Health Stream Literature Summary - Issue 56 - December 2009

Elevated ERCC1 gene expression in blood cells associated with exposure to arsenic from drinking water in inner Mongolia.
Mo, J., Xia, Y., Ning, Z., Wade, T.J. and Mumford, J.L. (2009) Anticancer Research, 29(8); 3253-3259.

Chronic exposure to arsenic through ingestion of contaminated drinking water is a major public health concern. Epidemiological studies have shown that long-term exposure to arsenic is associated with a wide range of health effects including increased risks of lung, bladder and skin cancer. The molecular mechanisms of arsenic toxicity and carcinogenesis are not well understood. Arsenic-induced oxidative stress and oxidative DNA damage are apparent in various tissue culture cells of animals and humans with chronic arsenic exposure. DNA damage can be repaired by a number of different DNA repair pathways depending on the nature of the damage. One such pathway is the nucleotide excision repair (NER) pathway which repairs a wide range of structurally unrelated lesions. An essential gene in the NER pathway is excision repair cross complementation group-1 (ERCC1) which encodes a subunit of endonucleases which make the 5-prime incision of DNA damage in NER. ERCC1 expression has been shown to correlate with the capacity for repair of DNA damage, and studies indicate that ERCC1 is inducible by DNA-damaging agents such as arsenic. This study was conducted in the Bayingmormen (Ba Men) region of Inner Mongolia, China, where the residents have been chronically exposed to a wide range of arsenic levels up to 1.8 mg/l for more than 20 years. The majority of the population (more than 80%) consume water from private wells. The relationship between arsenic concentrations in well water and toenail clippings and ERCC1 expression in the blood of Ba Men residents was investigated. It has previously been reported that elevated 8-oxo-guanine DNA glycosylase (OGG1) mRNA levels in blood cells of the exposed individuals are associated with arsenic concentrations in well water in this population. It is known that OGG1 and ERCC1 work in a coordinated way and play important roles in maintaining genomic integrity. The relationship between levels of ERCC1 and OGG1 gene expression was also investigated in this study.

There were 327 Inner Mongolia residents living in the sub-villages who participated in this study. Well water samples were collected and analysed for arsenic concentration prior to participant selection. Study participants were selected according to the following set of criteria: 70% or more individuals with arsenic exposure levels from non-detectable to 200 micro g/l and 30% with arsenic exposure levels greater than 200 micro g/l; approximately equal number of males and females and 30% of smokers and 70% nonsmokers, and age from 11-65 years with exposure of at least 5 years duration. Questionnaires were administered to all participants to obtain demographic information, history of well use, diet, smoking, occupation, pesticide use and medical information. Water samples were collected from each participant's home and analysed for arsenic using inductively coupled plasma mass spectrometry. Toenail samples were collected and analysed for arsenic content. Blood samples were collected to determine mRNA expression levels by real-time PCR.

The arsenic concentrations of the participant's well water ranged from 0.34 to 826 micro g/l with a mean exposure duration of 13 years. There were 76% of participants who had been exposed to arsenic at concentrations of 0.34 to 200 micro g/l and 24% to concentrations of 201-826 micro g/l. ERCC1 gene expression was positively associated with the arsenic level in drinking water (slope =0.313, p=0.0043). Arsenic concentrations in well water and toenails were highly correlated (Spearman r=0.8817, p less than 0.0001). ERCC1 expression was also positively associated with toenail arsenic concentrations (slope =0.474, p=0.0073). When different age groups were analysed separately, the association between ERCC1 mRNA expression and water arsenic was significant in the 19-50 years age group (slope =0.366, p=0.0065) and showed borderline significance in the 50 years and over age group (slope =0.438, p=0.069), while the youngest age group (11-18 years) did not show a statistically significant association. This could be due to the older groups having a higher intake of arsenic-contaminated water and therefore being exposed to greater oxidative stress and the associated DNA repair responses than the younger groups. There was a significant association between ERCC1 expression and water arsenic exposure in males (slope= 0.38, p=0.0264) and females showed borderline significance (slope =0.24, p=0.082). This may be due to a higher degree of outdoor physical activity in males than females and consequent higher drinking water intake. Exposure to UV radiation from sunlight has also been reported to increase ERCC1 expression in humans, and the higher outdoor activity of males and thus higher UV exposure may also play a role. Separate analysis of smokers and non-smokers showed a significant positive association between ERCC1 expression and water arsenic levels in non-smokers and a non-significant but still positive association in smokers. Levels of alcohol use or exposure to pesticides did not appear to affect ERCC1 gene expression. There was a positive correlation between ERCC1 mRNA levels and OGG1 mRNA levels (r =0.275, Spearman r =0.275, p less than 0.0001) suggesting that these genes may be have a common mechanisms of transcription regulation or the same mode of action.

This study showed a positive association of ERCC1 expression with chronic arsenic exposure in humans which suggests that arsenic exposure may induce a DNA damage repair response. This study also demonstrated the usefulness of real-time PCR technology for quantitative gene expression in human epidemiological studies in assessing health effects of environmental contaminants.

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