College of Veterinary Medicine, Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou 510642, China.
Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China.
Ecotoxicol Environ Saf. 2021 Sep 1;220:112394. doi: 10.1016/j.ecoenv.2021.112394. Epub 2021 Jun 4.
Arsenic (As) and antimony (Sb) are known as an environmental contaminant with cardiotoxicity properties. The endoplasmic reticulum (ER) is the largest calcium reservoir in the cell, and its calcium homeostasis disorder plays a vital role in endoplasmic reticulum stress (ERS) and apoptosis. The objective of this study was to investigate whether As and Sb induced apoptosis via endoplasmic reticulum stress (ERS) linked to calcium homeostasis disturbance. In this study, thirty-two adult mice were gavage-fed daily with AsO (4 mg/kg), SbCl (15 mg/kg) and co-treat with SbCl (15 mg/kg) and AsO (4 mg/kg) daily for 60 days. It was observed that As or/and Sb caused histopathological lesions and ER expansion of the heart. Meanwhile, the gene expression of ER Ca release channels (RyR2 and IP3R) and calmodulin-dependent protein kinase II (CaMKII) increased while the levels of mRNA and protein of ER Ca uptake channel (SERCA2) downregulated significantly compared to the controls. Then, As or/and Sb induced ERS and triggered the ER apoptotic pathway by activating unfolded protein response (UPR)-associated genes ((PERK, ATF6, IRE1, XBP1, JNK, GRP78), and apoptosis-related genes (Caspase12, Caspase3, p53, CHOP). Above indicators in As + Sb group became more severe than that of As group and Sb group. Overall, our results proved that the cardiotoxicity caused by As or/and Sb might be concerning disturbing calcium homeostasis, which induced apoptosis through the ERS pathway.
砷（As）和锑（Sb）是已知的具有心脏毒性的环境污染物。内质网（ER）是细胞中最大的钙库，其钙稳态紊乱在内质网应激（ERS）和细胞凋亡中起着至关重要的作用。本研究旨在探讨砷和锑是否通过与钙稳态紊乱相关的内质网应激（ERS）诱导细胞凋亡。在这项研究中，32 只成年小鼠每天用砷酸钠（4mg/kg）、三氯化锑（15mg/kg）灌胃，连续 60 天，同时每天用三氯化锑（15mg/kg）和砷酸钠（4mg/kg）共同处理。结果表明，砷或/和锑可引起心脏的组织病理学损伤和内质网扩张。同时，内质网 Ca 释放通道（RyR2 和 IP3R）和钙调蛋白依赖性蛋白激酶 II（CaMKII）的基因表达增加，而内质网 Ca 摄取通道（SERCA2）的 mRNA 和蛋白水平明显下调，与对照组相比。随后，砷或/和锑通过激活未折叠蛋白反应（UPR）相关基因（（PERK、ATF6、IRE1、XBP1、JNK、GRP78）和凋亡相关基因（Caspase12、Caspase3、p53、CHOP）引起 ERS，并触发 ER 凋亡途径。As + Sb 组的上述指标比 As 组和 Sb 组更为严重。总之，我们的结果证明，砷或/和锑引起的心脏毒性可能与干扰钙稳态有关，通过 ERS 途径诱导细胞凋亡。
