Joint Laboratory of Modern Agricultural Technology International Cooperation, Ministry of Education, Jilin Agricultural University, Changchun 130118, China.
Key Lab of Animal Production, Product Quality and Security, Ministry of Education, College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China.
Int J Mol Sci. 2022 Apr 29;23(9):4948. doi: 10.3390/ijms23094948.
Cadmium (Cd) is a common environmental heavy metal contaminant of reproduction toxicity. Cd accumulation in animals leads to the damage of granulosa cells. However, its mechanism needs to be elucidated. This research found that treating granulosa cells with Cd resulted in reduced cell viability. The flow cytometry results showed that Cd increased the degree of apoptosis and level of superoxide anion (O) in granulosa cells. Further analysis showed that Cd treatment resulted in reduced expression levels of nuclear factor erythroid 2-related factor-2 (Nrf2), superoxide dismutase (SOD), catalase (CAT) and NAD(P)H: quinone oxidoreductase 1 (NQO1), and an increased expression level of malondialdehyde (MDA); the expression levels of Bcl-2 associated X (Bax) and caspase-3 increased, whereas that of B-cell lymphoma 2 (Bcl-2) decreased. Changes in mA methylation-related enzymes were noted with Cd-induced damage to granulosa cells. The results of transcriptome and MeRIP sequencing revealed that the AKT pathway participated in Cd-induced damage in granulosa cells, and the MAX network transcriptional repressor () may be a potential target gene of fat mass and obesity-associated protein (FTO). FTO and YTH domain family member 2 (YTHDF2) regulated expression through mA modification. FTO overexpression alleviated Cd-induced apoptosis and oxidative stress through the activation of the AKT/Nrf2 pathway; this process could be reversed using siMNT. Overall, these findings associated mA with Cd-induced damage to granulosa cells and provided insights into Cd-induced granulosa cell cytotoxicity from a new perspective centered on mA modification.
镉（Cd）是一种常见的环境重金属生殖毒性污染物。动物体内的镉积累会导致颗粒细胞损伤。然而，其机制仍需阐明。本研究发现，用 Cd 处理颗粒细胞会导致细胞活力降低。流式细胞术结果显示，Cd 增加了颗粒细胞的凋亡程度和超氧阴离子（O）水平。进一步分析表明，Cd 处理导致核因子红细胞 2 相关因子 2（Nrf2）、超氧化物歧化酶（SOD）、过氧化氢酶（CAT）和 NAD（P）H：醌氧化还原酶 1（NQO1）的表达水平降低，丙二醛（MDA）表达水平升高；B 细胞淋巴瘤 2（Bcl-2）相关 X（Bax）和半胱天冬酶-3 的表达增加，而 Bcl-2 减少。Cd 诱导颗粒细胞损伤时，观察到 mA 甲基化相关酶的变化。转录组和 MeRIP 测序的结果表明，AKT 途径参与了 Cd 诱导的颗粒细胞损伤，MAX 网络转录抑制因子（）可能是肥胖相关蛋白（FTO）的潜在靶基因。FTO 和 YTH 结构域家族成员 2（YTHDF2）通过 mA 修饰调节表达。FTO 过表达通过激活 AKT/Nrf2 途径缓解 Cd 诱导的细胞凋亡和氧化应激；这一过程可以通过 siMNT 逆转。总之，这些发现将 mA 与 Cd 诱导的颗粒细胞损伤联系起来，从 mA 修饰为中心的新视角提供了对 Cd 诱导颗粒细胞细胞毒性的见解。
