BACKGROUND Over 57 million people in Bangladesh have been chronically exposed to arsenic-contamin... more BACKGROUND Over 57 million people in Bangladesh have been chronically exposed to arsenic-contaminated drinking water. They also face environmental exposure to elevated levels of cadmium (Cd), manganese (Mn), and lead (Pb), all of which have been previously observed in environmental and biological samples for this population. These metals have been linked to adverse neurocognitive outcomes in adults and children, though their effects on adolescents are not yet fully characterized. Additionally, previous studies have linked selenium (Se) to protective effects against the toxicity of these other metals. OBJECTIVES To examine the associations between mixed metals exposure and cognitive function in Bangladeshi adolescents. METHODS The Metals, Arsenic, & Nutrition in Adolescents study (MANAs) is a cross-sectional study of 572 Bangladeshi adolescents aged 14-16 years, whose parents were enrolled in the Health Effects of Arsenic Longitudinal Study (HEALS). Biosamples were collected from these adolescents for measurement of whole blood metalloid/metal levels of As, Cd, Mn, Pb, and Se. Participants also completed an abbreviated version of The Cambridge Neuropsychological Test Automated Battery (CANTAB), a cognitive function test designed to measure performance across several aspects of executive function. Linear regression was used to examine associations for each metal while controlling for the other metals. Bayesian Kernel Machine Regression (BKMR) assessed the overall mixture effect in addition to confirming the effects of individual metal components observed via linear regression. RESULTS Linear regression revealed negative associations for Spatial Working Memory and both As and Mn (As B=-2.40, Mn B=-5.31, p < 0.05). We also observed negative associations between Cd and Spatial Recognition Memory (B=-2.77, p < 0.05), and Pb and Delayed Match to Sample, a measure of visual recognition and memory (B=-3.67, p < 0.05). Finally, we saw a positive association for Se and Spatial Span Length (B=0.92, p < 0.05). BKMR results were largely consistent with the regression analysis, showing meaningful associations for individual metals and CANTAB subtests, but no overall mixture effect. Via BKMR, we observed negative associations between Pb and Delayed Match to Sample, and Cd and Spatial Recognition Memory; this analysis also showed positive associations for Se and the Planning, Reaction Time, and Spatial Span subtests. BKMR posterior inclusion probability consistently reported that Se, the only component of the mixture to show a positive association with cognition, was the most important member of the mixture. CONCLUSIONS Overall, we found Se to be positively associated with cognition, while Mn and As were linked to poorer working memory, and Cd and Pb were associated with poorer visual recognition and memory. Our observations are consistent with previous reports on the effects of these metal exposures in adults and children. Our findings also suggest agreement between linear regression and BKMR methods for analyzing metal mixture exposures. Additional studies are needed to evaluate the impact of mixed metals exposure on adverse health and poorer cognition later in life for those exposed during adolescence. Findings also suggest that metal exposure mitigation efforts aimed at adolescents might influence lifelong cognitive outcomes in regions where environmental exposure to metals is endemic.
This file contains complete eQTL results for all eQTLs used in co-localization analyses. Summary ... more This file contains complete eQTL results for all eQTLs used in co-localization analyses. Summary results for all SNPs within 250 kb of the lead eSNP are provided
Number of top 100 age-associated CpGs in common between analysis methdos Methylspectrum and RefFr... more Number of top 100 age-associated CpGs in common between analysis methdos Methylspectrum and RefFreeEWAS. (PDF 222 kb)
UCSC genome location information for a subset of the top 100 age-associated CpGs observed to be s... more UCSC genome location information for a subset of the top 100 age-associated CpGs observed to be significantly associated with its Illumina assigned gene expression (PDF 112 kb)
Top 100 results across BEST (original) and HEALS (validation) datasets based on top age-associate... more Top 100 results across BEST (original) and HEALS (validation) datasets based on top age-associated CpGs observed in BEST. (PDF 69 kb)
Background: Exposure to inorganic arsenic (As) is associated with modest deficits in intellectual... more Background: Exposure to inorganic arsenic (As) is associated with modest deficits in intellectual function in young children. Few studies have examined associations in adolescence or whether co-exp...
