DDT exposure induces cell cycle arrest and apoptosis of skin fibroblasts from Indo-Pacific humpback dolphin via mitochondria dysfunction
DDT exposure induces cell cycle arrest and apoptosis of skin fibroblasts from Indo-Pacific humpback dolphin via mitochondria dysfunction
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DDT暴露通过线粒体功能障碍诱导印度太平洋座头海豚皮肤成纤维细胞的细胞周期停滞和凋亡
DOI：
10.1016/j.aquatox.2019.105229
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发表时间：
2019
影响因子：
4.5
通讯作者：
Wu Yuping
中科院分区：
文献类型：
--
作者：
Yu Xinjian;Yu Ri-Qing;Zhang Xiyang;Zhan Fengping;Sun Xian;Wu Yuping
虽然1，1，1-三氯-2，2-双（4-氯苯基）乙烷（p，p '-DDT）的全球使用已被禁止，但其在环境中的持久性已导致海洋哺乳动物长期接触。我们的前期研究表明，中国珠江口海域中华白海豚体内存在着极高的滴滴涕残留水平。然而，p，p '-DDT对海豚毒性的分子机制在很大程度上是未知的。本研究首次探索p，p '-DDT对海豚皮肤成纤维细胞（ScSFs）的细胞毒性效应，以加深对DDT细胞和分子调控作用的认识。ScSF细胞暴露于p '-DDT（28 μM）24、48和72 h。暴露显着降低ScSF细胞的活力，可能是由于协同作用的细胞周期阻滞和细胞凋亡通过DNA损伤和线粒体功能障碍。细胞内活性氧（ROS）增加，线粒体膜电位改变，细胞内ATP水平降低，细胞周期蛋白激酶（CDK 1、CDK 4）、细胞周期蛋白B1（cyclin B1）、细胞周期蛋白D1（cyclin D1）和凋亡调节因子Bcl-2表达降低，细胞色素c释放，caspase-3、caspase-8和caspase-9活化，可能是导致DNA损伤和线粒体功能障碍的原因。caspase抑制剂对p，p '-DDT诱导的ScSF细胞凋亡具有保护作用，提示caspase在p，p'-DDT诱导的ScSF细胞凋亡中起重要作用。我们推测细胞凋亡可能在p，p '-DDT暴露诱导的杀细胞效应中起次要作用，但其机制尚不清楚。总之，本研究为p，p '-DDT暴露对海豚皮肤细胞的细胞毒性机制提供了新的证据，并表明p，p'-DDT污染是保护这种海洋哺乳动物的关键健康问题之一。
Although the global use of the 1,1,1-trichloro-2,2-bis (4-chlorophenyl) ethane (p,p’-DDT) has been prohibited, its persistence in the environment has caused long-lasting exposure on marine mammals. Our previous studies revealed exceedingly high residue levels of DDTs in Indo-Pacific humpback dolphins (Sousa chinensis) from the Pearl River Estuary region, China. However, the molecular mechanisms ofp,p’-DDT toxicity on the dolphin are largely unknown. This study conducted the first cytotoxicity effect exploration ofp,p’-DDT on the dolphin skin fibroblasts (ScSFs) to enhance the understanding of the cellular and molecular regulation impacts. ScSF cells were exposed top,p’-DDT (28∼168 μM) for 24, 48 and 72 h. The exposure remarkably decreased viability of ScSF cells, possibly due to the synergetic effects of cell cycle arrest and apoptosis via DNA damage and mitochondria dysfunction. The DNA damage and mitochondria dysfunction were likely triggered by an increase of cellular reactive oxygen species (ROS), alteration in mitochondrial membrane potential, reduction in the cellular ATP levels, decreased expression of the genesCDK1,CDK4,cyclin B1,cyclin D1and apoptosis regulatorBcl-2, release of cytochrome c, and activation of caspase-3, caspase-8 and caspase-9. Moreover, caspase inhibitor displayed protective activity againstp,p’-DDT-induced apoptosis, indicating that caspases played a central role inp,p’-DDT-triggered apoptosis in the ScSF cells. We hypothesize apoptosis likely plays a minor role in cytocidal effects induced byp,p’-DDT exposure, but the mechanisms remain unclear. Overall, this research provides new evidence of the cytotoxic mechanisms underlyingp,p’-DDT exposure on humpback dolphin skin cells, and suggests thatp,p’-DDT contamination is one of key health concern issues for the protection of this marine mammal.