Evaluating the effects between metal mixtures and serum vaccine antibody concentrations in children: a prospective birth cohort study.

BACKGROUND: Many populations are exposed to arsenic, lead, and manganese. These metals influence immune function. We evaluated the association between exposure to single and multiple metals, including arsenic, lead, and manganese, to humoral immunity as measured by antibody concentrations to diphtheria and tetanus toxoid among vaccinated Bangladeshi children. Additionally, we examined if this association was potentially mediated by nutritional status. METHODS: Antibody concentrations to diphtheria and tetanus were measured in children's serum at age 5 (n = 502). Household drinking water was sampled to quantify arsenic (W-As) and manganese (W-Mn), whereas lead was measured in blood (B-Pb). Exposure samples were taken during pregnancy, toddlerhood, and early childhood. Multiple linear regression models (MLRs) with single or combined metal predictors were used to determine the association with antibody outcomes. MLR results were transformed to units of percent change in outcome per doubling of exposure to improve interpretability. Structural equation models (SEMs) were used to further assess exposure to metal mixtures. SEMs regressed a latent exposure variable (Metals), informed by all measured metal variables (W-As, W-Mn, and B-Pb), on a latent outcome variable (Antibody), informed by measured antibody variables (diphtheria and tetanus). Weight-for-age z-score (WFA) at age 5 was evaluated as a mediator. RESULTS: Diphtheria antibody was negatively associated with W-As during pregnancy in MLR, but associations were attenuated after adjusting for W-Mn and B-Pb (- 2.9% change in diphtheria antibody per doubling in W-As, 95% confidence interval [CI]: - 7%, 1.5%). Conversely, pregnancy levels of B-Pb were positively associated with tetanus antibody, even after adjusting for W-As and W-Mn (13.3%, 95% CI: 1.7%, 26.3%). Overall, null associations were observed between W-Mn and antibody outcomes. Analysis by SEMs showed that the latent Metals mixture was significantly associated with the latent Antibody outcome (ß = - 0.16, 95% CI: - 0.26, - 0.05), but the Metals variable was characterized by positive and negative loadings of W-As and B-Pb, respectively. Sex-stratified MLR and SEM analyses showed W-As and B-Pb associations were exclusive to females. Mediation by WFA was null, indicating Metals only had direct effects on Antibody. CONCLUSIONS: We observed significant modulation of vaccine antibody concentrations among children with pregnancy and early life exposures to drinking water arsenic and blood lead. We found distinct differences by child sex, as only females were susceptible to metal-related modulations in antibody levels. Weight-for-age, a nutritional status proxy, did not mediate the association between the metal mixture and vaccine antibody.

A prospective cohort study of in utero and early childhood arsenic exposure and infectious disease in 4- to 5-year-old Bangladeshi children.

BACKGROUND: Previous research found that infants who were exposed to high levels of arsenic in utero had an increased risk of infectious disease in the first year of life. This prospective study examined the association between arsenic exposures during gestation, and respiratory, diarrheal, and febrile morbidity in children 4-5 years of age. METHODS: A cohort of pregnant women was recruited in 2008-2011 in Bangladesh. Their children (N = 989) were followed, and household drinking water samples were collected during pregnancy, toddlerhood (12-40 months of age), and childhood (4-5 years of age). We actively surveyed mothers every 2 weeks regarding their children's infectious diseases symptoms from 4 to 5 years of age. Poisson regression models were used to estimate the association between arsenic exposure and respiratory and febrile illness. RESULTS: Median drinking water arsenic was 4.6, 8.8, and 4.2 µg/L in pregnancy, toddlerhood, and childhood, respectively. We observed 0.01, 1.2, and 1.0 cases per 100 person-days of diarrhea, respiratory, and febrile illness, respectively. The incident rate ratios (IRRs) for each doubling of drinking water arsenic during pregnancy were 1.10 (95% confidence interval [CI] = 1.00, 1.22) and 0.93 (95% CI = 0.82, 1.05) for respiratory and febrile illness, respectively, after adjusting for covariates. The association between arsenic exposure measured during toddlerhood and childhood was attenuated and not significantly associated with either outcome. Diarrheal disease was too infrequent to assess. CONCLUSIONS: Drinking water arsenic exposure during pregnancy was associated with a higher risk of acute respiratory infections in children 4-5 years old in Bangladesh.

Arsenic exposure and serum antibody concentrations to diphtheria and tetanus toxoid in children at age 5: A prospective birth cohort in Bangladesh.

BACKGROUND: Arsenic can impair immune function. Timing of exposure can influence potential immunotoxicity of arsenic exposure. We examined the association between drinking water arsenic concentrations (W-As) measured repeatedly during different exposure windows in early life and serum concentrations of IgG antibodies against diphtheria and tetanus toxoids (diphtheria and tetanus antibody). METHODS: A prospective cohort of pregnant women was recruited in Bangladesh (2008-2011). Averaged W-As levels were calculated for: pregnancy (W-Aspregnancy): ≤16 weeks gestation and <1 month; toddlerhood (W-Astoddlerhood): 12 and 20-40 months; and early childhood (W-Aschildhood): 4-5 years. Serum was collected from 502 vaccinated children at age 5 and concentrations of diphtheria and tetanus toxoid IgG (i.e. antibody) were quantified. Antibody concentrations >0.1 IU/mL were considered clinically sufficient for protection. Associations were estimated using linear and logistic regression models. RESULTS: Inverse associations were observed between W-Aspregnancy and serum diphtheria antibody levels, while null associations were observed between W-As and tetanus antibody. Children within the highest versus lowest tertile of W-Aspregnancy had 91% greater odds of having clinically insufficient concentrations of diphtheria antibody (Odds ratio:1.91, 95% confidence interval (CI): 1.03, 3.56). Among females, a doubling in W-Aspregnancy was associated with 12.3% (95%CI: -20.1%, -4.5%) lower median concentrations of diphtheria antibody. Tetanus antibody was only associated with W-Aspregnancy among females (percent change in median: -9.5%, 95%CI: -17.6%, -1.3%). Among children who were stunted or underweight, a doubling in W-Aspregnancy was associated with decreased diphtheria antibody of 19.8% (95%CI: -32%, -7.5%) and 14.3% (95%CI: -26.7%, -2%), respectively. CONCLUSIONS: Among vaccinated children, W-As measured during pregnancy was associated with decreased diphtheria antibody levels, but not tetanus antibody. However, W-As measured during toddlerhood and early childhood were not associated with either antibody outcome. Children's sex and malnutrition status were important effect modifiers of W-As for both diphtheria and tetanus antibody levels, highlighting the importance of these factors and the timing of the exposure when evaluating the effect of arsenic on humoral immunity.