Background: Home remedies can be considered as ‘quick-fixes’ to diseases and which are administer... more Background: Home remedies can be considered as ‘quick-fixes’ to diseases and which are administered to a patient for simple illnesses, which does not necessitate visits to a physician. It is plausible that traditional medicines started initially with home remedies, where a person or family members by sheer chance happened to ‘discover’ a remedy. Home remedies are quite common throughout the world and can yield valuable data on disease treatment if adequately documented. Methods: The objective of the present study was to document the home remedies used by people of Kadipur village in Chuadanga district, Bangladesh. Surveys were carried out with the help of a semistructured questionnaire. Results: It was observed that the people of the village use 33 plants distributed into 28 families as home remedies. These plants are used to treat diseases like burns, anemia, pain, fever, gastrointestinal disorders, heart disorders, abscess, cataract, diabetes, helminthiasis, urinary tract disorder...
BACKGROUND Water-borne arsenic (As) exposure is a global health problem. Once ingested, inorganic... more 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.
BACKGROUND Associations of arsenic (As) with the sum of 5-mC and 5-hmC levels have been reported;... more BACKGROUND Associations of arsenic (As) with the sum of 5-mC and 5-hmC levels have been reported; however, As exposure-related differences of the separated 5-mC and 5-hmC markers have rarely been studied. METHODS In this study, we evaluated the association of arsenic exposure biomarkers and 5-mC and 5-hmC in 30 healthy men (43-55 years) from the Aragon Workers Health Study (AWHS) (Spain) and 31 healthy men (31-50 years) from the Folic Acid and Creatinine Trial (FACT) (Bangladesh). We conducted 5-mC and 5-hmC profiling using Infinium MethylationEPIC arrays, on paired standard and modified (ox-BS in AWHS and TAB in FACT) bisulfite converted blood DNA samples. RESULTS The median for the sum of urine inorganic and methylated As species (ΣAs) (μg/L) was 12.5 for AWHS and 89.6 for FACT. The median of blood As (μg/L) was 8.8 for AWHS and 10.2 for FACT. At a statistical significance p-value cut-off of 0.01, the differentially methylated (DMP) and hydroxymethylated (DHP) positions were mostly located in different genomic sites. DMPs and DHPs attributed to the DIP2C gene were consistently observed for urine ΣAs and blood models both in AWHS and FACT. Three DMPs (annotated to CLEC12A) for AWHS and one DHP (annotated to NPLOC4) for FACT remained statistically significant after FDR correction. Pathways related to chronic diseases including cardiovascular, cancer and neurological were enriched. CONCLUSIONS While we identified common 5-hmC and 5-mC signatures in two populations exposed to varying levels of inorganic As, differences in As-related epigenetic sites across the study populations may additionally reflect low and high As-specific associations. This work contributes a deeper understanding of potential epigenetic dysregulations of As. However, further research is needed to confirm biological consequences associated with DIP2C epigenetic regulation and to investigate the role of 5-hmC and 5-mC separately in As-induced health disorders at different exposure levels.
Background: In human genetics research, it has become common practice for researchers to consider... more Background: In human genetics research, it has become common practice for researchers to consider returning genetic information to participants who wish to receive it. Research participants in lower-resource settings may have barriers or competing interests that reduce the benefit or relevance of such information. Thus, the decision to return genetic information in these settings may involve special considerations of participants’ interests and preferences. In this project, our goal was to assess Bangladeshi research participants’ attitudes towards receiving information regarding genetic susceptibility to the effects of consuming arsenic-contaminated drinking water, a serious environmental health concern in Bangladesh and other countries. Methods: We administered a short questionnaire to 200 individuals participating in the Health Effects of Arsenic Longitudinal Study. Associations between survey responses and participant characteristics were estimated using logistic regression. Res...
