Non-Lethal Concentration of MeHg Causes Marked Responses in the DNA Repair, Integrity, and Replication Pathways in the Exposed Human Salivary Gland Cell Line.

Lygia Sega Nogueira,Leonardo Oliveira Bittencourt,Maria Sueli Da Silva Kataoka,Rafael Rodrigues Lima,Edivaldo H C De Oliveira,Geovanni Pereira Mitre,Jessica Rodrigues Plaça,Carolina P Vasconcelos

doi:10.3389/fphar.2021.698671

Lygia Sega Nogueira, Leonardo Oliveira Bittencourt + Show 6 more

Open Access

https://doi.org/10.3389/fphar.2021.698671

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Abstract

In Brazilian northern Amazon, communities are potentially exposed and vulnerable to methylmercury (MeHg) toxicity through the vast ingestion of fish. In vivo and in vitro studies demonstrated that the salivary glands as a susceptible organ to this potent environmental pollutant, reporting alterations on physiological, biochemical, and proteomic parameters. However, the alterations caused by MeHg on the gene expression of the exposed human salivary gland cells are still unknown. Therefore, the goal was to perform the transcriptome profile of the human salivary gland cell line after exposure to MeHg, using the microarray technique and posterior bioinformatics analysis. The cell exposure was performed using 2.5 µM MeHg. A previously published study demonstrated that this concentration belongs to a range of concentrations that caused biochemical and metabolic alterations in this linage. As a result, the MeHg exposure did not cause lethality in the human salivary gland cells line but was able to alter the expression of 155 genes. Downregulated genes (15) are entirety relating to the cell metabolism impairment, and according to KEGG analysis, they belong to the glycosphingolipid (GSL) biosynthesis pathway. On the other hand, most of the 140 upregulated genes were related to cell-cycle progression, DNA repair, and replication pathway, or cellular defenses through the GSH basal metabolism. These genomic changes revealed the effort to the cell to maintain physiological and genomic stability to avoid cell death, being in accordance with the nonlethality in the toxicity test. Last, the results support in-depth studies on nonlethal MeHg concentrations for biomarkers identification that interpret transcriptomics data in toxicological tests serving as an early alert of physiological changes in vitro biological models.

Highlights

Methylmercury (MeHg) is an organic form of mercury considered a potent environmental pollutant (Clarkson, 2002)
To deepen the understanding of the mechanisms related to exposure of human salivary gland cells line to MeHg, the present study aimed to investigate the transcriptome profile of these cells after exposure to a nonlethal concentration of MeHg
The cell viability of the human salivary gland cell line exposed to 2.5 μM MeHg indicated a value of 87.5 ± 3.8%, while the nonexposed cells a value of 93.5 ± 0.4%

Summary

Introduction

Methylmercury (MeHg) is an organic form of mercury considered a potent environmental pollutant (Clarkson, 2002). The central nervous system (CNS) is considered the principal target of MeHg due to the high affinity of this metal to the brain (Antunes Dos Santos et al, 2016); in vivo and in vitro studies have demonstrated that the salivary glands and cells from the oral cavity are susceptible to MeHg toxicity (Bittencourt et al, 2017; Farias-Junior et al, 2017; Nogueira et al, 2019; Nascimento et al, 2020; Nogueira et al, 2021). The sub-chronic (35 days) and chronic (60 days) exposure of rats to MeHg-generated oxidative imbalance in the parotid and submandibular glands, by the depression of total antioxidant capacity and increased lipid peroxidation (Bittencourt et al, 2017; Farias-Junior et al, 2017). The MeHg was able to induce changes in the proteomic profile with impairments on structural components of the cytoskeleton, metabolic pathways, and oxidative parameters (Bittencourt et al, 2017)

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