Family correlations of arsenic methylation patterns in children and parents exposed to high concentrations of arsenic in drinking water.

Abstract

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 microg/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 B6, selenium, and vitamin B12 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.

Intraindividual Variability in Arsenic Methylation in a U.S. Population

“…The results of several studies have shown that inherited genetic traits might play an important role in determining individual arsenic methylation patterns (14,(49)(50)(51)(52). In a study of 11 families in Chile, the correlation in %MMA in sibling-sibling pairs, whose genetic make-up is likely very similar, was greater than that in motherfather pairs, who would not necessarily share the same genetic traits (ICC = 0.69, P < 0.01 in sibling-sibling pairs versus an ICC = 0.01, P = 0.97 in mother-father pairs; ref.…”

“…In a study of 11 families in Chile, the correlation in %MMA in sibling-sibling pairs, whose genetic make-up is likely very similar, was greater than that in motherfather pairs, who would not necessarily share the same genetic traits (ICC = 0.69, P < 0.01 in sibling-sibling pairs versus an ICC = 0.01, P = 0.97 in mother-father pairs; ref. 51). In a study of arsenic-exposed residents in Taiwan, subjects with the null genotype of glutathione S-transferase M1 had a higher proportion of urinary arsenic in the inorganic form than those with the non-null genotype (regression coefficient, B = 3.8, SD = 1.9, P < 0.05; ref.…”

Electrocardiogram (ECG) Abnormality Among Residents in Arseniasis-Endemic and Non-Endemic Areas of Southwestern Taiwan – A Study of Gene-Gene and Gene-Environment Interactions

“…There is a long-standing observation of individual variability in susceptibility to arsenic toxicity 4 and this variation may be partly due to differences in age and sex distribution across areas, and also individual arsenic metabolism capabilities 5,6 . Inter-individual differences in the speciation and amounts of arsenic metabolites have been reported among subjects chronically exposed to arsenic 7 and significant genetic determinants of arsenic metabolism was supported by epidemiological study 8 . Toenail and hair arsenic has been reported to provided an integrated measure of internal arsenic exposure 9 .…”

Arsenic- Exposure, Mechanism of Action and Toxicity Analysis: A Prenatal View

“…At high doses of arsenic, the methylation efficiency appears to decrease in humans. It is seen that methylated arsenic species patterns in urine are alike among siblings and parents suggesting that methylation of arsenic is genetically linked (Chung et al 2002). Due to the increase in methylation capability of liver, increased levels of exposure to inorganic arsenic results in more accumulation in soft tissues.…”