Alterations of Gut-Derived Melatonin in Neurobehavioral Impairments Caused by Zinc Oxide Nanoparticles

Abstract

Cantao Yang,1,* Zhaohong Lu,1,* Yinyin Xia,1 Jun Zhang,2,3 Zhen Zou,2,3 Chengzhi Chen,1,3 Xiaoliang Wang,4 Xin Tian,5 Shuqun Cheng,1,3 Xuejun Jiang3,6 1Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2Molecular Biology Laboratory of Respiratory Diseases, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 3Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 4Medical Sciences Research Center, University-Town Hospital of Chongqing Medical University, Chongqing, 401331, People’s Republic of China; 5Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 6Center of Experimental Teaching for Public Health, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing, 400016, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuqun Cheng; Xuejun Jiang, Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Number 1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel [phone], Fax [phone], Email [email protected]; [email protected]: The widespread use of zinc oxide nanoparticles (ZnONPs) has raised concerns about its potential toxicity. Melatonin is a neurohormone with tremendous anti-toxic effects. The enterochromaffin cells are an essential source of melatonin in vivo. However, studies on the effects of ZnONPs on endogenous melatonin are minimal. In the present study, we aimed to investigate the effects of ZnONPs exposure on gut-derived melatonin.Methods: In the present study, 64 adult male mice were randomly and equally divided into four groups, and each group was exposed to ZnONPs (0, 6.5, 13, 26 mg/kg/day) for 30 days. Subsequently, the neurobehavioral changes were observed. The effects of ZnONPs on the expression of melatonin-related genes arylalkylamine N-acetyltransferase (Aanat), melatonin receptor1A (Mt1/Mtnr1a), melatonin receptor1B (Mt2/Mtnr1b), and neuropeptide Y (Npy) on melatonin synthesis and secretion in duodenum, jejunum, ileum and colon during day and night were also assessed.Results: The results revealed that oral exposure to ZnONPs induced impairments of locomotor activity and anxiety-like behavior in adult mice during the day. The transcriptional analysis of brain tissues revealed that exposure to ZnONPs caused profound effects on genes and transcriptional signaling pathways associated with melatonin synthesis and metabolic processes during the day and night. We also observed that, in the duodenum, jejunum, ileum and colon sites, ZnONPs resulted in a significant reduction in the expression of the gut-derived melatonin rate-limiting enzyme Aanat, the membrane receptors Mt1 and Mt2 and Npy during the day and night.Conclusion: Taken together, this is the first study shows that oral exposure to ZnONPs interferes with melatonin synthesis and secretion in different intestinal segments of adult mice. These findings will provide novelty insights into the neurotoxic mechanisms of ZnONPs and suggest an alternative strategy for the prevention of ZnONP neurotoxicity.Graphical Abstract: Keywords: gut-derived melatonin, neurobehavioral impairment, transcriptome sequencing, zinc oxide nanoparticle exposure

Keywords

• gut-derived melatonin
• neurobehavioral impairment
• transcriptome sequencing
• zinc oxide nanoparticle exposure