Diazepam and Its Disinfection Byproduct Promote the Early Development of Nervous System in Zebrafish Embryos

Xiaole Zhao,Jiachen Shi,Kui Zhu,Xiaoyong Huang,Bing Shao,Si Qin

doi:10.1155/2020/8878143

Abstract

The widely used diazepam, as central nervous system inhibitor, has found to be ubiquitous in surface water and drinking water. Moreover, a series of byproducts such as 2-methylamino-5-chlorobenzophenone (MACB) were generated after the chlorine disinfection process. However, little information is available about the neurobiological effects of these emerging chemicals at low doses, especially on infants and children. Here, we exposed zebrafish (Danio rerio) embryos to diazepam and MACB at 0.05, 0.5, and 5 nM, which were equivalent to environmental levels. Both diazepam and MACB increased the somite number and promoted nervous development of transgenic zebrafish [Tg (elavl3: EGFP) larvae] at 72 hours postfertilization ( hpf). Both diazepam and MACB also disrupted the homeostasis of adenosine monophosphate, valine, methionine, and fumaric acid in zebrafish embryos at 12 hpf. Additionally, the locomotor behavior activity of zebrafish was significantly enhanced after 120-hour sustained exposure to diazepam or MACB. Moreover, the mRNA expression levels of oct4, sox2, and nanog, modulating the pluripotency and self-renewal, were upregulated by diazepam and MACB in zebrafish embryo. Altogether, diazepam and MACB stimulate developmental neurogenesis and may induce neuronal excitotoxicity at quite low doses. These results indicated that the chronic exposure to psychoactive drugs may pose a potential risk to the development of the nervous system in infancy.

Highlights

Drinking water pollution by pharmaceuticals and personal care products (PPCPs) poses global concerns since it exhibit pharmacological action potencies even at low concentrations [1,2,3]
We found that developmental rates of somite were different among groups (Figure 1(a))
Previous studies have shown that DZP and MACB at drinking water pollution level interfere with the neurodevelopment of juvenile fish; we further explored the behavioral effect of DZP and MACB on the larval fish using the dark-light test [32, 33]

Summary

Introduction

Drinking water pollution by pharmaceuticals and personal care products (PPCPs) poses global concerns since it exhibit pharmacological action potencies even at low concentrations [1,2,3]. The offspring of Wistar rats presented neurobehavioral toxicity after prenatal exposure to different doses of DZP, manifesting as early physiological development and delayed neurobehavioral development [14], the malformation evidences for newborns when maternal exposed to diazepam are of contradictory [13]. Few information is available on adverse effects of DZP at low-dose exposure. There is little information on the developmental and ethological effects of the DZP and MCAB at low-dose exposure for newborn and infant, MACB was predicted to be more likely to accumulate in nervous system and toxic/mutagenic than the precursor drug base on quantitative structure-activity relationship [24]. The transcription factors in the pluripotency regulatory network were upregulated in the treated zebrafish embryo These findings supported the notion that psychoactive drugs at environmental concentration posed a serious risk to the neurodevelopment of infancy

Materials and Methods

Results

Discussion

Conclusion

Conflicts of Interest