摘要
目的探讨苯暴露对核因子E2相关因子2(nuclear factor erythroid 2-related factor 2,Nrf2)基因敲除雄性小鼠的生殖毒性及作用机制。方法选择Nrf2基因敲除(Nrf2^(-/-))和野生型(WT)C57BL/6小鼠,通过独立通气笼动态染毒系统建立苯暴露模型,苯染毒浓度分别为0、3.47、34.75 mg/m^(3),染毒情况为6 h/d,6 d/周,共染毒28 d。通过精子形态学分析及睾丸组织病理学评估雄性生殖系统损伤情况,结合基因转录组测序分析,探索其作用机制及潜在的信号通路。结果Nrf2基因敲除加剧了苯暴露诱导的小鼠雄性生殖系统损伤,低剂量(3.47 mg/m^(3))和高剂量(34.75 mg/m^(3))苯染毒组Nrf2^(-/-)小鼠精子畸形率分别增加14.46%和28.31%,精子存活率分别下降8.2%和39.2%;睾丸病理结果显示,Nrf2^(-/-)小鼠睾丸生精小管结构出现异常,管腔直径分别下降57.42、56.61μm,上皮厚度分别减少50.62、37.98μm,并伴有空泡化病变及炎性浸润。WT组在高剂量苯暴露时生精小管上皮细胞排列呈现出紊乱状态,同时精子畸形率显著增加24.49%。上述所有指标差异均有统计学意义(P<0.05)。睾丸转录组学结果显示,药物代谢通路、氧化应激通路和癌症相关通路发生了变化。结论苯暴露可能通过扰动药物代谢、癌症和氧化应激等通路造成Nrf2^(-/-)小鼠的雄性生殖系统损伤,Nrf2在苯暴露中起到保护作用,敲除Nrf2基因会加重苯诱导的小鼠雄性生殖系统损伤。
Objective To investigate the reproductive toxicity effects and mechanisms of benzene exposure in nuclear factor erythroid 2-related factor 2(Nrf2)knockout male mice.Methods Nrf2 knockout(Nrf2^(-/-))and wild-type(WT)C57BL/6 mice were exposed to benzene via an independent ventilation cage dynamic exposure system.The concentrations of benzene were 0,3.47,and 34.75 mg/m^(3) at 6 hours/day,6 days/week,for a total of 28 days.Sperm morphological analysis and testicular histopathology were employed to assess reproductive system damage,complemented by testicular transcriptome sequencing to explore mechanisms and potential signaling pathways.Results Nrf2^(-/-)exacerbated benzene-induced male reproductive system damage in mice.In Nrf2^(-/-)mice exposed to low-dose(3.47 mg/m^(3))and high-dose(34.75 mg/m^(3))benzene,the sperm malformation rate increased by 14.46%and 28.31%,respectively,while the sperm survival rate decreased by 8.2%and 39.2%,respectively.Testicular pathological examination showed structural abnormalities in the seminiferous tubules of Nrf2^(-/-)mice,with reduced lumen diameters of 57.42 and 56.61μm and decreased epithelial thicknesses of 50.62 and 37.98μm,accompanied by vacuolar lesions and inflammatory infiltration.In the WT mice,exposure to high-dose benzene resulted in a disorganized arrangement of seminiferous tubule epithelial cells,with a significant increase in sperm malformation rate by 24.49%.All the above indicators showed statistically significant differences(P<0.05).Transcriptomic analysis identified perturbations in drug metabolism,oxidative stress,and cancer-related pathways.Conclusions Benzene exposure could likely induce reproductive impairment in Nrf2^(-/-)mice through dysregulation of drug metabolism,cancer-related,and oxidative stress pathways.Nrf2 exerts protective effects against benzene-induced reproductive toxicity,and Nrf2 knockout aggravates male reproductive system damage.
作者
周昊
马星宇
高晨
邢秀梅
李道传
ZHOU Hao;MA Xingyu;GAO Chen;XING Xiumei;LI Daochuan(Department of Health Toxicology,School of Public Health,Sun Yat-sen University,Guangdong,Guangzhou 510080,China)
出处
《职业卫生与应急救援》
2025年第5期668-674,共7页
Occupational Health and Emergency Rescue
基金
国家自然科学基金项目(82473670)。
关键词
苯
生殖毒性
NRF2
氧化应激
benzene
reproductive toxicity
Nrf2
oxidative stress
