcinogenesis by such agents as a sole causative factor. Further, based on a hypothesized lower sensitivity of humans to this MOA, prior reviews have concluded that rodent hepatocarcinogenesis by PPAR-alpha agonists is irrelevant to human carcinogenic risk.
Herein, we review recent studies that experimentally challenge the PPAR-alpha activation MOA hypothesis, providing evidence that DEHP is hepatocarcinogenic in PPAR-alpha-null mice and that the MOA but not hepatocarcinogenesis is evoked by PPAR-alpha activation in a transgenic mouse model. We further examine whether relative potency for PPAR-alpha activation or other steps in the MOA correlates with tumorigenic potency. In addition, for most PPAR-alpha agonists of environmental concern, available data are insufficient to characterize relative human sensitivity to this rodent MOA or to induction of hepatocarcinogenesis.
Our review and analyses raise questions about the hypothesized PPAR-alpha activation MOA as a sole explanation for rodent hepatocarcinogenesis by PPAR-alpha agonists and therefore its utility as a primary basis for assessing human carcinogenic risk from the diverse compounds that activate PPAR-alpha. These findings have broad implications for how MOA hypotheses are developed, tested, and applied in human health risk assessment. We discuss alternatives to the current approaches to these key aspects of mechanistic data evaluation.
包括增塑剂邻苯二甲酸二（2-乙基己基）酯（DEHP）在内的各种环境污染物是啮齿动物中的肝致癌物过氧化物酶体增殖物激活受体-α（PPAR-α）激活物。过氧化物酶体增殖物激活受体-α（PPAR-α）的激活及其后果被认为是此类物质作为单一致病因素导致肝癌的作用机制（MOA）的一部分。此外，基于假设人类对这种 MOA 的敏感性较低，先前的综述得出结论认为，PPAR-α 激动剂诱导的啮齿动物肝癌与人类致癌风险无关。
在此，我们回顾了最近的研究，这些研究对 PPAR-α 激活 MOA 假说进行了实验性挑战，提供了证据表明 DEHP 在 PPAR-α 缺失小鼠中具有致癌性，并且在转基因小鼠模型中，MOA 而不是肝癌是由 PPAR-α 激活引起的。我们进一步研究了 PPAR-α 激活的相对效力或 MOA 的其他步骤是否与肿瘤发生效力相关。此外，对于大多数具有环境关注的 PPAR-α 激动剂，可用数据不足以表征人类对这种啮齿动物 MOA 的相对敏感性或诱导肝癌的情况。
我们的综述和分析对假设的 PPAR-α 激活 MOA 作为 PPAR-α 激动剂诱导啮齿动物肝癌的唯一解释提出了质疑，因此，将其作为评估不同激活 PPAR-α 的化合物对人类致癌风险的主要依据的效用提出了质疑。这些发现对 MOA 假说的开发、测试和应用在人类健康风险评估中具有广泛的意义。我们讨论了替代当前方法的方法，以解决这些机制数据评估的关键方面。
