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The Die Is Cast: Arsenic Exposure in Early Life and Disease Susceptibility David J. Thomas Pharmacokinetics Branch, Integrated Systems Toxicology Division, National Health and Environmental Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27709, United States ABSTRACT: Early life exposure to arsenic in humans and mice produces similar patterns of disease in later life. Given the long interval between exposure and effect, epigenetic effects of early life exposure to arsenic may account for the development and progression of disease in both species. Mode of action and dosimetric studies in the mouse may help assess the role of age at exposure as a factor in susceptibility to the toxic and carcinogenic effects of arsenic in humans.
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CONSEQUENCES OF EARLY LIFE EXPOSURE TO ARSENIC IN HUMANS Epidemiological and laboratory-based studies identify several factors that modify the susceptibility of humans to adverse health effects associated with chronic exposure to arsenic. For example, gender and nutritional status modify the capacity to convert inorganic arsenic into methylated metabolites.1 The AS3MT genotype and haplotype also affect the capacity for enzymatically catalyzed methylation of arsenic and are associated with interinidividual differences in susceptibility to arsenic-induced disease.2,3 To this list of modifiers of response, age at exposure to arsenic can be added. That age at exposure as an important modifier is best illustrated by epidemiological studies from Antofagasta, Chile.4 In this northern Chilean city, a change in drinking water source in 1958 abruptly increased the concentration of inorganic arsenic from about 90 to about 870 parts per billion (ppb). In 1970, the use of an alternate water source reduced the concentration of inorganic arsenic in the city’s water supply to about 110 ppb. Thus, we can identify a cohort of individuals who were born immediately before the rise in the concentration of arsenic in drinking water (born between 1940 and 1957) and a cohort born during the period of elevated exposure (born between 1958 and 1970). Standardized mortality ratios (SMRs) can be used to compare the mortality experience of these two cohorts with that of an age-matched cohort from elsewhere in Chile where arsenic exposure did not follow the unique pattern seen in Antofagasta. Figure 1 shows that in both Antofagasta cohorts SMRs for cancers (urinary bladder, respiratory tract, kidney, liver, and all cancer) and for noncancer diseases (bronchiectasis and other chronic obstructive pulmonary disease, acute myocardial infarction, chronic renal disease, and all noncancer) are all significantly greater than those in the reference population. These results suggest that developing humans exposed to inorganic arsenic in utero or in early life are primed for an increased risk of cancer and other diseases in adult life. Evidence from other population-based studies indicates that developing humans are particularly susceptible to the toxic and carcinogenic effects of arsenic. For example, increased all-cause, This article not subject to U.S. Copyright. Published 2013 by the American Chemical Society
cancer, and cardiovascular disease mortalities are seen in Bangladeshis exposed to inorganic arsenic in utero or in early life.5 In addition, arsenic exposure in utero and/or in early life is linked to increased susceptibility to infection, impaired lung and thymic function, altered ponderal and longitudinal growth, and altered motor function and neurodevelopment.6−11 The protean nature of the effects of arsenic in developing humans suggest that fundamental processes involved in cell growth and differentiation are affected by inorganic arsenic or one of its metabolites. Understanding the biological basis of this increased risk is important to those who make decisions about acceptable levels of exposure in what appears to be an exceptionally susceptible segment of the population.
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CONSEQUENCES OF EARLY LIFE EXPOSURE TO ARSENIC IN THE MOUSE Notably, exposure of developing mice to arsenicals produces an array of adverse health effects that mirror those seen in humans. Although studies of the carcinogenicity of arsenic in adult rodents often yield inconsistent results, arsenite and its metabolite monomethylarsonous acid consistently act as transplacental carcinogens in mice.12−14 In this model, pregnant mice receive drinking water containing up to 85 parts per million (ppm) of arsenic between gestational days 8 and 18 so that exposure is confined to the in utero period. Observation of the offspring of these dams for up to 2 years of age finds that exposure in utero to either arsenical increases tumor incidences in the lung, liver, adrenal cortex, uterus, and ovary. Hence, a restricted period of exposure to an arsenical during early development is sufficient to initiate events that transform cells to a malignant phenotype in later life. In a variation on this model, offspring of ApoE knockout mice exposed to 49 ppm of arsenic in drinking water from gestational day 8 until birth develop early onset cardiovascular disease.15−17 Notably, early onset cardiovascular disease in arsenic-exposed ApoE knockout Received: September 11, 2013 Published: November 5, 2013 1778
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Figure 1. SMRs for men and women 30 to 49 years old who were born in Antofagasta, Chile, before (1940−1957) and during (1958−1970) the period of high exposure to arsenic in the drinking water supply. Reproduced with permission from ref 4.
