Li Lei, Carratt Sarah, Hartog Matthew, Kovalchik Nataliia, Jia Kunzhi, Wang Yanan, Zhang Qing-Yu, Edwards Patricia, Winkle Laura Van, Ding Xinxin
Wadsworth Center, New York State Department of Health, Albany, New York, USA
Center for Health and the Environment, University of California, Davis (UC Davis), Davis, California, USA
Environ Health Perspect. 2017 Jun 8;125(6):067004. doi: 10.1289/EHP844.
The potential carcinogenicity of naphthalene (NA), a ubiquitous environmental pollutant, in human respiratory tract is a subject of intense debate. Chief among the uncertainties in risk assessment for NA is whether human lung CYP2A13 and CYP2F1 can mediate NA's respiratory tract toxicity.
We aimed to assess the function of CYP2A13 and CYP2F1 in NA bioactivation and NA-induced respiratory tract toxicity in mouse models.
Rates of microsomal NA bioactivation and the effects of an anti-CYP2A antibody were determined for lung and nasal olfactory mucosa (OM) from -null, CYP2A13-humanized, and CYP2A13/2F1-humanized mice. The extent of NA respiratory toxicity was compared among wild-type, -null, and CYP2A13/2F1-humanized mice following inhalation exposure at an occupationally relevant dose (10 ppm for 4 hr).
studies indicated that the NA bioactivation activities in OM and lung of the CYP2A13/2F1-humanized mice were primarily contributed by, respectively, CYP2A13 and CYP2F1. CYP2A13/2F1-humanized mice showed greater sensitivity to NA than -null mice, with greater depletion of nonprotein sulfhydryl and occurrence of cytotoxicity (observable by routine histology) in the OM, at 2 or 20 hr after termination of NA exposure, in humanized mice. Focal, rather than gross, lung toxicity was observed in -null and CYP2A13/2F1-humanized mice; however, the extent of NA-induced lung injury (shown as volume fraction of damaged cells) was significantly greater in the terminal bronchioles of CYP2A13/2F1-humanized mice than in -null mice.
CYP2F1 is an active enzyme. Both CYP2A13 and CYP2F1 are active toward NA in the CYP2A13/2F1-humanized mice, where they play significant roles in NA-induced respiratory tract toxicity. https://doi.org/10.1289/EHP844.
萘（NA）作为一种普遍存在的环境污染物，其在人类呼吸道中的潜在致癌性是一个激烈争论的话题。NA风险评估中主要的不确定性在于人类肺CYP2A13和CYP2F1是否能介导NA的呼吸道毒性。
我们旨在评估CYP2A13和CYP2F1在小鼠模型中对NA生物活化及NA诱导的呼吸道毒性的作用。
测定了来自CYP2A13基因敲除、CYP2A13人源化及CYP2A13/2F1人源化小鼠的肺和鼻嗅黏膜（OM）的微粒体NA生物活化速率以及抗CYP2A抗体的作用。在职业相关剂量（10 ppm，4小时）吸入暴露后，比较了野生型、CYP2A13基因敲除及CYP2A13/2F1人源化小鼠的NA呼吸道毒性程度。
研究表明，CYP2A13/2F1人源化小鼠的OM和肺中的NA生物活化活性分别主要由CYP2A13和CYP2F1贡献。CYP2A13/2F1人源化小鼠对NA的敏感性高于CYP2A13基因敲除小鼠，在NA暴露终止后2或20小时，人源化小鼠的OM中非蛋白巯基的消耗更大且出现了细胞毒性（通过常规组织学可观察到）。在CYP2A13基因敲除和CYP2A13/2F1人源化小鼠中观察到的是局灶性而非广泛性的肺毒性；然而，CYP2A13/2F1人源化小鼠终末细支气管中NA诱导的肺损伤程度（以受损细胞的体积分数表示）显著高于CYP2A13基因敲除小鼠。
CYP2F1是一种活性酶。在CYP2A13/2F1人源化小鼠中，CYP2A13和CYP2F1对NA均有活性，它们在NA诱导的呼吸道毒性中起重要作用。https://doi.org/10.1289/EHP844