BACKGROUND Over 57 million people in Bangladesh have been chronically exposed to arsenic-contamin... more BACKGROUND Over 57 million people in Bangladesh have been chronically exposed to arsenic-contaminated drinking water. They also face environmental exposure to elevated levels of cadmium (Cd), manganese (Mn), and lead (Pb), all of which have been previously observed in environmental and biological samples for this population. These metals have been linked to adverse neurocognitive outcomes in adults and children, though their effects on adolescents are not yet fully characterized. Additionally, previous studies have linked selenium (Se) to protective effects against the toxicity of these other metals. OBJECTIVES To examine the associations between mixed metals exposure and cognitive function in Bangladeshi adolescents. METHODS The Metals, Arsenic, & Nutrition in Adolescents study (MANAs) is a cross-sectional study of 572 Bangladeshi adolescents aged 14-16 years, whose parents were enrolled in the Health Effects of Arsenic Longitudinal Study (HEALS). Biosamples were collected from these adolescents for measurement of whole blood metalloid/metal levels of As, Cd, Mn, Pb, and Se. Participants also completed an abbreviated version of The Cambridge Neuropsychological Test Automated Battery (CANTAB), a cognitive function test designed to measure performance across several aspects of executive function. Linear regression was used to examine associations for each metal while controlling for the other metals. Bayesian Kernel Machine Regression (BKMR) assessed the overall mixture effect in addition to confirming the effects of individual metal components observed via linear regression. RESULTS Linear regression revealed negative associations for Spatial Working Memory and both As and Mn (As B=-2.40, Mn B=-5.31, p < 0.05). We also observed negative associations between Cd and Spatial Recognition Memory (B=-2.77, p < 0.05), and Pb and Delayed Match to Sample, a measure of visual recognition and memory (B=-3.67, p < 0.05). Finally, we saw a positive association for Se and Spatial Span Length (B=0.92, p < 0.05). BKMR results were largely consistent with the regression analysis, showing meaningful associations for individual metals and CANTAB subtests, but no overall mixture effect. Via BKMR, we observed negative associations between Pb and Delayed Match to Sample, and Cd and Spatial Recognition Memory; this analysis also showed positive associations for Se and the Planning, Reaction Time, and Spatial Span subtests. BKMR posterior inclusion probability consistently reported that Se, the only component of the mixture to show a positive association with cognition, was the most important member of the mixture. CONCLUSIONS Overall, we found Se to be positively associated with cognition, while Mn and As were linked to poorer working memory, and Cd and Pb were associated with poorer visual recognition and memory. Our observations are consistent with previous reports on the effects of these metal exposures in adults and children. Our findings also suggest agreement between linear regression and BKMR methods for analyzing metal mixture exposures. Additional studies are needed to evaluate the impact of mixed metals exposure on adverse health and poorer cognition later in life for those exposed during adolescence. Findings also suggest that metal exposure mitigation efforts aimed at adolescents might influence lifelong cognitive outcomes in regions where environmental exposure to metals is endemic.
This file contains complete eQTL results for all eQTLs used in co-localization analyses. Summary ... more This file contains complete eQTL results for all eQTLs used in co-localization analyses. Summary results for all SNPs within 250 kb of the lead eSNP are provided
Number of top 100 age-associated CpGs in common between analysis methdos Methylspectrum and RefFr... more Number of top 100 age-associated CpGs in common between analysis methdos Methylspectrum and RefFreeEWAS. (PDF 222 kb)
UCSC genome location information for a subset of the top 100 age-associated CpGs observed to be s... more UCSC genome location information for a subset of the top 100 age-associated CpGs observed to be significantly associated with its Illumina assigned gene expression (PDF 112 kb)
Top 100 results across BEST (original) and HEALS (validation) datasets based on top age-associate... more Top 100 results across BEST (original) and HEALS (validation) datasets based on top age-associated CpGs observed in BEST. (PDF 69 kb)
Background: Exposure to inorganic arsenic (As) is associated with modest deficits in intellectual... more Background: Exposure to inorganic arsenic (As) is associated with modest deficits in intellectual function in young children. Few studies have examined associations in adolescence or whether co-exp...
