Interaction between a Mixture of Heavy Metals (Lead, Mercury, Arsenic, Cadmium, Manganese, Aluminum) and GSTP1, GSTT1, and GSTM1 in Relation to Autism Spectrum Disorder.

BACKGROUND: Exposure to many environmental chemicals, including metals, often does not occur in isolation, hence requires assessment of the associations between exposure to mixtures of chemicals and human health. OBJECTIVES: To investigate associations of a metal mixture of lead (Pb), mercury (Hg), arsenic (As), cadmium (Cd), manganese (Mn), and aluminum (Al) in children with autism spectrum disorder (ASD), additively or interactively with each of three glutathione S-transferase (GST) genes (GSTP1, GSTT1, and GSTM1). METHOD: Using data from 266 case-control pairs of Jamaican children (2-8 years old), we fitted negative and positive generalized weighted quantile sum (gWQS) regression models to assess the aforementioned associations. RESULTS: Based on additive and interactive negative gWQS models adjusted for maternal age, parental education, child's parish, and seafood consumption, we found inverse associations of the overall mixture score with ASD [MOR (95% CI): 0.70 (0.49, 0.99); P < 0.05) and [MOR (95%CI): 0.46 (0.25, 0.84); P = 0.01], respectively. In an unadjusted negative gWQS model, we found a marginally significant interaction between GSTP1 and a mixture of three metals (Pb, Hg, and Mn) (P = 0.07) while the association was no longer significant after adjustment for the same covariates (P = 0.24). CONCLUSIONS: Differences in diet between ASD and control groups may play a role in the inverse associations we found. The possible interactive association between Mn and GSTP1 in ASD based on gWQS is consistent with our previous reports. However, possible interaction of GSTP1 with Pb and Hg in ASD requires further investigation and replication.

Association of Polychlorinated Biphenyls and Organochlorine Pesticides with Autism Spectrum Disorder in Jamaican Children.

BACKGROUND: Polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides are suspected to play a role in autism spectrum disorder (ASD). OBJECTIVES: To investigate associations of PCBs and OC pesticides with ASD in Jamaican children and explore possible interaction between PCBs or OC pesticides with glutathione S-transferase (GST) genes (GSTT1, GSTM1, GSTP1) in relation to ASD. METHODS: Participants included n=169 age- and sex-matched case-control pairs of Jamaican children 2-8 years old. Socioeconomic status and food frequency data were self-reported by the parents/guardians. Blood from each participant was analyzed for 100 PCB congeners and 17 OC pesticides and genotyped for three GST genes. PCBs and OC pesticides concentrations below the limit of detection (LoD) were replaced with (LoD/√2). We used conditional logistic regression (CLR) models to assess associations of PCBs and OC pesticides with ASD, individually or interactively with GST genes (GSTT1, GSTM1, GSTP1). RESULTS: We found inverse associations of PCB-153 [adjusted MOR (95% CI) = 0.44 (0.23-0.86)] and PCB-180 [adjusted MOR (95% CI) = 0.52 (0.28-0.95)] with ASD. When adjusted for covariates in a CLR the interaction between GSTM1 and PCB-153 became significant (P < 0.01). DISCUSSION: Differences in diet between ASD and typically developing control groups may play a role in the observed findings of lower concentrations of PCB-153 and PCB-180 in individuals with ASD than in controls. Considering the limited sample size and high proportion of concentrations below the LoD, these results should be interpreted with caution but warrant further investigation into associations of PCBs and OC pesticides with ASD.

Perinatal Factors Associated with Autism Spectrum Disorder in Jamaican Children.

Mode of delivery, preterm birth, and low birth weight (LBW) are hypothesized to be associated with autism spectrum disorder (ASD) in the offspring. Using data from 343 ASD cases (2-8 years) and their age- and sex-matched typically developing controls in Jamaica we investigated these hypotheses. Our statistical analyses revealed that the parish of residence could modify the association between cesarean delivery and ASD, with a difference found in this relationship in Kingston parish [matched odds ratio (MOR) (95% confidence interval (CI)) 2.30 (1.17-4.53)] and other parishes [MOR (95% CI) 0.87 (0.48-1.59)]. Although the associations of LBW and preterm birth with ASD were not significant, we observed a significant interaction between LBW and the household socioeconomic status. These findings require replication.

Concentrations of Lead, Mercury, Arsenic, Cadmium, Manganese, and Aluminum in Blood of Romanian Children Suspected of Having Autism Spectrum Disorder.

Environmental exposure to lead (Pb), mercury (Hg), arsenic (As), cadmium (Cd), manganese (Mn), and aluminum (Al) has been associated with neurodevelopmental disorders including autism spectrum disorder (ASD). We conducted a pilot study during May 2015-May 2107 to estimate blood concentrations of six metals (Pb, Hg, As, Cd, Mn, and Al) and identify their associated factors for children with ASD or suspected of having ASD in Romania. Sixty children, age 2-8 years, were administered versions of ADOS or ADI-R translated from English to Romanian. After assessment, 2-3 mL of blood was obtained and analyzed for the concentrations of the six metals. The mean age of children was 51.9 months and about 90% were male. More than half (65%) of the children were born in Bucharest. Over 90% of concentrations of As and Cd were below limits of detection. Geometric mean concentrations of Pb, Mn, Al, and Hg were 1.14 µg/dL, 10.84 µg/L, 14.44 µg/L, and 0.35 µg/L, respectively. Multivariable linear regression analysis revealed that children who were female, had less educated parents, exhibited pica, and ate cold breakfast (e.g., cereal), watermelon, and lamb had significantly higher concentrations of Pb compared to their respective referent categories (all p < 0.05 except for eating lamb, which was marginally significant, p = 0.053). Although this is the first study that provides data on concentrations of the six metals for Romanian children with ASD, the findings from this study could be useful for designing future epidemiologic studies for investigating the role of these six metals in ASD in Romanian children.

A generalized weighted quantile sum approach for analyzing correlated data in the presence of interactions.

A weighted quantile sum (WQS) regression has been used to assess the associations between environmental exposures and health outcomes. However, the currently available WQS approach, which is based on additive effects, does not allow exploring for potential interactions of exposures with other covariates in relation to a health outcome. In addition, the current WQS cannot account for clustering, thus it may not be valid for analysis of clustered data. We propose a generalized WQS approach that can assess interactions by estimating stratum-specific weights of exposures in a mixture, while accounting for potential clustering effect of matched pairs of cases and controls as well as censored exposure data due to being below the limits of detection. The performance of the proposed method in identifying interactions is evaluated through simulations based on various scenarios of correlation structures among the exposures and with an outcome. We also assess how well the proposed method performs in the presence of the varying levels of censoring in exposures. Our findings from the simulation study show that the proposed method outperforms the traditional WQS, as indicated by higher power of detecting interactions. We also find no strong evidence that the proposed method falsely identifies interactions when there are no true interactive effects. We demonstrate application of the proposed method to real data from the Epidemiological Research on Autism Spectrum Disorder (ASD) in Jamaica (ERAJ) by examining interactions between exposure to manganese and glutathione S-transferase family gene, GSTP1 in relation to ASD.