A growing body of literature has linked early-life exposures to polycyclic aromatic hydrocarbons (PAH) with adverse neurodevelopmental effects. Once in the body, metabolism serves as a powerful mediator of PAH toxicity by bioactivating and detoxifying PAH metabolites. Since enzyme expression and activity vary considerably throughout human development, we evaluated infant metabolism of PAHs as a potential contributing factor to PAH susceptibility. We measured and compared rates of phenanthrene and retene (two primary PAH constituents of woodsmoke) metabolism in human hepatic microsomes from individuals ≤21 months of age to a pooled sample (n = 200) consisting primarily of adults. We used activity-based protein profiling (ABPP) to characterize cytochrome P450 enzymes (CYPs) in the same hepatic microsome samples. Once incubated in microsomes, phenanthrene demonstrated rapid depletion. Best-fit models for phenanthrene metabolism demonstrated either 1 or 2 phases, depending on the sample, indicating that multiple enzymes could metabolize phenanthrene. We observed no statistically significant differences in phenanthrene metabolism as a function of age, although samples from the youngest individuals had the slowest phenanthrene metabolism rates. We observed slower rates of retene metabolism compared with phenanthrene also in multiple phases. Rates of retene metabolism increased in an age-dependent manner until adult (pooled) metabolism rates were achieved at ∼12 months. ABPP identified 28 unique CYPs among all samples, and we observed lower amounts of active CYPs in individuals ≤21 months of age compared to the pooled sample. Phenanthrene metabolism correlated to CYPs 1A1, 1A2, 2C8, 4A22, 3A4, and 3A43 and retene metabolism correlated to CYPs 1A1, 1A2, and 2C8 measured by ABPP and vendor-supplied substrate marker activities. These results will aid efforts to determine human health risk and susceptibility to PAHs exposure during early life.

中文翻译：

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基于活性的蛋白质分析，探讨细胞色素 P450 酶与两种多环芳烃 (PAH)：菲和 Retene 的早期代谢之间的关系


越来越多的文献将生命早期接触多环芳烃 (PAH) 与神经发育不良影响联系起来。一旦进入体内，新陈代谢通过对 PAH 代谢物进行生物激活和解毒，成为 PAH 毒性的强大介质。由于酶的表达和活性在整个人类发育过程中存在很大差异，因此我们将婴儿的多环芳烃代谢评估为多环芳烃易感性的潜在影响因素。我们测量并比较了 21 个月以下个体和主要由成年人组成的混合样本 (n = 200) 的人肝微粒体中菲和瑞烯（木烟的两种主要 PAH 成分）的代谢率。我们使用基于活性的蛋白质分析 (ABPP) 来表征相同肝微粒体样品中的细胞色素 P450 酶 (CYP)。一旦在微粒体中孵育，菲就会迅速耗尽。菲代谢的最佳拟合模型显示出 1 相或 2 相（具体取决于样品），表明多种酶可以代谢菲。我们观察到菲代谢随年龄的变化没有统计学上的显着差异，尽管来自最年轻个体的样本具有最慢的菲代谢率。我们在多个阶段也观察到与菲相比，视网膜代谢速率较慢。视网膜代谢率以年龄依赖性方式增加，直到约 12 个月时达到成人（合并）代谢率。 ABPP 在所有样本中识别出 28 种独特的 CYP，并且我们观察到与合并样本相比，≤21 个月大的个体中活性 CYP 的含量较低。 通过 ABPP 和供应商提供的底物标记物活性测量，菲代谢与 CYP 1A1、1A2、2C8、4A22、3A4 和 3A43 相关，而 retene 代谢与 CYP 1A1、1A2 和 2C8 相关。这些结果将有助于确定人类健康风险和生命早期对多环芳烃暴露的易感性。