Arsenic Exposure Perturbs the Gut Microbiome and Its Metabolic Profile in Mice: An Integrated Metagenomics and Metabolomics Analysis

Background: The human intestine is host to an enormously complex, diverse, and vast microbial community—the gut microbiota. The gut microbiome plays a profound role in metabolic processing, energy production, immune and cognitive development, epithelial homeostasis, and so forth. However, the composition and diversity of the gut microbiome can be readily affected by external factors, which raises the possibility that exposure to toxic environmental chemicals leads to gut microbiome alteration, or dysbiosis. Arsenic exposure affects large human populations worldwide and has been linked to a number of diseases, including cancer, diabetes, and cardiovascular disorders.Objectives: We investigated the impact of arsenic exposure on the gut microbiome composition and its metabolic profiles.Methods: We used an integrated approach combining 16S rRNA gene sequencing and mass spectrometry–based metabolomics profiling to examine the functional impact of arsenic exposure on the gut microbiome.Results: 16S rRNA gene sequencing revealed that arsenic significantly perturbed the gut microbiome composition in C57BL/6 mice after exposure to 10 ppm arsenic for 4 weeks in drinking water. Moreover, metabolomics profiling revealed a concurrent effect, with a number of gut microflora–related metabolites being perturbed in multiple biological matrices.Conclusions: Arsenic exposure not only alters the gut microbiome community at the abundance level but also substantially disturbs its metabolic profiles at the function level. These findings may provide novel insights regarding perturbations of the gut microbiome and its functions as a potential new mechanism by which arsenic exposure leads to or exacerbates human diseases.Citation: Lu K, Abo RP, Schlieper KA, Graffam ME, Levine S, Wishnok JS, Swenberg JA, Tannenbaum SR, Fox JG. 2014. Arsenic exposure perturbs the gut microbiome and its metabolic profile in mice: an integrated metagenomics and metabolomics analysis. Environ Health Perspect 122:284–291; http://dx.doi.org/10.1289/ehp.1307429     

Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Research Trends and Scientific Gaps

Background

Millions of individuals worldwide, particularly those living in rural and developing areas, are exposed to harmful levels of inorganic arsenic (iAs) in their drinking water. Inorganic As exposure during key developmental periods is associated with a variety of adverse health effects, including those that are evident in adulthood. There is considerable interest in identifying the molecular mechanisms that relate early-life iAs exposure to the development of these latent diseases, particularly in relationship to cancer.

Objectives

This work summarizes research on the molecular mechanisms that underlie the increased risk of cancer development in adulthood that is associated with early-life iAs exposure.

Discussion

Epigenetic reprogramming that imparts functional changes in gene expression, the development of cancer stem cells, and immunomodulation are plausible underlying mechanisms by which early-life iAs exposure elicits latent carcinogenic effects.

Conclusions

Evidence is mounting that relates early-life iAs exposure and cancer development later in life. Future research should include animal studies that address mechanistic hypotheses and studies of human populations that integrate early-life exposure, molecular alterations, and latent disease outcomes.

Citation

Bailey KA, Smith AH, Tokar EJ, Graziano JH, Kim KW, Navasumrit P, Ruchirawat M, Thiantanawat A, Suk WA, Fry RC. 2016. Mechanisms underlying latent disease risk associated with early-life arsenic exposure: current research trends and scientific gaps. Environ Health Perspect 124:170–175; http://dx.doi.org/10.1289/ehp.1409360     

Long-Term Exposure to Low-Level Arsenic in Drinking Water and Diabetes Incidence: A Prospective Study of the Diet,Cancer and Health Cohort

