Neonicotinoid insecticides triggers mitochondrial bioenergetic dysfunction via manipulating ROS-calcium influx pathway in the liver

Siwen Li; Yang Cao; Qiangwen Pan; Yewei Xiao; Yanling Wang; Xiali Wang; Xinlian Li; Qiuyue Li; Xiaoqing Tang; Bing Ran

doi:10.1016/j.ecoenv.2021.112690

Neonicotinoid insecticides triggers mitochondrial bioenergetic dysfunction via manipulating ROS-calcium influx pathway in the liver

Ecotoxicol Environ Saf. 2021 Aug 20:224:112690. doi: 10.1016/j.ecoenv.2021.112690. Online ahead of print.

Authors

Siwen Li¹, Yang Cao², Qiangwen Pan², Yewei Xiao², Yanling Wang², Xiali Wang², Xinlian Li², Qiuyue Li², Xiaoqing Tang², Bing Ran³

Affiliations

¹ Department of Physiology, College of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, Sichuan, PR China. Electronic address: lisiwen0529@163.com.
² Department of Physiology, College of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, Sichuan, PR China.
³ Department of Physiology, College of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, Sichuan, PR China. Electronic address: rbfx@163.com.

PMID: 34425541
DOI: 10.1016/j.ecoenv.2021.112690

Abstract

Extensive use of neonicotinoids insecticides (NNIs) rapidly garnered widespread attention in the toxicology, since they have been found in human samples, including urine, blood, breast milk and hair. However, the precise mechanism is not completely clear regarding the NNIs-induced hepatotoxicity. In this study, we exposed male mice to three neonicotinoids (dinotefuran (DIN), nitenpyram (NIT) and acetamiprid (ACET) for 30 days. Our results showed that NNIs remarkably induced morphological damage in the liver. Simultaneously, we found that three neonicotinoids could activate the store operated Ca²⁺ entry (SOCE) in the liver. Further results confirmed that reactive oxide species (ROS) scavenger n-acetylcysteine (NAC) attenuated DIN-induced calcium ion (Ca²⁺) overload and S-phase arrest via restoring protein expression of SOCE and S phase related genes in L02 hepatocytes. Moreover, we found that NAC obviously combated mitochondrial dysfunction caused by DIN via restoring mitochondrial membrane potential. Meanwhile, DIN treatment significantly increased pyruvate content, impaired the activities of tricarboxylic acid (TCA) cycle rate-limiting enzymes and inhibited adenosine triphosphate (ATP) generation, but these effects were reversed by Serca specific activator CDN1163. Collectively, perturbation of redox states can be recognized as the center of S-phase arrest and Ca²⁺ overload after NNIs exposure. In this regard, Ca²⁺ homeostasis dysregulation is a causative event of mitochondrial bioenergetic dysfunction in the liver. These data provides a new perspective for understanding NNI-induced hepatotoxicity mechanisms.

Keywords: Calcium ion (Ca(2+)); Hepatotoxicity; Mitochondrial bioenergetic dysfunction; Neonicotinoids insecticides (NNIs); Reactive oxide species (ROS).