Association between body mass index and arsenic methylation in three studies of Bangladeshi adults and adolescents

Abstract

Background: Water-borne arsenic (As) exposure is a global health problem. Once ingested, inorganic As (iAs) is methylated to mono-methyl (MMA) and dimethyl (DMA) arsenicals via one-carbon metabolism (OCM). People with higher relative percentage of MMA (MMA%) in urine (inefficient As methylation), have been shown to have a higher risk of cardiovascular disease and several cancers but appear to have a lower risk of diabetes and obesity in populations from the US, Mexico, and Taiwan. It is unknown if this opposite pattern with obesity is present in Bangladesh, a country with lower adiposity and higher As exposure in drinking water.

Objective: To characterize the association between body mass index (BMI) and As methylation in Bangladeshi adults and adolescents participating in the Folic Acid and Creatine Trial (FACT); Folate and Oxidative Stress (FOX) study; and Metals, Arsenic, and Nutrition in Adolescents Study (MANAS).

Methods: Arsenic species (iAs, MMA, DMA) were measured in urine and blood. Height and weight were measured to calculate BMI. The associations between concurrent BMI with urine and blood As species were analyzed using linear regression models, adjusting for nutrients involved in OCM such as choline. In FACT, we also evaluated the prospective association between weight change and As species.

Results: Mean BMIs were 19.2/20.4, 19.8/21.0, and 17.7/18.7 kg/m² in males/females in FACT, FOX, and MANAS, respectively. BMI was associated with As species in female but not in male participants. In females, after adjustment for total urine As, age, and plasma folate, the adjusted mean differences (95% confidence) in urinary MMA% and DMA% for a 5 kg/m² difference in BMI were -1.21 (-1.96, -0.45) and 2.47 (1.13, 3.81), respectively in FACT, -0.66 (-1.56, 0.25) and 1.43 (-0.23, 3.09) in FOX, and -0.59 (-1.19, 0.02) and 1.58 (-0.15, 3.30) in MANAS. The associations were attenuated after adjustment for choline. Similar associations were observed with blood As species. In FACT, a 1-kg of weight increase over 2 to 10 (mean 5.4) years in males/females was prospectively associated with mean DMA% that was 0.16%/0.19% higher.

Discussion: BMI was negatively associated with MMA% and positively associated with %DMA in females but not males in Bangladesh; associations were attenuated after plasma choline adjustment. These findings may be related to the role of body fat on estrogen levels that can influence one-carbon metabolism, e.g. by increasing choline synthesis. Research is needed to determine whether the associations between BMI and As species are causal and their influence on As-related health outcomes.

Keywords: Arsenic; Arsenic biomarkers; Arsenic methylation; Bangladesh; Body mass index; One-carbon metabolism.

Figure A.1

Correlation matrices for female and male participants in FACT (A & B), FOX (C & D), and MANAS (E & F), respectively. Spearman Correlations between arsenic species, BMI, and OCM metabolites of interest. ΣAs is log-transformed. Abbreviations: Total uAs (sum of inorganic arsenic and its methylated species); uiAs (urinary inorganic arsenic); uMMA (urinary monomethylarsonic acid); uDMA (urinary dimethylarsinic acid); Folate (plasma folate); Choline (plasma choline); and BMI (body mass index).

Figure A.1

Correlation matrices for female and male participants in FACT (A & B), FOX (C & D), and MANAS (E & F), respectively. Spearman Correlations between arsenic species, BMI, and OCM metabolites of interest. ΣAs is log-transformed. Abbreviations: Total uAs (sum of inorganic arsenic and its methylated species); uiAs (urinary inorganic arsenic); uMMA (urinary monomethylarsonic acid); uDMA (urinary dimethylarsinic acid); Folate (plasma folate); Choline (plasma choline); and BMI (body mass index).

Figure A.1.2

Correlation matrices for female and male participants in FACT (A & B), FOX (C & D), respectively. Spearman Correlations between arsenic species, BMI, and OCM metabolites of interest. ΣAs is log-transformed. Abbreviations: Total bAs (sum of inorganic arsenic and its methylated species in blood); biAs (blood inorganic arsenic); bMMA (blood monomethylarsonic acid); bDMA (blood dimethylarsinic acid); Folate (plasma folate); Choline (plasma choline); and BMI (body mass index).

Figure A.2.

Triplots and compositional means of female participants’ uAs species by BMI levels in FACT (A), FOX (B), and MANAS (C). This triplot illustrates the distribution of uAs species in female participants from the lowest (lightest), to highest (darkest) BMI levels. The large circle, square, diamond, and triangle represent the uAs species compositional means for participants in the respective BMI groups. The compositional means represent the average values for each of the three uAs species. DMA% is shown along the left axis, MMA% along the right axis, and iAs% along the bottom axis. (A) FACT, (B) FOX, (C) MANAS

Figure A.2.1

Triplots and compositional means of male participants’ uAs species by BMI levels in FACT (A), FOX (B), and MANAS (C). This triplot illustrates the distribution of uAs species in male participants from the lowest (lightest), to highest (darkest) BMI levels. The large circle, square, diamond, and triangle represent the uAs species compositional means for participants in the respective BMI groups. The compositional means represent the average values for each of the three uAs species. DMA% is shown along the left axis, MMA% along the right axis, and iAs% along the bottom axis. (A) FACT, (B) FOX, (C) MANAS

Figure A.2.2

Triplots and compositional means of female and male participants’ bAs species by BMI levels in FACT (A & B) and FOX (B & C), respectively. This triplot illustrates the distribution of bAs species in male participants from the lowest (lightest), to highest (darkest) BMI levels. The large circle, square, diamond, and triangle represent the bAs species compositional means for participants in the respective BMI groups. The compositional means represent the average values for each of the three bAs species. DMA% is shown along the left axis, MMA% along the right axis, and iAs% along the bottom axis.

Figure A.3

Conceptual diagram of known and proposed associations between adiposity, arsenic, and choline. Solid black arrows indicate known associations based on prior evidence or evidence provided by this research. Dashed blue arrows indicate proposed reasons for associations.

Figure 1.

One-carbon metabolism (OCM) and nutrients relevant for this study.

Figure 2.

Participants recruited from HEALS for the three Bangladeshi studies analyzed with corresponding sample sizes. Complete metabolite data refers to participants that had measures for all predictor and outcome variables used in analyses.

Figure 3.

Median (IQR) urinary inorganic arsenic (iAs) and mono-methyl (MMA) and dimethyl (DMA) arsenical percentages among female participants in the underweight, normal, and overweight and obese BMI categories in all three Bangladeshi studies.

Figure 4.

Adjusted mean difference in urinary and blood arsenic species (%) for a 5- kg/m² difference in BMI in (A) FACT and (B) FOX. All models were adjusted for log-transformed total As (uAs for urine species and bAs for blood species), age and log-transformed plasma folate. Models 2 and 3 were further separately adjusted for plasma betaine/DMG and choline, respectively.