Background: Established causes of diabetes do not fully explain the present epidemic. High-level arsenic exposure has been implicated in diabetes risk, but the effect of low-level arsenic exposure in drinking water remains unclear.Objective: We sought to determine whether long-term exposure to low-level arsenic in drinking water in Denmark is associated with an increased risk of diabetes using a large prospective cohort.Methods: During 1993–1997, we recruited 57,053 persons. We followed each cohort member for diabetes occurrence from enrollment until 31 December 2006. We traced and geocoded residential addresses of the cohort members and used a geographic information system to link addresses with water-supply areas. We estimated individual exposure to arsenic using all addresses from 1 January 1971 until the censoring date. Cox proportional hazards models were used to model the association between arsenic exposure and diabetes incidence, separately for two definitions of diabetes: all cases and a more strict definition in which cases of diabetes based solely on blood glucose results were excluded.Results: Over a mean follow-up period of 9.7 years for 52,931 eligible participants, there were a total of 4,304 (8.1%) diabetes cases, and 3,035 (5.8%) cases of diabetes based on the more strict definition. The adjusted incidence rate ratios (IRRs) per 1-μg/L increment in arsenic levels in drinking water were as follows: IRR = 1.03 (95% CI: 1.01, 1.06) and IRR = 1.02 (95% CI: 0.99, 1.05) for all and strict diabetes cases, respectively.Conclusions: Long-term exposure to low-level arsenic in drinking water may contribute to the development of diabetes.Citation: Bräuner EV, Nordsborg RB, Andersen ZJ, Tjønneland A, Loft S, Raaschou-Nielsen O. 2014. Long-term exposure to low-level arsenic in drinking water and diabetes incidence: a prospective study of the Diet, Cancer and Health cohort. Environ Health Perspect 122:1059–1065; http://dx.doi.org/10.1289/ehp.1408198     

Estimated Exposure to Arsenic in Breastfed and Formula-Fed Infants in a United States Cohort

Background: Previous studies indicate that concentrations of arsenic in breast milk are relatively low even in areas with high drinking-water arsenic. However, it is uncertain whether breastfeeding leads to reduced infant exposure to arsenic in regions with lower arsenic concentrations.Objective: We estimated the relative contributions of breast milk and formula to arsenic exposure during early infancy in a U.S. population.Methods: We measured arsenic in home tap water (n = 874), urine from 6-week-old infants (n = 72), and breast milk from mothers (n = 9) enrolled in the New Hampshire Birth Cohort Study (NHBCS) using inductively coupled plasma mass spectrometry. Using data from a 3-day food diary, we compared urinary arsenic across infant feeding types and developed predictive exposure models to estimate daily arsenic intake from breast milk and formula.Results: Urinary arsenic concentrations were generally low (median, 0.17 μg/L; maximum, 2.9 μg/L) but 7.5 times higher for infants fed exclusively with formula than for infants fed exclusively with breast milk (β = 2.02; 95% CI: 1.21, 2.83; p < 0.0001, adjusted for specific gravity). Similarly, the median estimated daily arsenic intake by NHBCS infants was 5.5 times higher for formula-fed infants (0.22 μg/kg/day) than for breastfed infants (0.04 μg/kg/day). Given median arsenic concentrations measured in NHBCS tap water and previously published for formula powder, formula powder was estimated to account for ~ 70% of median exposure among formula-fed NHBCS infants.Conclusions: Our findings suggest that breastfed infants have lower arsenic exposure than formula-fed infants, and that both formula powder and drinking water can be sources of exposure for U.S. infants.Citation: Carignan CC, Cottingham KL, Jackson BP, Farzan SF, Gandolfi AJ, Punshon T, Folt CL, Karagas MR. 2015. Estimated exposure to arsenic in breastfed and formula-fed infants in a United States cohort. Environ Health Perspect 123:500–506; http://dx.doi.org/10.1289/ehp.1408789     

Association between Arsenic Exposure from Drinking Water and Longitudinal Change in Blood Pressure among HEALS Cohort Participants

Background

Cross-sectional studies have shown associations between arsenic exposure and prevalence of high blood pressure; however, studies examining the relationship of arsenic exposure with longitudinal changes in blood pressure are lacking.

Method

We evaluated associations of arsenic exposure in relation to longitudinal change in blood pressure in 10,853 participants in the Health Effects of Arsenic Longitudinal Study (HEALS). Arsenic was measured in well water and in urine samples at baseline and in urine samples every 2 years after baseline. Mixed-effect models were used to estimate the association of baseline well and urinary creatinine-adjusted arsenic with annual change in blood pressure during follow-up (median, 6.7 years).

Result

In the HEALS population, the median water arsenic concentration at baseline was 62 μg/L. Individuals in the highest quartile of baseline water arsenic or urinary creatinine-adjusted arsenic had a greater annual increase in systolic blood pressure compared with those in the reference group (β = 0.48 mmHg/year; 95% CI: 0.35, 0.61, and β = 0.43 mmHg/year; 95% CI: 0.29, 0.56 for water arsenic and urinary creatinine-adjusted arsenic, respectively) in fully adjusted models. Likewise, individuals in the highest quartile of baseline arsenic exposure had a greater annual increase in diastolic blood pressure for water arsenic and urinary creatinine-adjusted arsenic, (β = 0.39 mmHg/year; 95% CI: 0.30, 0.49, and β = 0.45 mmHg/year; 95% CI: 0.36, 0.55, respectively) compared with those in the lowest quartile.