Background: Home remedies can be considered as ‘quick-fixes’ to diseases and which are administer... more Background: Home remedies can be considered as ‘quick-fixes’ to diseases and which are administered to a patient for simple illnesses, which does not necessitate visits to a physician. It is plausible that traditional medicines started initially with home remedies, where a person or family members by sheer chance happened to ‘discover’ a remedy. Home remedies are quite common throughout the world and can yield valuable data on disease treatment if adequately documented. Methods: The objective of the present study was to document the home remedies used by people of Kadipur village in Chuadanga district, Bangladesh. Surveys were carried out with the help of a semistructured questionnaire. Results: It was observed that the people of the village use 33 plants distributed into 28 families as home remedies. These plants are used to treat diseases like burns, anemia, pain, fever, gastrointestinal disorders, heart disorders, abscess, cataract, diabetes, helminthiasis, urinary tract disorder...
BACKGROUND Water-borne arsenic (As) exposure is a global health problem. Once ingested, inorganic... more 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.
BACKGROUND Associations of arsenic (As) with the sum of 5-mC and 5-hmC levels have been reported;... more BACKGROUND Associations of arsenic (As) with the sum of 5-mC and 5-hmC levels have been reported; however, As exposure-related differences of the separated 5-mC and 5-hmC markers have rarely been studied. METHODS In this study, we evaluated the association of arsenic exposure biomarkers and 5-mC and 5-hmC in 30 healthy men (43-55 years) from the Aragon Workers Health Study (AWHS) (Spain) and 31 healthy men (31-50 years) from the Folic Acid and Creatinine Trial (FACT) (Bangladesh). We conducted 5-mC and 5-hmC profiling using Infinium MethylationEPIC arrays, on paired standard and modified (ox-BS in AWHS and TAB in FACT) bisulfite converted blood DNA samples. RESULTS The median for the sum of urine inorganic and methylated As species (ΣAs) (μg/L) was 12.5 for AWHS and 89.6 for FACT. The median of blood As (μg/L) was 8.8 for AWHS and 10.2 for FACT. At a statistical significance p-value cut-off of 0.01, the differentially methylated (DMP) and hydroxymethylated (DHP) positions were mostly located in different genomic sites. DMPs and DHPs attributed to the DIP2C gene were consistently observed for urine ΣAs and blood models both in AWHS and FACT. Three DMPs (annotated to CLEC12A) for AWHS and one DHP (annotated to NPLOC4) for FACT remained statistically significant after FDR correction. Pathways related to chronic diseases including cardiovascular, cancer and neurological were enriched. CONCLUSIONS While we identified common 5-hmC and 5-mC signatures in two populations exposed to varying levels of inorganic As, differences in As-related epigenetic sites across the study populations may additionally reflect low and high As-specific associations. This work contributes a deeper understanding of potential epigenetic dysregulations of As. However, further research is needed to confirm biological consequences associated with DIP2C epigenetic regulation and to investigate the role of 5-hmC and 5-mC separately in As-induced health disorders at different exposure levels.
Background: In human genetics research, it has become common practice for researchers to consider... more Background: In human genetics research, it has become common practice for researchers to consider returning genetic information to participants who wish to receive it. Research participants in lower-resource settings may have barriers or competing interests that reduce the benefit or relevance of such information. Thus, the decision to return genetic information in these settings may involve special considerations of participants’ interests and preferences. In this project, our goal was to assess Bangladeshi research participants’ attitudes towards receiving information regarding genetic susceptibility to the effects of consuming arsenic-contaminated drinking water, a serious environmental health concern in Bangladesh and other countries. Methods: We administered a short questionnaire to 200 individuals participating in the Health Effects of Arsenic Longitudinal Study. Associations between survey responses and participant characteristics were estimated using logistic regression. Res...
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