The epitranscriptomic writer Alkylation Repair Homolog 8 (ALKBH8) is a transfer RNA (tRNA) methyltransferase that modifies the wobble uridine of selenocysteine tRNA to promote the specialized translation of selenoproteins. Using Alkbh8 deficient (Alkbh8^def) mice, we have investigated the importance of epitranscriptomic systems in the response to naphthalene, an abundant polycyclic aromatic hydrocarbon and environmental toxicant. We performed basal lung analysis and naphthalene exposure studies using wild type (WT), Alkbh8^{de f} and Cyp2abfgs-null mice, the latter of which lack the cytochrome P450 enzymes required for naphthalene bioactivation. Under basal conditions, lungs from Alkbh8^def mice have increased markers of oxidative stress and decreased thioredoxin reductase protein levels, and have reprogrammed gene expression to differentially regulate stress response transcripts. Alkbh8^def mice are more sensitive to naphthalene induced death than WT, showing higher susceptibility to lung damage at the cellular and molecular levels. Further, WT mice develop a tolerance to naphthalene after 3 days, defined as resistance to a high challenging dose after repeated exposures, which is absent in Alkbh8^def mice. We conclude that the epitranscriptomic writer ALKBH8 plays a protective role against naphthalene-induced lung dysfunction and promotes naphthalene tolerance. Our work provides an early example of how epitranscriptomic systems can regulate the response to environmental stress in vivo.

转录组作者Alkylation Repair Homolog 8（ALKBH8）是一种转移RNA（tRNA）甲基转移酶，可修饰硒代半胱氨酸tRNA的摆动尿苷以促进硒蛋白的专门翻译。使用Alkbh8缺陷（Alkbh8 ^def）小鼠，我们研究了转录组系统对萘，丰富的多环芳烃和环境毒物的响应的重要性。我们使用野生型（WT），Alkbh8 ^{de f}和Cyp2abfgs-null小鼠进行了基础肺部分析和萘暴露研究，其中后者缺乏萘生物激活所需的细胞色素P450酶。在基础条件下，Alkbh8 ^def 小鼠的氧化应激标记物增加，硫氧还蛋白还原酶蛋白水平降低，并且已经对基因表达进行了重新编程，以差异调节应激反应的转录本。Alkbh8 ^def 小鼠比WT对萘诱导的死亡更敏感，在细胞和分子水平上显示出更高的肺损伤敏感性。此外，WT小鼠在3天后对萘产生耐受性，定义为对反复暴露后高挑战剂量的耐受性，而Alkbh8 ^def则不存在 老鼠。我们得出结论，转录组作者ALKBH8对萘诱导的肺功能障碍具有保护作用，并促进了萘的耐受性。我们的工作提供了一个早期的例子，说明转录组系统如何在体内调节对环境压力的反应。