Conclusion

Our findings suggest that long-term arsenic exposure may accelerate age-related increases in blood pressure. These findings may help explain associations between arsenic exposure and cardiovascular disease.

Citation

Jiang J, Liu M, Parvez F, Wang B, Wu F, Eunus M, Bangalore S, Newman JD, Ahmed A, Islam T, Rakibuz-Zaman M, Hasan R, Sarwar G, Levy D, Slavkovich V, Argos M, Scannell Bryan M, Farzan SF, Hayes RB, Graziano JH, Ahsan H, Chen Y. 2015. Association between arsenic exposure from drinking water and longitudinal change in blood pressure among HEALS cohort participants. Environ Health Perspect 123:806–812; http://dx.doi.org/10.1289/ehp.1409004     

Effects of in Utero Exposure to Arsenic during the Second Half of Gestation on Reproductive End Points and Metabolic Parameters in Female CD-1 Mice

Background

Mice exposed to high levels of arsenic in utero have increased susceptibility to tumors such as hepatic and pulmonary carcinomas when they reach adulthood. However, the effects of in utero arsenic exposure on general physiological functions such as reproduction and metabolism remain unclear.

Objectives

We evaluated the effects of in utero exposure to inorganic arsenic at the U.S. Environmental Protection Agency (EPA) drinking water standard (10 ppb) and at tumor-inducing levels (42.5 ppm) on reproductive end points and metabolic parameters when the exposed females reached adulthood.

Methods

Pregnant CD-1 mice were exposed to sodium arsenite [none (control), 10 ppb, or 42.5 ppm] in drinking water from gestational day 10 to birth, the window of organ formation. At birth, exposed offspring were fostered to unexposed dams. We examined reproductive end points (age at vaginal opening, reproductive hormone levels, estrous cyclicity, and fertility) and metabolic parameters (body weight changes, hormone levels, body fat content, and glucose tolerance) in the exposed females when they reached adulthood.

Results

Arsenic-exposed females (10 ppb and 42.5 ppm) exhibited early onset of vaginal opening. Fertility was not affected when females were exposed to the 10-ppb dose. However, the number of litters per female was decreased in females exposed to 42.5 ppm of arsenic in utero. In both 10-ppb and 42.5-ppm groups, arsenic-exposed females had significantly greater body weight gain, body fat content, and glucose intolerance.

Conclusion

Our findings revealed unexpected effects of in utero exposure to arsenic: exposure to both a human-relevant low dose and a tumor-inducing level led to early onset of vaginal opening and to obesity in female CD-1 mice.

Citation

Rodriguez KF, Ungewitter EK, Crespo-Mejias Y, Liu C, Nicol B, Kissling GE, Yao HH. 2016. Effects of in utero exposure to arsenic during the second half of gestation on reproductive end points and metabolic parameters in female CD-1 mice. Environ Health Perspect 124:336–343; http://dx.doi.org/10.1289/ehp.1509703     

Association between Lifetime Exposure to Inorganic Arsenic in Drinking Water and Coronary Heart Disease in Colorado Residents

Background: Chronic diseases, including coronary heart disease (CHD), have been associated with ingestion of drinking water with high levels of inorganic arsenic (> 1,000 μg/L). However, associations have been inconclusive in populations with lower levels (< 100 μg/L) of inorganic arsenic exposure.Objectives: We conducted a case-cohort study based on individual estimates of lifetime arsenic exposure to examine the relationship between chronic low-level arsenic exposure and risk of CHD.Methods: This study included 555 participants with 96 CHD events diagnosed between 1984 and 1998 for which individual lifetime arsenic exposure estimates were determined using data from structured interviews and secondary data sources to determine lifetime residence, which was linked to a geospatial model of arsenic concentrations in drinking water. These lifetime arsenic exposure estimates were correlated with historically collected urinary arsenic concentrations. A Cox proportional-hazards model with time-dependent CHD risk factors was used to assess the association between time-weighted average (TWA) lifetime exposure to low-level inorganic arsenic in drinking water and incident CHD.Results: We estimated a positive association between low-level inorganic arsenic exposure and CHD risk [hazard ratio (HR): = 1.38, 95% CI: 1.09, 1.78] per 15 μg/L while adjusting for age, sex, first-degree family history of CHD, and serum low-density lipoprotein levels. The risk of CHD increased monotonically with increasing TWAs for inorganic arsenic exposure in water relative to < 20 μg/L (HR = 1.2, 95% CI: 0.6, 2.2 for 20–30 μg/L; HR = 2.2; 95% CI: 1.2, 4.0 for 30–45 μg/L; and HR = 3, 95% CI: 1.1, 9.1 for 45–88 μg/L).Conclusions: Lifetime exposure to low-level inorganic arsenic in drinking water was associated with increased risk for CHD in this population.Citation: James KA, Byers T, Hokanson JE, Meliker JR, Zerbe GO, Marshall JA. 2015. Association between lifetime exposure to inorganic arsenic in drinking water and coronary heart disease in Colorado residents. Environ Health Perspect 123:128–134; http://dx.doi.org/10.1289/ehp.1307839     

