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Joyce S. Chung,¹ David A. Kalman,² Lee E. Moore,¹ Michael J. Kosnett,³ Alex P. Arroyo,⁴ Martin Beeris,⁵ D. N. Guha Mazumder,⁶ Alexandra L. Hernandez,¹ and Allan H. Smith¹

¹School of Public Health, University of California, Berkeley, California, USA; ² Department of Environmental Health, University of Washington, Seattle, Washington, USA; ³ Division of Clinical Pharmacology and Toxicology, University of Colorado Health Sciences Center, Denver, Colorado, USA; ⁴Department of Medical Sciences, University of Antofagasta, Antofagasta, Chile; ⁵Cosmo Andino, San Pedro de Atacama, II Region, Chile; ⁶Institute of Post Graduate Medical Education and Research, Calcutta, India

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 µg/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. 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/2002/110p729-733chung/ abstract.html

Address correspondence to A.H. Smith, School of Public Health, 140 Warren Hall, University of California, Berkeley, CA 94720-7360 USA. Telephone: (510) 843-1736. Fax: (510) 843-5539. E-mail: ahsmith@uclink4.berkeley.edu

We thank the participants in Chiu Chiu and the excellent staff support provided by Corporacion de Desarrollo Social de Calama, Chile.

This work was supported by National Institute of Environmental Health Sciences grants P30 ES01896 and P42 ES04705, the University of California's Toxic Substances Research and Teaching Program, and the Center for Occupational and Environmental Health.

Received 4 September 2001 ; accepted 17 December 2002.