mice does not require the consumption of a hyperlipidemic diet; that is, in utero exposure to arsenic produces an altered physiological state that mimics one usually induced with an atherosclerotic diet. Exposure to inorganic arsenic during in utero and early postnatal life also affects lung structure and function. Offspring of mice exposed up to 100 ppb of arsenic in drinking water between gestational day 8 and birth show altered lung mechanics and patterns of gene expression.18,19 Airway reactivity and morphology are altered in offspring of mice exposed to arsenic in drinking water (up to 100 ppb of sodium arsenite) throughout gestation and the first postnatal month.20 The developing nervous system in the mouse also shows exquisite sensitivity to inorganic arsenic. Exposure to drinking water containing 50 ppb of arsenic in utero and in early postnatal life alters hippocampal cell morphology and affects gene expression patterns in this brain region.21 These changes may underlie altered learning and memory behavior seen in adult mice after in utero and early postnatal life exposure to inorganic arsenic.22 In sum, sites and patterns of tissue injury are strongly concordant in humans or mice exposed to arsenic in utero and/ or in early life (Figure 2). Sites of tumor occurrence and effects on cardiovascular and respiratory systems are similar in humans and mice, and effects of in utero and in early life exposure to arsenic on nervous systems function are similar in these species. This concordance suggests that common biological processes may underlie responses seen in both species and raises the possibility that the mouse model can provide insights into molecular processes and dose−response relationships that cannot be easily achieved in studies in arsenic-exposed humans.
Figure 2. Concordance of organs showing adverse effects related to early life exposure to inorganic arsenic in humans and mice. Organs connected by a red line are sites of noncancer effects in both species. Organs connected by a blue line are sites of cancers in both species. Organs connected by a black line show discordant effects in these species. Illustration by John Havel, SRA International, Inc.
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induces all three types of epigenetic change. These include hypomethylation of GC-rich regions in liver genomic DNA, hypermethylation in promoter regions of tumor suppressor genes in the liver, and altered methylation and histone acetylation patterns in the brain.24−27 Exposure in utero to arsenic also alters the developmental trajectory of microRNAs in mouse liver and may contribute to a persistent proinflammatory state in the liver after prenatal exposure to arsenic.16 In humans, samples for analysis of epigenetic changes are typically limited to tissues such as peripheral blood leucocytes or blood samples from mother and newborn collected at delivery. In adults chronically exposed to inorganic
EPIGENETICS AND EARLY LIFE EXPOSURE TO ARSENIC Epigenetic changes, heritable changes in gene expression that are not due to changes in DNA sequence, may account for the relatively long temporal separation between arsenic exposure and tumor development in humans and mice. Methylation of cytosine residues in GC pairs in DNA, post-translational modification of histones involved in transcriptional regulation, and microRNAs that regulate gene expression underlie epigenetic changes.23 In mice, in utero exposure to arsenic 1779
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Chemical Research in Toxicology arsenic in drinking water, an interactome of hypermethylated genes is associated with the occurrence of arsenic-induced diseases.28,29 Global DNA hypomethylation in an infant’s cord blood sample increases with the concentration of arsenic in mother’s urine, suggesting that in utero exposure affects genomic imprinting.30 Hypermethylation in the promoter region of p53 and in some CG islands increases in infants exposed in utero to arsenic.31,32
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AUTHOR INFORMATION
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ABBREVIATIONS
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REFERENCES
Perspective
ppb, parts per billion; SMRs, standardized mortality ratios; ppm, parts per million; AdoMet, S-adenosylmethionine
(1) Tseng, C. H. (2009) A review on environmental factors regulating arsenic methylation in humans. Toxicol. Appl. Pharmacol. 235, 338−350. (2) Valenzuela, O. L., Drobna, Z., Hernandez-Castellanos, E., Sanchez-Pena, L. C., Garcia-Vargas, G. G., Borja-Aburto, V. H., Styblo, M., and Del Razo, L. M. (2009) Association of AS3MT polymorphisms and the risk of premalignant arsenic skin lesions. Toxicol. Appl. Pharmacol. 239, 200−207. (3) Engstrom, K. S., Hossain, M. B., Lauss, M., Ahmed, S., Raqib, R., Vahter, M., and Broberg, K. (2013) Efficient arsenic metabolism–the AS3MT haplotype is associated with DNA methylation and expression of multiple genes around AS3MT. PLoS One 8, e53732. (4) Smith, A. H., Marshall, G., Liaw, J., Yuan, Y., Ferreccio, C., and Steinmaus, C. (2012) Mortality in young adults following in utero and childhood exposure to arsenic in drinking water. Environ. Health Perspect. 