Expression profiles of DNA repair-related genes in rat target organs under subchronic cadmium exposure

Abstract

ABSTRACT. We aimed to evaluate the toxicity of long-term exposure to different cadmium (Cd) doses in rats and expression profiles of DNA repair-related genes. The model rats were exposed to different concentrations of CdCl 2 for 3 months, and 5 DNA repair-related genes -hMSH2, MLH1, XRCC1, hOGG1, ERCC1 -were cloned in different tissues, including the liver, kidney, heart, and lung. Accumulated amounts of Cd were detected in the tissues. Gene and protein detections were conducted via fluorescence quantitative realtime polymerase chain reaction and Western blotting, respectively. Methylated sequences of the 5 DNA repair-related gene promoters were used to investigate whether the low expression levels of the genes were related to methylation of the promoter. In the Cd-exposed group, 3 DNA repair genes (i.e., XRCC1, hOGG1, and ERCC1) significantly decreased in the rat liver, kidney, heart, and lung according to the β-actin internal standard (P < 0.01). Western blotting indicated the same trend for the different tissues. Each of the DNA repair genes had special characteristics; for example, hOGG1 gene expression decreased by 75% in the kidney, and XRCC1 gene expression decreased by 5% in the liver and heart when compared to the control group (P < 0.01). A negative correlation between the DNA repair gene expression levels and the cumulative levels of Cd was also suggested by malignancy pathology. The expression levels of 3 DNA repair genes (i.e., ERCC1, XRCC1, and hOGG1) played an important role in the rat response to Cd exposure but not DNA methylated protection.

Lasting DNA Damage and Aberrant DNA Repair Gene Expression Profile Are Associated with Post-Chronic Cadmium Exposure in Human Bronchial Epithelial Cells

“…Unlike previous studies where most DNA repair genes were reported to be suppressed upon acute or chronic Cd exposure [4,6,7,8,13,29,30], up-regulation of 10 out of 12 DNA repair genes in this study suggests that acute/chronic and post-chronic Cd-exposed cells have different transcriptomic landscapes of DNA repair. Most importantly, the DNA repair transcriptome of the CR0 cells also suggests that chronic Cd exposure has long-term effects on the expression of DNA repair-related genes in human lung cells.…”

“…Cd occurs naturally in the living environment and has been widely used in the field of industry since the beginning of the 1940s [35]. Although the exact molecular mechanisms are not yet fully understood, the potential of acute and chronic Cd exposure to cause cytotoxicity and carcinogenicity has been documented in many experimental and epidemiological studies [10,11,12,13,14,15]. However, knowledge regarding post-chronic Cd exposure is lacking.…”

“…Previously, the expression of many important DNA repair genes (e.g., CRY1 , ERCC1 , LIG4 , MLH1 , MSH2 , MSH6 , MSH7 , OGG1 , PCNA , RAD21 , RAD50 , XRCC1 , and XRCC4 ) in human, animal, or plant cells were found to be suppressed by Cd [6,8,13,29,30]. In Zhou et al, the overexpression of DNA methyltransferase genes ( DNMT1 and DNMT3a ) resulted in the silencing of DNA repair genes ( MSH2 , ERCC1 , XRCC1 , and OGG1 ) in CdCl 2 -transformed human bronchial epithelial 16HBE cells and tumorigenic cells isolated from a xenograft nude mouse model [7].…”

“…In order to better understand the mechanisms of Cd carcinogenesis, one must look at the impacts of Cd on the overall DNA repair systems instead of a single DNA repair enzyme. Also, almost all previous studies on Cd-induced toxicity and carcinogenicity focused only on examining the effects of either acute [10,11,12] or chronic [13,14,15] Cd exposure but have neglected the potential implications of post-chronic Cd exposure on human health.…”

Diethylnitrosamine aggravates cadmium-induced hepatorenal oxidative damage in prepubertal rats

“…The mechanisms identified to be associated with Cd-induced toxicity are multifactorial. Previous experimental data clearly demonstrated the ability of Cd to elicit indirect cellular oxidative damage resulting in induction of cellular proliferation, inhibition of DNA repair, and apoptotic mechanisms (Binte Hossain et al, 2018;Lei et al, 2015). Noteworthy, oxidative stress is recognized to be the primary molecular basis underpinning Cd-mediated cytotoxicity.…”