With the spread of hexavalent chromium [Cr(VI)] contamination, risk of exposure in non-occupational populations is increasing. The liver is the main target organ for Cr(VI) accumulation; however, the effect of long-term Cr(VI) exposure on liver toxicity is largely unknown. In this study, we investigated the effect of chronic Cr(VI) exposure on liver fibrosis and its possible mechanism. Mice were injected with Cr(VI) for two months, and our results showed Cr(VI) treatment caused liver toxicity characterized by liver structure disorganization, liver dysfunction, and antioxidant enzyme system inhibition. The development of liver fibrosis was also found via the emergence of collagen fibril deposition, increased expression of extracellular matrix-related genes, activation of hepatic stellate cells (HSCs) and increase the expression levels of Hedgehog (Hh) signaling pathway-related molecules. To demonstrate the role of Hh signaling in the regulation of Cr(VI)-induced liver fibrosis, genetically modified mice with heterozygous deficiency of Shh (Shh+/-) were used. In the Shh+/- mice, Hh signaling, HSCs activation and liver fibrosis development were all ameliorated. In conclusion, we demonstrated that Cr(VI)-induced liver fibrosis development resulted from Hh pathway-mediated HSCs activation. Our findings strongly suggest that inhibition of Hh pathway may help in the development of new strategies for Cr(VI)-associated liver fibrosis.

中文翻译：

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Hedgehog信号通路激活肝星状细胞调控六价铬诱导的肝纤维化

随着六价铬 [Cr(VI)] 污染的蔓延，非职业人群接触的风险正在增加。肝脏是 Cr(VI) 积累的主要靶器官；然而，长期接触六价铬对肝毒性的影响在很大程度上是未知的。在这项研究中，我们调查了慢性 Cr(VI) 暴露对肝纤维化的影响及其可能的机制。给小鼠注射 Cr(VI) 两个月，我们的结果显示 Cr(VI) 治疗引起肝毒性，其特征是肝结构紊乱、肝功能障碍和抗氧化酶系统抑制。还发现肝纤维化的发展是通过胶原纤维沉积的出现、细胞外基质相关基因的表达增加、激活肝星状细胞 (HSC) 并增加刺猬 (Hh) 信号通路相关分子的表达水平。为了证明 Hh 信号在调节 Cr(VI) 诱导的肝纤维化中的作用，使用了具有 Shh 杂合缺陷 (Shh+/-) 的转基因小鼠。在 Shh+/- 小鼠中，Hh 信号传导、HSC 激活和肝纤维化发展都得到了改善。总之，我们证明了 Cr(VI) 诱导的肝纤维化发展是由 Hh 通路介导的 HSC 激活引起的。我们的研究结果强烈表明，抑制 Hh 通路可能有助于开发针对 Cr(VI) 相关肝纤维化的新策略。使用具有 Shh 杂合缺陷 (Shh+/-) 的转基因小鼠。在 Shh+/- 小鼠中，Hh 信号传导、HSC 激活和肝纤维化发展都得到了改善。总之，我们证明了 Cr(VI) 诱导的肝纤维化发展是由 Hh 通路介导的 HSC 激活引起的。我们的研究结果强烈表明，抑制 Hh 通路可能有助于开发针对 Cr(VI) 相关肝纤维化的新策略。使用具有 Shh 杂合缺陷 (Shh+/-) 的转基因小鼠。在 Shh+/- 小鼠中，Hh 信号传导、HSC 激活和肝纤维化发展都得到了改善。总之，我们证明了 Cr(VI) 诱导的肝纤维化发展是由 Hh 通路介导的 HSC 激活引起的。我们的研究结果强烈表明，抑制 Hh 通路可能有助于开发针对 Cr(VI) 相关肝纤维化的新策略。