120, 1527−1531. (5) Rahman, M., Sohel, N., Yunus, M., Chowdhury, M. E., Hore, S. K., Zaman, K., Bhuiya, A., and Streatfield, P. K. (2013) Increased childhood mortality and arsenic in drinking water in Matlab, Bangladesh: a population-based cohort study. PLoS One 8, e55014. (6) Farzan, S. F., Korrick, S., Li, Z., Enelow, R., Gandolfi, A. J., Madan, J., Nadeau, K., and Karagas, M. R. (2013) In utero arsenic exposure and infant infection in a United States cohort: A prospective study. Environ. Res. 126, 24−30. (7) Dauphine, D. C., Ferreccio, C., Guntur, S., Yuan, Y., Hammond, S. K., Balmes, J., Smith, A. H., and Steinmaus, C. (2011) Lung function in adults following in utero and childhood exposure to arsenic in drinking water: preliminary findings. Int. Arch. Occup. Environ. Health 84, 591−600. (8) Ahmed, S., Ahsan, K. B., Kippler, M., Mily, A., Wagatsuma, Y., Hoque, A. M., Ngom, P. T., El Arifeen, S., Raqib, R., and Vahter, M. (2012) In utero arsenic exposure is associated with impaired thymic function in newborns possibly via oxidative stress and apoptosis. Toxicol. Sci. 129, 305−314. (9) Saha, K,K., Engstrom, A., Hamadani, J. D., Tofail, F., Rasmussen, K. M., and Vahter, M. (2012) Pre- and postnatal arsenic exposure and body size to 2 years of age: a cohort study in rural Bangladesh. Environ. Health Perspect. 120, 1208−1214. (10) Parvez, F., Wasserman, G. A., Factor-Litvak, P., Liu, X., Slavkovich, V., Siddique, A. B., Sultana, R., Sultana, R., Islam, T., Levy, D., Mey, J. L., van Geen, A., Khan, K., Kline, J., Ahsan, H., and Graziano, J. H. (2011) Arsenic exposure and motor function among children in Bangladesh. Environ. Health Perspect. 119, 1665−1670. (11) Hamadani, J. D., Tofail, F., Nermell, B., Gardner, R., Shiraji, S., Bottai, M., Arifeen, S. E., Huda, S. N., and Vahter, M. (2011) Critical windows of exposure for arsenic-associated impairment of cognitive function in pre-school girls and boys: a population-based cohort study. Int. J. Epidemiol. 40, 1593−1604. (12) International Agency for Research on Cancer (2012) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 100C, A Review of Human Carcinogens, Part C: Arsenic, Metals, Fibres, and Dusts, pp 41−94, IARC, Lyon, France. (13) Tokar, E. J., Benbrahim-Tallaa, L., Ward, J. M., Lunn, R., Sams, R. L., II, and Waalkes, M. P. (2010) Cancer in experimental animals exposed to arsenic and arsenic compounds. Crit. Rev. Toxicol. 40, 912− 927. (14) Tokar, E. J., Diwan, B. A., Thomas, D. J., and Waalkes, M. P. (2012) Tumors and proliferative lesions in adult offspring after maternal exposure to methylarsonous acid during gestation in CD1 mice. Arch. Toxicol. 86, 975−982. (15) Srivastava, S., D’Souza, S. E., Sen, U., and States, J. C. (2007) In utero arsenic exposure induces early onset of atherosclerosis in ApoE−/− mice. Reprod. Toxicol. 23, 449−456.
The concordance of findings in humans and mice after in utero exposure to inorganic arsenic strengthens confidence in the results of epidemiological studies and suggests that the mouse model can be used productively to understand both disease processes and critical dose−response relationships. A focus on epigenetic changes induced by arsenic in developing organisms links this work to the emerging research on stem cell-based diseases.33 Similarly, if altered patterns of DNA methylation induced by arsenic exposure during development account for disease in later life, effects of early life exposure on the onecarbon metabolic pathway that provides S-adenosylmethionine (AdoMet) for the methylation of arsenic and DNA must be clarified. Manipulation of AdoMet status produces a complex pattern of effects on DNA methylation and arsenic methylation capacity in mice; additional work is needed to elucidate underlying processes.34,35 Finally, dosimetric profiles for distribution and clearance of inorganic arsenic and its metabolites in tissues during in utero or early life exposure must be determined. There are little quantitative data on arsenic exposure of the developing human during gestation. In the mouse model, arsenic exposure varies over a 1000-fold (50 ppb to 85 ppm in drinking water); these exposures must produce a wide range of tissue concentrations of metabolite(s) that mediate adverse effects. Reconciling human and mouse exposure scenarios will require improved analytical methods to quantify arsenicals in tissues after low level exposures and more tissue dosimetric data. These efforts will support the development of refined human and mouse pharmacokinetic models that incorporate fetal and maternal components to clarify critical dose−response relationships in both species. In sum, the confluence of research findings in humans and the mouse should generate great interest in the design of animal-based research that can be translated into better estimates of risk associated with early life exposure of humans to arsenic. Although the die may be cast by the lifetime history of exposure, additional understanding of molecular processes and dosimetry may affect final outcomes at individual and population levels.
Notes
This manuscript has been reviewed in accordance with the policy of the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The authors declare no competing financial interest. 1780
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