Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing, 100191, China.
Department of Laboratory Animal Science, Health Science Center, Peking University, Beijing, 100191, China.
J Appl Toxicol. 2019 May;39(5):807-819. doi: 10.1002/jat.3769. Epub 2019 Jan 15.
Existing literature pointed out that the liver may be the target organ of toxicity induced by titanium dioxide nanoparticles (TiO NPs) via oral exposure. Gender differences in health effects widely exist and relevant toxicological research is important for safety assessment. To explore the gender susceptibility of TiO NP-induced hepatic toxicity and the underlying mechanism, we examined female and male Sprague-Dawley rats administrated with TiO NPs orally at doses of 0, 2, 10 and 50 mg/kg body weight per day for 90 days. The serum biochemical indicators and liver pathological observation were used to assess hepatic toxicity. We found significant hepatic toxicity could be induced by subchronic oral exposure to TiO NPs, which was more obvious and severe in female rats. No accumulation of TiO NPs in the liver was observed, indicating that hepatic toxicity may not be caused through direct pathways. Oxidized glutathione, lipid peroxidation products increased significantly and reduced glutathione decreased significantly in the liver of rats in repeated TiO NP-exposed groups. Hematological parameters of white blood cells and inflammatory cytokines in serum including interleukin 1α, interleukin 4 and tumor necrosis factor also increased significantly. Indirect pathways through initiating oxidative stress and inflammatory responses were suggested as the possible mechanism of the hepatic toxicity in this experiment. The higher sensitivity to redox homeostasis imbalance and inflammation of female rats may be the main reason for gender differences. Our research suggested that gender should be a susceptible factor for identifying and monitoring long-term oral toxicity of TiO NPs.
现有文献指出，肝脏可能是通过口服暴露于二氧化钛纳米颗粒（TiO NPs）而引起毒性的靶器官。健康影响存在性别差异，相关毒理学研究对于安全性评估很重要。为了探讨 TiO NP 诱导的肝毒性的性别易感性及其潜在机制，我们以 0、2、10 和 50 mg/kg 体重/天的剂量对雄性和雌性 Sprague-Dawley 大鼠进行了 90 天的口服 TiO NPs 处理。通过血清生化指标和肝脏病理观察来评估肝毒性。我们发现，亚慢性口服 TiO NPs 可引起明显的肝毒性，且雌性大鼠更为明显和严重。未观察到 TiO NPs 在肝脏中的积累，表明肝毒性可能不是通过直接途径引起的。在重复 TiO NP 暴露组的大鼠肝脏中，氧化型谷胱甘肽、脂质过氧化产物显著增加，还原型谷胱甘肽显著减少。血清中白细胞的血液学参数和包括白细胞介素 1α、白细胞介素 4 和肿瘤坏死因子在内的炎症细胞因子也显著增加。通过引发氧化应激和炎症反应的间接途径被认为是该实验中肝毒性的可能机制。雌性大鼠对氧化还原平衡失衡和炎症的更高敏感性可能是性别差异的主要原因。我们的研究表明，性别应成为识别和监测 TiO NPs 长期口服毒性的易感因素。