A Population-based Case–Control Study of Urinary Arsenic Species and Squamous Cell Carcinoma in New Hampshire,USA

Background: Chronic high arsenic exposure is associated with squamous cell carcinoma (SCC) of the skin, and inorganic arsenic (iAs) metabolites may play an important role in this association. However, little is known about the carcinogenicity of arsenic at levels commonly observed in the United States.Objective: We estimated associations between total urinary arsenic and arsenic species and SCC in a U.S. population.Methods: We conducted a population-based case–control SCC study (470 cases, 447 controls) in a U.S. region with moderate arsenic exposure through private well water and diet. We measured urinary iAs, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA), and summed these arsenic species (ΣAs). Because seafood contains arsenolipids and arsenosugars that metabolize into DMA through alternate pathways, participants who reported seafood consumption within 2 days before urine collection were excluded from the analyses.Results: In adjusted logistic regression analyses (323 cases, 319 controls), the SCC odds ratio (OR) was 1.37 for each ln-transformed microgram per liter increase in ln-transformed ΣAs concentration [ln(ΣAs)] (95% CI: 1.04, 1.80). Urinary ln(MMA) and ln(DMA) also were positively associated with SCC (OR = 1.34; 95% CI: 1.04, 1.71 and OR = 1.34; 95% CI: 1.03, 1.74, respectively). A similar trend was observed for ln(iAs) (OR = 1.20; 95% CI: 0.97, 1.49). Percent iAs, MMA, and DMA were not associated with SCC.Conclusions: These results suggest that arsenic exposure at levels common in the United States relates to SCC and that arsenic metabolism ability does not modify the association.Citation: Gilbert-Diamond D, Li Z, Perry AE, Spencer SK, Gandolfi AJ, Karagas MR. 2013. A population-based case–control study of urinary arsenic species and squamous cell carcinoma in New Hampshire, USA. Environ Health Perspect 121:1154–1160; http://dx.doi.org/10.1289/ehp.1206178     

Carotid Intima-Media Thickness and Plasma Asymmetric Dimethylarginine in Mexican Children Exposed to Inorganic Arsenic

Background: Arsenic exposure is a risk factor for atherosclerosis in adults, but there is little information on arsenic and early risk biomarkers for atherosclerosis in children. Carotid intima-media thickness (cIMT) is an indicator of subclinical atherosclerotic burden that has been associated with plasma asymmetric dimethylarginine (ADMA), a predictor of cardiovascular disease risk.Objectives: The aim of this study was to investigate associations of arsenic exposure with cIMT, ADMA, and endothelial adhesion molecules [soluble intercellular cell adhesion molecule-1 (sICAM-1); soluble vascular cell adhesion molecule-1 (sVCAM-1)] in children who had been exposed to environmental inorganic arsenic (iAs).Methods: We conducted a cross-sectional study in 199 children 3–14 years of age who were residents of Zimapan, México. We evaluated cIMT using ultrasonography, and plasma lipid profiles by standard methods. We analyzed ADMA, sICAM-1, and sVCAM-1 by ELISA, and measured the concentrations of total speciated arsenic (tAs) in urine using hydride generation cryotrapping atomic absorption spectrometry.Results: In the multiple linear regression model for cIMT, tAs categories were positively associated with cIMT increase. The estimated cIMT diameter was greater in 35- to 70-ng/mL and > 70-ng/mL groups (0.035 mm and 0.058 mm per 1-ng/mL increase in urinary tAs, respectively), compared with the < 35-ng/mL group. In addition to tAs level, plasma ADMA was a significant predictor of cIMT. In the adjusted regression model, cIMT, percent iAs, and plasma sVCAM-1 were significant predictors of ADMA levels (e.g., 0.419-μmol/L increase in ADMA per 1-mm increase in cIMT).Conclusions: Arsenic exposure and plasma ADMA levels were positively associated with cIMT in a population of Mexican children with environmental arsenic exposure through drinking water.Citation: Osorio-Yáñez C, Ayllon-Vergara JC, Aguilar-Madrid G, Arreola-Mendoza L, Hernández-Castellanos E, Barrera-Hernández A, De Vizcaya-Ruíz A, Del Razo LM. 2013. Carotid intima-media thickness and plasma asymmetric dimethylarginine in Mexican children exposed to inorganic arsenic. Environ Health Perspect 121:1090–1096; http://dx.doi.org/10.1289/ehp.1205994     

