Academic journal article Environmental Health Perspectives

Family Correlations of Arsenic Methylation Patterns in Children and Parents Exposed to High Concentrations of Arsenic in Drinking Water. (Children's Health Articles)

Academic journal article Environmental Health Perspectives

Family Correlations of Arsenic Methylation Patterns in Children and Parents Exposed to High Concentrations of Arsenic in Drinking Water. (Children's Health Articles)

Article excerpt

We investigated the evidence of a familial contribution to urinary methylation patterns in families ingesting arsenic in drinking water. Arsenic methylation can be assessed by measuring urinary levels of inorganic arsenic (InAs) and its methylated metabolites, monomethylarsonate (MMA), and dimethylarsinate (DMA). Methylation activity is reflected in the ratios: InAs/methylated arsenic (InAs/metAs) and MMA/DMA. Eleven families from Chile were selected because of their long-term exposure to very high levels of arsenic in drinking water (735-762 [micro] g/L). Each family consisted of a father, a mother, and two children. We measured urinary arsenic and its methylated metabolites for each participant (n = 44). The intraclass correlation coefficients showed that 13-52% of the variations in the methylation patterns were from being a member of a specific family. Family correlations were calculated for father-mother, parent-child, and sibling-sibling pairs. Methylation patterns correlated strongly between siblings [r = 0.78 for InAs/metAs, 95% confidence interval (CI), 0.34-0.94; r = 0.82 for MMA/DMA, 95%CI, 0,43-0.95] compared to lower correlations in father-mother pairs (r = 0.18, r = -0.01, respectively), after adjustment for total urinary arsenic, age, and sex. Family correlations were not notably altered when adjustments were made for specific blood micronutrients (methionine, homocysteine, folate, vitamin [B.sub.6], selenium, and vitamin [B.sub.12]) potentially related to methylation. We also report on a family pedigree with high prevalence of arsenic-induced effects. Participants from this family had low InAs/metAs values, which is consistent with increased toxicity of trivalent methylated arsenic species. Despite our small sample size, we observed that methylation patterns aggregate in families and are correlated in siblings, providing evidence of a genetic basis for the variation in arsenic methylation. Larger studies with more extensive pedigrees will need to be conducted to confirm these findings. Key words: arsenic, family correlations, metabolism, methylation, susceptibility, urine, Environ Health Perspect 110:729-733 (2002). [Online 5 June 2002] http://ehpnet1.niehs.nih.gov/docs/2002/110p 729-733chung/abstract.html

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Long-term ingestion of inorganic arsenic causes various health effects, including cancers of the bladder, skin, and lung and development of skin lesions (1). The biotransformation of arsenic in humans occurs through the methylation process. Few data exist that link methylation patterns to arsenic-induced disease (2,3). Although it has been suggested that genetic polymorphisms cause variation in arsenic methylation (4-7), little evidence has been found to substantiate this hypothesis.

Family correlation studies assist in determining whether variations in methylation patterns may be caused by genetic polymorphisms. If genetic factors contribute to arsenic methylation capacity, family studies should demonstrate that siblings have a higher correlation of methylation activity than their parents. The application of family correlation studies such as this was used to determine whether there were genetic polymorphisms in drug methylation systems (8,9).

Ingested inorganic arsenic (InAs) is methylated in two steps, first to monomethylarsenate (MMA) and then to dimethylarsinate (DMA). The total of urinary InAs, MMA, and DMA is considered a biomarker of recent inorganic arsenic exposure (10). Methylation patterns can be assessed by the relative distributions in urine of inorganic arsenic and its metabolites (InAs, MMA, and DMA) (7). The activity of the first methylation step is indicated by the index InAs/methylated arsenic (metAs), the ratio of inorganic arsenic to the sum of methylated arsenic species (MMA + DMA). A high ratio of InAs/metAs indicates poor methylation at the first step. The activity of the second methylation step is represented by the ratio of MMA to DMA (MMA/DMA) (11,12). …

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