Associations of maternal arsenic exposure with adult fasting glucose and insulin resistance in the Strong Heart Study and Strong Heart Family Study

Experimental and prospective epidemiologic evidence suggest that arsenic exposure has diabetogenic effects. However, little is known about how family exposure to arsenic may affect risk for type 2 diabetes (T2D)-related outcomes in adulthood. We evaluated the association of both maternal and offspring arsenic exposure with fasting glucose and incident T2D in 466 participants of the Strong Heart Family Study. Total arsenic (ΣAs) exposure was calculated as the sum of inorganic arsenic (iAs) and methylated (MMA, DMA) arsenic species in maternal and offspring baseline urine. Median maternal ΣAs at baseline (1989-91) was 7.6 µg/g creatinine, while median offspring ΣAs at baseline (2001-03) was 4.5 µg/g creatinine. Median offspring glucose in 2006-2009 was 94 mg/dL, and 79 participants developed T2D. The fully adjusted mean difference (95% CI) for offspring glucose was 4.40 (-3.46, 12.26) mg/dL per IQR increase in maternal ΣAs vs. 2.72 (-4.91 to 10.34) mg/dL per IQR increase in offspring ΣAs. The fully adjusted odds ratio (95%CI) of incident T2D was 1.35 (1.07, 1.69) for an IQR increase in maternal ΣAs and 1.15 (0.92, 1.43) for offspring ΣAs. The association of maternal ΣAs with T2D outcomes were attenuated with adjustment for offspring adiposity markers. Familial exposure to arsenic, as measured in mothers 15-20 years before offspring follow-up, is associated with increased odds of offspring T2D. More research is needed to confirm findings and better understand the importance of family exposure to arsenic in adult-onset diabetes.This study was supported by the National Institute of EnvironmentalHealth Sciences, Unites States (P42ES010349, P30ES009089,R01ES028758, R01ES025216).N.T., P.F.-L., and A.N.-A. contributed to the preparation of researchdata and writing of the manuscript. N.T, M.J.S, A.D.-R., M.T.-P., M.G.-P., and A.N.-A. contributed to the statistical analysis. B.V.H., J.M., K.N.,J.G.U., and S.C. contributed as the primary investigators of the SHS andSHFS, and to the preparation of the research data. K.A.F. and W.G.contributed to the arsenic measurements in the SHS and SHFS partici-pants. A.N.-A. is the guarantor of this work and, as such, had full accessto all the data in the study and takes responsibility for the integrity ofthe data and the accuracy of the data analysis.S

The Association of Arsenic Exposure and Metabolism With Type 1 and Type 2 Diabetes in Youth: The SEARCH Case-Control Study

Little is known about arsenic and diabetes in youth. We examined the association of arsenic with type 1 and type 2 diabetes in the SEARCH for Diabetes in Youth Case-Control (SEARCH-CC) study. Because one-carbon metabolism can influence arsenic metabolism, we also evaluated the potential interaction of folate and vitamin B12 with arsenic metabolism on the odds of diabetes