Effects of Developmental Activation of the AhR on CD4+ T-Cell Responses to Influenza Virus Infection in Adult Mice

Background: Epidemiological and animal studies indicate that maternal exposure to pollutants that bind the aryl hydrocarbon receptor (AhR) correlates with poorer ability to combat respiratory infection and lower antibody levels in the offspring. These observations point to an impact on CD4⁺ T cells. Yet, the consequence of developmental exposure to AhR ligands on the activation and differentiation of CD4⁺ T cells has not been directly examined.Objectives: Our goal was to determine whether maternal exposure to an AhR ligand directly alters CD4⁺ T cell differentiation and function later in life.Methods: C57BL/6 mice were exposed to a prototypical AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in utero and via suckling. We then measured CD4⁺ T-cell activation and differentiation into distinct effector populations in adult offspring that were infected with influenza A virus (IAV). Reciprocal adoptive transfers were used to define whether modifications in CD4⁺ T-cell responses resulted from direct effects of developmental TCDD exposure on CD4⁺ T cells.Results: Developmental exposure skewed CD4⁺ T-cell responses to IAV infection. We observed fewer virus-specific, activated CD4⁺ T cells and a reduced frequency of conventional CD4⁺ effector-cell subsets. However, there was an increase in regulatory CD4⁺ T cells. Direct effects of AhR activation on CD4⁺ T cells resulted in impaired differentiation into conventional effector subsets; this defect was transferred to mice that had not been developmentally exposed to TCDD.Conclusions: Maternal exposure to TCDD resulted in durable changes in the responsive capacity and differentiation of CD4⁺ T cells in adult C57BL/6 mice.Citation: Boule LA, Winans B, Lawrence BP. 2014. Effects of developmental activation of the AhR on CD4⁺ T-cell responses to influenza virus infection in adult mice. Environ Health Perspect 122:1201–1208; http://dx.doi.org/10.1289/ehp.1408110     

Blood Pressure Changes in Relation to Arsenic Exposure in a U.S. Pregnancy Cohort

Background

Inorganic arsenic exposure has been related to the risk of increased blood pressure based largely on cross-sectional studies conducted in highly exposed populations. Pregnancy is a period of particular vulnerability to environmental insults. However, little is known about the cardiovascular impacts of arsenic exposure during pregnancy.

Objectives

We evaluated the association between prenatal arsenic exposure and maternal blood pressure over the course of pregnancy in a U.S. population.

Methods

The New Hampshire Birth Cohort Study is an ongoing prospective cohort study in which > 10% of participant household wells exceed the arsenic maximum contaminant level of 10 μg/L established by the U.S. EPA. Total urinary arsenic measured at 24–28 weeks gestation was measured and used as a biomarker of exposure during pregnancy in 514 pregnant women, 18–45 years of age, who used a private well in their household. Outcomes were repeated blood pressure measurements (systolic, diastolic, and pulse pressure) recorded during pregnancy.

Results

Using linear mixed effects models, we estimated that, on average, each 5-μg/L increase in urinary arsenic was associated with a 0.15-mmHg (95% CI: 0.02, 0.29; p = 0.022) increase in systolic blood pressure per month and a 0.14-mmHg (95% CI: 0.02, 0.25; p = 0.021) increase in pulse pressure per month over the course of pregnancy.

Conclusions

In our U.S. cohort of pregnant women, arsenic exposure was associated with greater increases in blood pressure over the course of pregnancy. These findings may have important implications because even modest increases in blood pressure impact cardiovascular disease risk.

