PDF(Pubmed)
Abstract：
Introduction: Cigarette smoke (CS) exacerbates the severity of diseases not only in lungs, but also in systemic organs having no direct contact with smoke. In addition, smoking during pregnancy can have severe health consequences for both the mother and the fetus. Therefore, our aim was to evaluate effects of prenatal exposure to CS on acetaminophen (APAP)-induced acute liver injury (ALI) in offspring. Methods: Female C57BL/6 mice on day 6 of gestation were exposed to mainstream CS (MSCS) at 0, 150, 300, or 600 μg/L for 2 h a day, 5 days a week for 2 weeks using a nose-only exposure system. At four weeks old, male offspring mice were injected intraperitoneally with a single dose of APAP at 300 mg/kg body weight to induce ALI. Results: Maternal MSCS exposure significantly amplified pathological effects associated with ALI as evidenced by elevated serum alanine aminotransferase levels, increased hepatocellular apoptosis, higher oxidative stress, and increased inflammation. Interestingly, maternal MSCS exposure reduced microRNA (miR)-34a-5p expression in livers of offspring. Moreover, treatment with a miR-34a-5p mimic significantly mitigated the severity of APAP-induced hepatotoxicity. Overexpression of miR-34a-5p completely abrogated adverse effects of maternal MSCS exposure in offspring with ALI. Mechanistically, miR-34a-5p significantly decreased expression levels of hepatocyte nuclear factor 4 alpha, leading to down-regulated expression of cytochrome P450 (CYP)1A2 and CYP3A11. Discussion: Prenatal exposure to MSCS can alter the expression of miRNAs, even in the absence of additional MSCS exposure, potentially increasing susceptibility to APAP exposure in male offspring mice.
摘要：
简介：香烟烟雾（CS）不仅会加剧肺部疾病的严重程度，而且在与烟雾没有直接接触的全身器官中也是如此。此外,怀孕期间吸烟会对母亲和胎儿造成严重的健康后果。因此,我们的目的是评估产前接触CS对对乙酰氨基酚(APAP)诱导的子代急性肝损伤(ALI)的影响.方法：将雌性C57BL/6小鼠在妊娠第6天暴露于0、150、300或600μg/L的主流CS（MSCS），每天2h，使用仅鼻子暴露系统，每周5天，持续2周。四周大的时候，雄性后代小鼠腹膜内注射单剂量的300mg/kg体重的APAP以诱导ALI。结果：母体MSCS暴露显著放大与ALI相关的病理效应，如血清丙氨酸转氨酶水平升高所证明，肝细胞凋亡增加，较高的氧化应激，增加炎症。有趣的是,母体MSCS暴露可降低子代肝脏中microRNA（miR）-34a-5p的表达。此外，miR-34a-5p模拟物治疗可显着减轻APAP诱导的肝毒性的严重程度。miR-34a-5p的过表达完全消除了ALI后代中母体MSCS暴露的不利影响。机械上,miR-34a-5p显著降低肝细胞核因子4α的表达水平,导致细胞色素P450（CYP）1A2和CYP3A11的表达下调。讨论：产前暴露于MSCS可以改变miRNA的表达，即使没有额外的MSCS暴露，雄性后代小鼠对APAP暴露的易感性可能增加。