ARSENIC, TARGETED METABOLOMICS AND DIABETES-RELATED OUTCOMES: CONNECTING THE DOTS IN THE STRONG HEART STUDY

Diabetes, and related outcomes, is a global epidemic with an enormous cost both to the economy and in terms of lives lost. Exposure to inorganic arsenic, a ubiquitous naturally occurring environmental carcinogen, as well as the efficiency of its metabolism in the body, has been identified as a risk factor for diabetes development. One carbon metabolism (OCM), a biochemical pathway essential to numerous methylation reactions, including arsenic metabolism, appears to play an important role both in arsenic metabolism and diabetes-related outcomes. This dissertation aimed to better understand the relationships between each of these variables and determine whether arsenic metabolism is truly a risk factor for diabetes, or if the association is an epidemiological artifact confounded by OCM status. We used data from both the Strong Heart Study (SHS), a population-based cohort, as well as the Strong Heart Family Study (SHFS), a family-based extension of the SHS. Both populations are comprised of American Indian tribal members from Oklahoma, Arizona and North and South Dakota, exposed to low-moderate arsenic in drinking water and food, with high rates of diabetes and diabetes-related outcomes. First, we conducted a cross-sectional analysis evaluating the association of dietary intake of OCM nutrients (folate and vitamins B2, B6 and B12) with urinary arsenic methylation patterns (iAs%, MMA% and DMA%) in a subset (n=405) of participants from the SHS. Higher vitamin B6 and B2 were associated with higher DMA% and lower MMA% (i.e., a more efficient arsenic metabolism profile). We also observed an antagonistic interaction between folate and vitamin B6 with higher folate being associated with higher DMA% and lower iAs% only in the presence of high vitamin B6. Second, we conducted a prospective analysis in 1,047 SHFS participants free of prevalent metabolic syndrome, evaluating the association of arsenic exposure and arsenic metabolism with incident metabolic syndrome and each of its individual components (elevated waist circumference, elevated triglycerides, reduced HDL, hypertension and elevated fasting plasma glucose (FPG)). Arsenic exposure was associated with increased risk for elevated FPG but not with metabolic syndrome or other individual components. Arsenic metabolism patterns, independent of arsenic exposure, were associated with both incident metabolic syndrome and elevated waist circumference, but not with other components of the syndrome. Third, we conducted a pilot (n=59) cross-sectional targeted metabolomic analysis in the SHFS. Eight metabolites were identified as having significant correlations with both a diabetes-related outcome (HOMA2-IR, FPG, waist circumference) and at least one arsenic metabolism biomarker (iAs%, MMA% or DMA%). Consistent with previous studies, higher MMA% was associated with lower HOMA2-IR and waist circumference, and higher DMA% was associated with higher HOMA2-IR and waist circumference After adjustment for the eight OCM-related metabolites, associations between arsenic metabolism and diabetes-related outcomes were substantially attenuated and no longer significant. Fourth, we conducted a set of analyses using data from the SHFS to better understand the role OCM status plays in arsenic metabolism, diabetes-related outcomes and the relationship between the two. We first conducted cross-sectional analyses evaluating the association between OCM variables (both genetic and nutrient intake) and arsenic metabolism (iAs%, MMA% and DMA%). Next, we evaluated the associations between both OCM nutrients and OCM-related genetic variants with diabetes-related outcomes (diabetes, metabolic syndrome, waist circumference and HOMA2-IR). OCM nutrients were not associated with arsenic metabolism in the SHFS, however, higher vitamin B6 was consistently associated with three of the four diabetes-related outcomes studied (higher HOMA2-IR and increased risk for diabetes and metabolic syndrome). One OCM-related genetic variant (methionine synthase) was associated with both higher MMA% and lower HOMA2-IR per 5 years of follow-up. After adjustment for MMA% the association between the MTR variant and all diabetes-related outcomes were attenuated or reversed direction. In conclusion, arsenic exposure and arsenic metabolism may be risk factors for diabetes-related outcomes, even at low-moderate arsenic exposure. OCM status may also be a risk factor for diabetes-related outcomes as well as for arsenic metabolism, although these associations may differ based on the underlying nutritional state of the population. OCM status, diabetes-related outcomes and arsenic metabolism appear to be linked; more research is needed to understand the direction of the associations, in order leverage these findings into diabetes preventative efforts

Usage of Children’s Makeup and Body Products in the United States and Implications for Childhood Environmental Exposures

There is growing evidence of toxicity associated with ingredients found in cosmetics and personal care products. Children’s makeup and body products (CMBPs) are widely marketed to children throughout the US; however, little is known about how and why children use them. We administered a survey to parents/guardians of children aged ≤12 years about the use of CMBPs. Among all the children (n = 312) of survey respondents (n = 207), 219 (70%) have used CMBPs in their lifetime. Older children used CMBPs at higher rates than younger children, and female children used CMBPs at higher rates than male children. Children of Hispanic/Latinx parents/guardians used CMBPs more often and for shorter durations and a greater proportion used lip, hair, and fragrance products than children of non-Hispanic parents/guardians. Approximately half the children that use CMBPs were reported to use them with play intentions. Compared to children of non-Hispanic parents/guardians, children of Hispanic/Latinx parents/guardians reported more play motivations for CMBP use. Using qualitative analysis approaches, responses suggest CMBPs are commonly used for fun or play activities. This mixed methods analysis serves as an introduction to understanding early life exposures to this unique and understudied class of products

Association of Low-Moderate Arsenic Exposure and Arsenic Metabolism with Incident Diabetes and Insulin Resistance in the Strong Heart Family Study.