Citation

Farzan SF, Chen Y, Wu F, Jiang J, Liu M, Baker E, Korrick SA, Karagas MR. 2015. Blood pressure changes in relation to arsenic exposure in a U.S. pregnancy cohort. Environ Health Perspect 123:999–1006; http://dx.doi.org/10.1289/ehp.1408472     

Effects of Arsenite Exposure during Fetal Development on Energy Metabolism and Susceptibility to Diet-Induced Fatty Liver Disease in Male Mice

Background

Chronic exposure to arsenicals at various life stages and across a range of exposures has been implicated in cardiometabolic and liver disease, but disease predisposition from developmental exposures remains unclear.

Objectives

In utero and post-weaning exposure to trivalent arsenic (As^III) was examined on the background of a Western-style diet to determine whether As^III exposure affects metabolic disease.

Methods

Male Swiss Webster mice were exposed to 100 ppb As^III in utero, after weaning, or both. Ad libitum access to a Western-style diet was provided after weaning, and the plasma metabolome, liver histopathology, liver enzyme activity, and gene expression were analyzed.

Results

Hepatic lipid composition and histopathology revealed that developmental As^III exposure exacerbated Western-style diet–induced fatty liver disease. Continuous As^III exposure increased cardiometabolic risk factors including increased body weight, insulin resistance, hyperglycemia, and plasma triglycerides. As^III exposure produced a decrease in the intermediates of glycolysis and the TCA cycle while increasing ketones. Hepatic isocitrate dehydrogenase activity was also decreased, which confirmed disruption of the TCA cycle. Developmental As^III exposure increased the expression of genes involved in fatty acid synthesis, lipogenesis, inflammation, and packaging of triglycerides, suggesting an increased acetyl coenzyme A (acetyl-CoA) load.

Conclusions

In utero and continuous early-life exposure to As^III disrupted normal metabolism and elevated the risk for fatty liver disease in mice maintained on a high-fat diet. Our findings suggest that individuals exposed to As^III during key developmental periods and who remain exposed to As^III on the background of a Western-style diet may be at increased risk for metabolic disease later in life.

Citation

Ditzel EJ, Nguyen T, Parker P, Camenisch TD. 2016. Effects of arsenite exposure during fetal development on energy metabolism and susceptibility to diet-induced fatty liver disease in male mice. Environ Health Perspect 124:201–209; http://dx.doi.org/10.1289/ehp.1409501     

Interaction between Arsenic Exposure from Drinking Water and Genetic Polymorphisms on Cardiovascular Disease in Bangladesh: A Prospective Case-Cohort Study

Background: Epidemiologic data on genetic susceptibility to cardiovascular effects of arsenic exposure from drinking water are limited.Objective: We investigated whether the association between well-water arsenic and cardiovascular disease (CVD) differed by 170 single nucleotide polymorphisms (SNPs) in 17 genes related to arsenic metabolism, oxidative stress, inflammation, and endothelial dysfunction.Method: We conducted a prospective case-cohort study nested in the Health Effects of Arsenic Longitudinal Study, with a random subcohort of 1,375 subjects and 447 incident fatal and nonfatal cases of CVD. Well-water arsenic was measured in 2000 at baseline. The CVD cases, 56 of which occurred in the subcohort, included 238 coronary heart disease cases, 165 stroke cases, and 44 deaths due to other CVD identified during follow-up from 2000 to 2012.Results: Of the 170 SNPs tested, multiplicative interactions between well-water arsenic and two SNPs, rs281432 in ICAM1 (p_adj = 0.0002) and rs3176867 in VCAM1 (p_adj = 0.035), were significant for CVD after adjustment for multiple testing. Compared with those with GC or CC genotype in rs281432 and lower well-water arsenic, the adjusted hazard ratio (aHR) for CVD was 1.82 (95% CI: 1.31, 2.54) for a 1-SD increase in well-water arsenic combined with the GG genotype, which was greater than expected given aHRs of 1.08 and 0.96 for separate effects of arsenic and the genotype alone, respectively. Similarly, the joint aHR for arsenic and the rs3176867 CC genotype was 1.34 (95% CI: 0.95, 1.87), greater than expected given aHRs for their separate effects of 1.02 and 0.84, respectively.Conclusions: Associations between CVD and arsenic exposure may be modified by genetic variants related to endothelial dysfunction.Citation: Wu F, Jasmine F, Kibriya MG, Liu M, Cheng X, Parvez F, Islam T, Ahmed A, Rakibuz-Zaman M, Jiang J, Roy S, Paul-Brutus R, Slavkovich V, Islam T, Levy D, VanderWeele TJ, Pierce BL, Graziano JH, Ahsan H, Chen Y. 2015. Interaction between arsenic exposure from drinking water and genetic polymorphisms on cardiovascular disease in Bangladesh: a prospective case-cohort study. Environ Health Perspect 123:451–457; http://dx.doi.org/10.1289/ehp.1307883     

