Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA.
Neurotoxicol Teratol. 2012 Sep-Oct;34(5):513-21. doi: 10.1016/j.ntt.2012.06.004. Epub 2012 Jul 2.
Mercury (Hg) is neurotoxic, and children may be particularly susceptible to this effect. A current major challenge is the identification of children who may be uniquely susceptible to Hg toxicity because of genetic disposition. We examined the hypothesis that CPOX4, a genetic variant of the heme pathway enzyme coproporphyrinogen oxidase (CPOX) that affects susceptibility to mercury toxicity in adults, also modifies the neurotoxic effects of Hg in children. Five hundred seven children, 8-12 years of age at baseline, participated in a clinical trial to evaluate the neurobehavioral effects of Hg from dental amalgam tooth fillings in children. Subjects were evaluated at baseline and at 7 subsequent annual intervals for neurobehavioral performance and urinary mercury levels. Following the completion of the clinical trial, genotyping assays for CPOX4 allelic status were performed on biological samples provided by 330 of the trial participants. Regression modeling strategies were employed to evaluate associations between CPOX4 status, Hg exposure, and neurobehavioral test outcomes. Among girls, few significant CPOX4-Hg interactions or independent main effects for Hg or CPOX4 were observed. In contrast, among boys, numerous significant interaction effects between CPOX4 and Hg were observed spanning all 5 domains of neurobehavioral performance. All underlying dose-response associations between Hg exposure and test performance were restricted to boys with the CPOX4 variant, and all of these associations were in the expected direction where increased exposure to Hg decreased performance. These findings are the first to demonstrate genetic susceptibility to the adverse neurobehavioral effects of Hg exposure in children. The paucity of responses among same-age girls with comparable Hg exposure provides evidence of sexual dimorphism in genetic susceptibility to the adverse neurobehavioral effects of Hg in children and adolescents.
汞（Hg）具有神经毒性，儿童可能尤其容易受到这种影响。目前的主要挑战是确定可能由于遗传易感性而对汞毒性特别敏感的儿童。我们检验了一个假设，即血红素途径酶粪卟啉原氧化酶（CPOX）的遗传变异 CPOX4 会影响成年人对汞毒性的易感性，也会改变儿童体内汞的神经毒性作用。507 名 8-12 岁的儿童参加了一项临床试验，以评估儿童从汞合金牙填充物中摄入汞的神经行为影响。在基线和随后的 7 个年度间隔内对儿童进行神经行为表现和尿液汞水平评估。临床试验完成后，对 330 名试验参与者提供的生物样本进行了 CPOX4 等位基因状态的基因分型检测。采用回归建模策略评估 CPOX4 状态、Hg 暴露与神经行为测试结果之间的关联。在女孩中，观察到 CPOX4-Hg 相互作用或 Hg 或 CPOX4 的独立主要作用很少有统计学意义。相比之下，在男孩中，观察到 CPOX4 和 Hg 之间存在许多显著的相互作用效应，涵盖了所有 5 个神经行为表现领域。Hg 暴露与测试表现之间的所有潜在剂量反应关联均限于具有 CPOX4 变异的男孩，并且所有这些关联都在预期方向上，即 Hg 暴露增加会降低表现。这些发现是首次证明儿童对 Hg 暴露的不良神经行为影响存在遗传易感性。具有类似 Hg 暴露的同龄女孩中反应较少，这为儿童和青少年对 Hg 的不良神经行为影响存在遗传易感性的性别二态性提供了证据。