BACKGROUND: High arsenic exposure has been related to diabetes, but at low-moderate levels the evidence is mixed. Arsenic metabolism, which is partly genetically controlled and may rely on certain B vitamins, plays a role in arsenic toxicity. OBJECTIVE: We evaluated the prospective association of arsenic exposure and metabolism with type 2 diabetes and insulin resistance. METHODS: We included 1,838 American Indian men and women free of diabetes (median age, 36 y). Arsenic exposure was assessed as the sum of inorganic arsenic (iAs), monomethylarsonate (MMA), and dimethylarsinate (DMA) urine concentrations (ΣAs). Arsenic metabolism was evaluated by the proportions of iAs, MMA, and DMA over their sum (iAs%, MMA%, and DMA%). Homeostasis model assessment for insulin resistance (HOMA2-IR) was measured at baseline and follow-up visits. Incident diabetes was evaluated at follow-up. RESULTS: Median ΣAs, iAs%, MMA%, and DMA% was 4.4 μg/g creatinine, 9.5%, 14.4%, and 75.6%, respectively. Over 10,327 person-years of follow-up, 252 participants developed diabetes. Median HOMA2-IR at baseline was 1.5. The fully adjusted hazard ratio [95% confidence interval (CI)] for incident diabetes per an interquartile range increase in ΣAs was 1.57 (95% CI: 1.18, 2.08) in participants without prediabetes at baseline. Arsenic metabolism was not associated with incident diabetes. ΣAs was positively associated with HOMA2-IR at baseline but negatively with HOMA2-IR at follow-up. Increased MMA% was associated with lower HOMA2-IR when either iAs% or DMA% decreased. The association of arsenic metabolism with HOMA2-IR differed by B-vitamin intake and AS3MT genetics variants. CONCLUSIONS: Among participants without baseline prediabetes, arsenic exposure was associated with incident diabetes. Low MMA% was cross-sectional and prospectively associated with higher HOMA2-IR. Research is needed to confirm possible interactions of arsenic metabolism with B vitamins and AS3MT variants on diabetes risk. https://doi.org/10.1289/EHP2566

Maternal DNA methylation signatures of arsenic exposure is associated with adult offspring insulin resistance in the Strong Heart Study

Exposure to low to moderate arsenic (As) levels has been associated with type 2 diabetes (T2D) and other chronic diseases in American Indian communities. Prenatal exposure to As may also increase the risk for T2D in adulthood, and maternal As has been associated with adult offspring metabolic health measurements. We hypothesized that T2D-related outcomes in adult offspring born to women exposed to low to moderate As can be evaluated utilizing a maternally-derived molecular biosignature of As exposure. Herein, we evaluated the association of maternal DNA methylation with incident T2D and insulin resistance (Homeostatic model assessment of insulin resistance [HOMA2-IR]) in adult offspring. For DNA methylation, we used 20 differentially methylated cytosine-guanine dinucleotides (CpG) previously associated with the sum of inorganic and methylated As species (ΣAs) in urine in the Strong Heart Study (SHS). Of these 20 CpGs, we found six CpGs nominally associated (p < 0.05) with HOMA2-IR in a fully adjusted model that included clinically relevant covariates and offspring adiposity measurements; a similar model that adjusted instead for maternal adiposity measurements found three CpGs nominally associated with HOMA2-IR, two of which overlapped the offspring adiposity model. After adjusting for multiple comparisons, cg03036214 remained associated with HOMA2-IR (q < 0.10) in the offspring adiposity model. The odds ratio of incident T2D increased with an increase in maternal DNA methylation at one HOMA2-IR associated CpG in the model adjusting for offspring adiposity, cg12116137, whereas adjusting for maternal adiposity had a minimal effect on the association. Our data suggests offspring adiposity, rather than maternal adiposity, potentially influences the effects of maternal DNAm signatures on offspring metabolic health parameters. Here, we have presented evidence supporting a role for epigenetic biosignatures of maternal As exposure as a potential biomarker for evaluating risk of T2D-related outcomes in offspring later in life