Dose-Dependent Incidence of Hepatic Tumors in Adult Mice following Perinatal Exposure to Bisphenol A

Background: Bisphenol A (BPA) is a high production volume chemical with hormone-like properties that has been implicated as a potential carcinogen. Early-life exposure has been linked to increased risk for precancerous lesions in mammary and prostate glands and the uterus, but no prior study has shown a significant association between BPA exposure and cancer development.Objective: We explored the effects of BPA exposure during gestation and lactation on adult incidence of hepatic tumors in mice.Methods: Isogenic mice were perinatally exposed to BPA through maternal diets containing one of four environmentally relevant doses of BPA (0, 50 ng, 50 μg, or 50 mg per kilogram of diet), and we followed approximately one male and one female per litter until they were 10 months of age. Animals were tested for known risk factors for hepatocellular carcinoma, including bacterial and viral infections.Results: We found dose-dependent incidence of hepatic tumors in 10-month-old BPA-exposed mice. Of the offspring examined, 23% presented with hepatic tumors or preneoplastic lesions. We observed a statistically significant dose–response relationship, with an odds ratio for neoplastic and preneoplastic lesions of 7.23 (95% CI: 3.23, 16.17) for mice exposed to 50 mg BPA/kg diet compared with unexposed controls. Observed early disease onset, absence of bacterial or viral infection, and lack of characteristic sexual dimorphism in tumor incidence support a nonclassical etiology.Conclusions: To our knowledge, this is the first report of a statistically significant association between BPA exposure and frank tumors in any organ. Our results link early-life exposure to BPA with the development of hepatic tumors in rodents, and have potential implications for human health and disease.Citation: Weinhouse C, Anderson OS, Bergin IL, Vandenbergh DJ, Gyekis JP, Dingman MA, Yang J, Dolinoy DC. 2014. Dose-dependent incidence of hepatic tumors in adult mice following perinatal exposure to bisphenol A. Environ Health Perspect 122:485–491; http://dx.doi.org/10.1289/ehp.1307449     

Non-Renal Effects and the Risk Assessment of Environmental Cadmium Exposure

Background: Exposure to cadmium (Cd) has long been recognized as a health hazard, both in industry and in general populations with high exposure. Under the currently prevailing health risk assessment, the relationship between urinary Cd (U-Cd) concentrations and tubular proteinuria is used. However, doubts have recently been raised regarding the justification of basing the risk assessment on this relationship at very low exposure.Objectives: Our objective was to review available information on health effects of Cd exposure with respect to human health risk assessment.Discussion: The associations between U-Cd and urinary proteins at very low exposure may not be due to Cd toxicity, and the clinical significance of slight proteinuria may also be limited. More importantly, other effects have been reported at very low Cd exposure. There is reason to challenge the basis of the existing health risk assessment for Cd. Our review of the literature found that exposure to low concentrations of Cd is associated with effects on bone, including increased risk of osteoporosis and fractures, and that this observation has implications for the health risk assessment of Cd. Other effects associated with Cd should also be considered, in particular cancer, although the information is still too limited for appropriate use in quantitative risk assessment.Conclusion: Non-renal effects should be considered critical effects in the health risk assessment of Cd.Citation: Åkesson A, Barregard L, Bergdahl IA, Nordberg GF, Nordberg M, Skerfving S. 2014. Non-renal effects and the risk assessment of environmental cadmium exposure. Environ Health Perspect 122:431–438; http://dx.doi.org/10.1289/ehp.1307110     

A Prospective Analysis of Airborne Metal Exposures and Risk of Parkinson Disease in the Nurses’ Health Study Cohort

