Zhu Mingkun, Miao Sasa, Zhou Wenting, Elnesr Shaaban Saad, Dong Xinyang, Zou Xiaoting
Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, The Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang 212018, PR China.
Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, The Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China.
Ecotoxicol Environ Saf. 2021 May;214:112091. doi: 10.1016/j.ecoenv.2021.112091. Epub 2021 Mar 8.
The occurrence of cadmium (Cd) in feed is a major problem in animal health and production. Studies have confirmed that Cd depresses egg production of laying hens, which is closely related to follicular atresia. This study aimed to assess the toxic impacts of Cd on the ovarian tissue, and to examine the mechanism of Cd-induced granulosa cell proliferation and apoptosis. Results from the nitric oxide (NO) and malondialdehyde (MDA) content, total superoxide dismutase (T-SOD), glutathione peroxide (GSH-Px), total nitric oxide synthase (T-NOS) and adenosine triphosphatase (ATPase) activities, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, and hematoxylin-eosin (H & E) staining indicated that excess Cd induced oxidative stress, granulosa cell apoptosis and follicular atresia in the layer ovary. Low-dose Cd exposure (1 μM) induced the granulosa cell proliferation, upregulated the mRNA levels of RSK1 and RHEB, activated FoxO3a, AKT, ERK1/2, mTOR and p70S6K1 phosphorylation, and promoted cell cycle progression from phase G1 to S. However, high-dose Cd exposure (15 μM) induced reactive oxygen species (ROS) generation and cell apoptosis, upregulated the mRNA levels of the inflammatory factors, ASK1, JNK, p38 and TAK1, downregulated the expressions of RSK1 and RHEB genes, and inhibited the phosphorylation of ERK1/2, mTOR and p70S6K1 proteins, and the cell cycle progression. Rapamycin pre-treatment completely blocked the phosphorylation of mTOR and p70S6K1 proteins, and the cell cycle progression induced by 1 μM Cd, and accelerated 15 μM Cd-induced cell apoptosis and cell cycle arrest. The microRNA sequencing result showed that 15 μM Cd induced differential expression of microRNA genes, which may regulate AKT, ERK1/2 and mTOR signaling and cell cycle progression by regulating the activity of G proteins and cell cycle-related proteins. Conclusively, these results indicated that Cd can cause the ovarian damage and follicular atresia, and regulate cell cycle, cell proliferation or apoptosis of granulosa cells through MAPK, AKT/FoxO3a and mTOR pathways in laying hens.
饲料中镉（Cd）的存在是动物健康和生产中的一个主要问题。研究证实，镉会降低蛋鸡的产蛋量，这与卵泡闭锁密切相关。本研究旨在评估镉对卵巢组织的毒性影响，并探讨镉诱导颗粒细胞增殖和凋亡的机制。一氧化氮（NO）和丙二醛（MDA）含量、总超氧化物歧化酶（T-SOD）、谷胱甘肽过氧化物酶（GSH-Px）、总一氧化氮合酶（T-NOS）和腺苷三磷酸酶（ATPase）活性、末端脱氧核苷酸转移酶介导的dUTP生物素缺口末端标记（TUNEL）分析以及苏木精-伊红（H&E）染色结果表明，过量的镉会诱导蛋鸡卵巢氧化应激、颗粒细胞凋亡和卵泡闭锁。低剂量镉暴露（1μM）诱导颗粒细胞增殖，上调RSK1和RHEB的mRNA水平，激活FoxO3a、AKT、ERK1/2、mTOR和p70S6K1磷酸化，并促进细胞周期从G1期进展到S期。然而，高剂量镉暴露（15μM）诱导活性氧（ROS）生成和细胞凋亡，上调炎症因子ASK1、JNK、p38和TAK1的mRNA水平，下调RSK1和RHEB基因的表达，并抑制ERK1/2、mTOR和p70S6K1蛋白的磷酸化以及细胞周期进程。雷帕霉素预处理完全阻断了mTOR和p70S6K1蛋白的磷酸化以及1μM镉诱导的细胞周期进程，并加速了15μM镉诱导的细胞凋亡和细胞周期停滞。微小RNA测序结果表明，15μM镉诱导微小RNA基因差异表达，其可能通过调节G蛋白和细胞周期相关蛋白的活性来调控AKT、ERK1/2和mTOR信号通路以及细胞周期进程。总之，这些结果表明，镉可导致卵巢损伤和卵泡闭锁，并通过丝裂原活化蛋白激酶（MAPK）、AKT/FoxO3a和mTOR信号通路调节蛋鸡颗粒细胞的细胞周期、细胞增殖或凋亡。
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