College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Chifeng Animal Health Supervision Institute, Chifeng County, 024000, PR China.
College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
Chemosphere. 2020 Jun;249:125858. doi: 10.1016/j.chemosphere.2020.125858. Epub 2020 Feb 7.
Cadmium (Cd) has been implicated in the pathogenesis of inflammation, myocardial infarction, angiocardiopathy, even cancers. However, it is unknown that Cd-induced cardiac toxicity through Nrf2-mediate antioxidant defense and Cytochrome P450 (CYP450) system. To ascertain the chemoprevention of Cd-induced cardiac toxicity, total 60 newborn chicks were fed with different doses of Cd (0 mg/kg, 35 mg/kg and 70 mg/kg) for a period of 90 days feed administration. Results indicated Cd exposure caused cardiac histopathology changed and functions abnormal, induced NOS activities raised and cardiac inflammation, triggering inflammation factors (IL-6, IL-8, TNF-α, and NF-κb) upregulation and inhabitation of IL-10. Cd caused increase of total CYP450 and Cytochrome b5 (Cyt b5) contents, while erythromycin N-demethylase (ERND), aminopyrin N-demethylase (APND), aniline-4-hydeoxylase (AH) and NADPH-cytochrome c reductase (NCR) indicated opposite situations with different degrees of reduction in microsomes. The mRNA level of most CYP450s isoforms (CYP1A1, CYP1A2, CYP1A5, CYP1B1, CYP2C18, CYP2C45, CYP3A4, CYP3A7 and CYP3A9) were significantly increase but CYP2D6 expression level changed not obvious. Furthermore, Cd treatment caused increased the peroxidation product (MDA) and HO over accumulation, the decreased of T-AOC accompanied by decreased activity of antioxidant enzymes (T-SOD, GST and GPX). Over accumulation of Cd lead to oxidative stress and activated Nrf2 signal pathway through upregulating pivotal target genes (HO-1, NQO1, GCLC, GCLM and SOD). These findings suggested Cd exposure caused cardiotoxicity through CYP450s enzymes homeostasis disturbance and Nrf2-mediated oxidative stress signal pathways defense. These results may provide new evidence on molecular mechanism of Cd-induced cardiac toxicity.
镉 (Cd) 已被牵连进炎症、心肌梗死、血管心脏病，甚至癌症的发病机制中。然而，镉通过 Nrf2 介导的抗氧化防御和细胞色素 P450 (CYP450) 系统引起心脏毒性的机制尚不清楚。为了确定镉诱导的心脏毒性的化学预防作用，将 60 只新生小鸡用不同剂量的镉 (0mg/kg、35mg/kg 和 70mg/kg) 喂养 90 天。结果表明，镉暴露导致心脏组织病理学改变和功能异常，诱导 NOS 活性升高和心脏炎症，触发炎症因子 (IL-6、IL-8、TNF-α 和 NF-κb) 的上调和 IL-10 的抑制。镉导致总 CYP450 和细胞色素 b5 (Cyt b5) 含量增加，而红霉素 N-脱甲基酶 (ERND)、氨基比林 N-脱甲基酶 (APND)、苯胺-4-羟化酶 (AH) 和 NADPH-细胞色素 c 还原酶 (NCR) 则以不同程度的降低显示出相反的情况。大多数 CYP450 同工型 (CYP1A1、CYP1A2、CYP1A5、CYP1B1、CYP2C18、CYP2C45、CYP3A4、CYP3A7 和 CYP3A9) 的 mRNA 水平显著增加，但 CYP2D6 的表达水平变化不明显。此外，镉处理导致过氧化产物 (MDA) 和 HO 过度积累，T-AOC 减少，抗氧化酶 (T-SOD、GST 和 GPX) 活性降低。镉的积累导致氧化应激，并通过上调关键靶基因 (HO-1、NQO1、GCLC、GCLM 和 SOD) 激活 Nrf2 信号通路。这些发现表明，镉暴露通过 CYP450 酶的内稳态失调和 Nrf2 介导的氧化应激信号通路防御引起心脏毒性。这些结果可能为镉诱导的心脏毒性的分子机制提供新的证据。