Background: Exposure to metals has been implicated in the pathogenesis of Parkinson disease (PD).Objectives: We sought to examine in a large prospective study of female nurses whether exposure to airborne metals was associated with risk of PD.Methods: We linked the U.S. Environmental Protection Agency (EPA)’s Air Toxics tract-level data with the Nurses’ Health Study, a prospective cohort of female nurses. Over the course of 18 years of follow-up from 1990 through 2008, we identified 425 incident cases of PD. We examined the association of risk of PD with the following metals that were part of the first U.S. EPA collections in 1990, 1996, and 1999: arsenic, antimony, cadmium, chromium, lead, manganese, mercury, and nickel. To estimate hazard ratios (HRs) and 95% CIs, we used the Cox proportional hazards model, adjusting for age, smoking, and population density.Results: In adjusted models, the HR for the highest compared with the lowest quartile of each metal ranged from 0.78 (95% CI: 0.59, 1.04) for chromium to 1.33 (95% CI: 0.98, 1.79) for mercury.Conclusions: Overall, we found limited evidence for the association between adulthood ambient exposure to metals and risk of PD. The results for mercury need to be confirmed in future studies.Citation: Palacios N, Fitzgerald K, Roberts AL, Hart JE, Weisskopf MG, Schwarzschild MA, Ascherio A, Laden F. 2014. A prospective analysis of airborne metal exposures and risk of Parkinson disease in the Nurses’ Health Study Cohort. Environ Health Perspect 122:933–938; http://dx.doi.org/10.1289/ehp.1307218     

Environmental Health Research Recommendations from the Inter-Environmental Health Sciences Core Center Working Group on Unconventional Natural Gas Drilling Operations

Background: Unconventional natural gas drilling operations (UNGDO) (which include hydraulic fracturing and horizontal drilling) supply an energy source that is potentially cleaner than liquid or solid fossil fuels and may provide a route to energy independence. However, significant concerns have arisen due to the lack of research on the public health impact of UNGDO.Objectives: Environmental Health Sciences Core Centers (EHSCCs), funded by the National Institute of Environmental Health Sciences (NIEHS), formed a working group to review the literature on the potential public health impact of UNGDO and to make recommendations for needed research.Discussion: The Inter-EHSCC Working Group concluded that a potential for water and air pollution exists that might endanger public health, and that the social fabric of communities could be impacted by the rapid emergence of drilling operations. The working group recommends research to inform how potential risks could be mitigated.Conclusions: Research on exposure and health outcomes related to UNGDO is urgently needed, and community engagement is essential in the design of such studies.Citation: Penning TM, Breysse PN, Gray K, Howarth M, Yan B. 2014. Environmental health research recommendations from the Inter-Environmental Health Sciences Core Center Working Group on Unconventional Natural Gas Drilling Operations. Environ Health Perspect 122:1155–1159; http://dx.doi.org/10.1289/ehp.1408207     

Diversity Outbred Mice Identify Population-Based Exposure Thresholds and Genetic Factors that Influence Benzene-Induced Genotoxicity

Background

Inhalation of benzene at levels below the current exposure limit values leads to hematotoxicity in occupationally exposed workers.

Objective

We sought to evaluate Diversity Outbred (DO) mice as a tool for exposure threshold assessment and to identify genetic factors that influence benzene-induced genotoxicity.

Methods

We exposed male DO mice to benzene (0, 1, 10, or 100 ppm; 75 mice/exposure group) via inhalation for 28 days (6 hr/day for 5 days/week). The study was repeated using two independent cohorts of 300 animals each. We measured micronuclei frequency in reticulocytes from peripheral blood and bone marrow and applied benchmark concentration modeling to estimate exposure thresholds. We genotyped the mice and performed linkage analysis.

Results

We observed a dose-dependent increase in benzene-induced chromosomal damage and estimated a benchmark concentration limit of 0.205 ppm benzene using DO mice. This estimate is an order of magnitude below the value estimated using B6C3F1 mice. We identified a locus on Chr 10 (31.87 Mb) that contained a pair of overexpressed sulfotransferases that were inversely correlated with genotoxicity.

Conclusions

The genetically diverse DO mice provided a reproducible response to benzene exposure. The DO mice display interindividual variation in toxicity response and, as such, may more accurately reflect the range of response that is observed in human populations. Studies using DO mice can localize genetic associations with high precision. The identification of sulfotransferases as candidate genes suggests that DO mice may provide additional insight into benzene-induced genotoxicity.

Citation

French JE, Gatti DM, Morgan DL, Kissling GE, Shockley KR, Knudsen GA, Shepard KG, Price HC, King D, Witt KL, Pedersen LC, Munger SC, Svenson KL, Churchill GA. 2015. Diversity Outbred mice identify population-based exposure thresholds and genetic factors that influence benzene-induced genotoxicity. Environ Health Perspect 123:237–245; http://dx.doi.org/10.1289/ehp.1408202