Search

BackgroundPrenatal exposures to metallic and metalloid trace elements have been linked to altered immune function in animal studies, but few epidemiologic studies have investigated immunological effects in humans. We evaluated the risk of bacterial sepsis (an extreme immune response to bacterial infection) in relation to prenatal metal/metalloid exposures, individually and jointly, within a US-based cohort of infants born extremely preterm.MethodsWe analyzed data from 269 participants in the US-based ELGAN cohort, which enrolled infants delivered at in utero fetal exposures. The infants were followed from birth to postnatal day 28 with bacterial blood culture results reported weekly to detect sepsis. Discrete-time hazard and quantile g-computation models were fit to estimate associations for individual trace elements and their mixtures with sepsis incidence.ResultsApproximately 30% of the extremely preterm infants developed sepsis during the follow-up period (median follow-up: 2 weeks). After adjustment for potential confounders, no trace element was individually associated with sepsis risk. However, there was some evidence of a non-monotonic relationship for cadmium, with hazard ratios (HRs) for the second, third, and fourth (highest) quartiles being 1.13 (95% CI: 0.51–2.54), 1.94 (95% CI: 0.87–4.32), and 1.88 (95% CI: 0.90–3.93), respectively. The HRs for a quartile increase in concentrations of all 8 elements, all 4 non-essential elements, and all 4 essential elements were 0.92 (95% CI: 0.68–1.25), 1.19 (95% CI: 0.92–1.55), and 0.77 (95% CI: 0.57–1.06). Cadmium had the greatest positive contribution whereas arsenic, copper, and selenium had the greatest negative contributions to the mixture associations.ConclusionsWe found some evidence that greater prenatal exposure to cadmium was associated with an increased the risk of bacterial sepsis in extremely preterm infants. However, this risk was counteracted by a combination of arsenic, copper, and selenium. Future studies are needed to confirm these findings and to evaluate the potential for nutritional interventions to prevent sepsis in high-risk infants.

Prenatal organophosphorus pesticide (OPP) exposure has been associated with child attention-deficit/hyperactivity disorder (ADHD) in agricultural communities and those that are exposed to residentially applied insecticides. To examine this association in populations that are exposed primarily through diet, we estimate the associations between prenatal OPP exposure and preschool ADHD in the Norwegian Mother, Father and Child Cohort Study (MoBa), and describe modification by paraoxonase 1 (PON1) gene variants. We used participants from the MoBa Preschool ADHD Sub-study (n = 259 cases) and a random sample of MoBa sub-cohort participants (n = 547) with birth years from 2004 to 2008. Prenatal urinary dialkylphosphate (DAP) metabolites (total diethylphosphate [∑DEP] and total dimethylphosphate [∑DMP]) were measured by an ultra-performance liquid chromatography-time-of-flight system and summed by molar concentration. Maternal DNA was genotyped for coding variants of PON1 (Q192R and L55M). We used a multivariable logistic regression to calculate the odds ratios (OR) and 95% confidence intervals, adjusted for maternal education, parity, income dependency, age, marital status, ADHD-like symptoms, pesticide use, produce consumption, and season. We found no associations between DAP metabolite concentrations and preschool ADHD. The adjusted ORs for exposure quartiles 2–4 relative to 1 were slightly inverse. No monotonic trends were observed, and the estimates lacked precision, likely due to the small sample size and variation in the population. We found no evidence of modification by PON1 SNP variation or child sex. Maternal urinary DAP concentrations were not associated with preschool ADHD.

INTRODUCTION: Prenatal exposure to organophosphorus pesticides (OPPs) has been associated with neurodevelopmental deficits in children, however evidence linking OPPs with specific cognitive mechanisms, such as executive function (EF), is limited. OBJECTIVE: This study aims to evaluate the association between prenatal exposure to OPPs with multiple measures of EF in preschool-aged children, while considering the role of variant alleles in OPP metabolism genes. METHODS: We included 262 children with preschool attention-deficit/hyperactivity disorder (ADHD), and 78 typically developing children, from the Preschool ADHD substudy of the Norwegian, Mother, Father, and Child Cohort Study. Participants who gave birth between 2004–2008 were invited to participate in an on-site clinical assessment when the child was approximately 3.5 years; measurements of EF included parent and teacher rating on Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P), and three performance-based assessments. We measured OPP metabolites in maternal urines collected at ~17 weeks’ gestation to calculate total dimethyl- (ΣDMP) and diethyl phosphate (ΣDEP) metabolite concentrations. We estimated multivariable adjusted β’s and 95% confidence intervals (CIs) corresponding to a change in z-score per unit increase in log-ΣDMP/DEP. We further characterized gene-OPP interactions for maternal variants in PON1 (Q192R, M55L), CYP1A2 (1548T>C), CYP1A1 (IntG>A) and CYP2A6 (−47A>C). RESULTS: Prenatal OPP metabolite concentrations were associated with worse parent and teacher ratings of emotional control, inhibition, and working memory. A one log-∑DMP increase was associated with poorer teacher ratings of EF on the BRIEF-P (e.g. emotional control domain: β = 0.55, 95% CI: 0.35, 0.74), when weighted to account for sampling procedures. We found less consistent associations with performance-based EF assessments. We found some evidence of modification for PON1 Q192R and CYP2A6 −47A>C. Association with other variants were inconsistent. CONCLUSIONS: Biomarkers of prenatal OPP exposure were associated with more adverse teacher and parent ratings of EF in preschool-aged children.

Prenatal organophosphorus pesticides (OPs) are ubiquitous and have been linked to adverse neurodevelopmental outcomes. However, few studies have examined prenatal OPs in relation to diagnosed attention-deficit/hyperactivity disorder (ADHD), with only two studies exploring this relationship in a population primarily exposed through diet. In this study, we used a nested case-control study to evaluate prenatal OP exposure and ADHD diagnosis in the Norwegian Mother, Father, and Child Cohort Study (MoBa). For births that occurred between 2003 and 2008, ADHD diagnoses were obtained from linkage of MoBa participants with the Norwegian Patient Registry (N = 297), and a reference population was randomly selected from the eligible population (N = 552). Maternal urine samples were collected at 17 weeks’ gestation and molar sums of diethyl phosphates (ΣDEP) and dimethyl phosphates metabolites (ΣDMP) were calculated. Multivariable adjusted logistic regression models were used to estimate the association between prenatal OP metabolite exposure and child ADHD diagnosis. Additionally, multiplicative effect measure modification (EMM) by child sex was assessed. In most cases, mothers in the second and third tertiles of ΣDMP and ΣDEP exposure had slightly lower odds of having a child with ADHD, although confidence intervals were wide and included the null. EMM by child sex was not observed for either ΣDMP or ΣDEP. In summary, we did not find evidence that OPs at 17 weeks’ gestation increased the odds of ADHD in this nested case-control study of ADHD in MoBa, a population primarily experiencing dietary exposure.

OBJECTIVE: To evaluate the prevalence, co-occurrence, sex differences and functional correlates of DSM-5 psychiatric disorders in 15-year-old adolescents born extremely preterm. METHOD: The Extremely Low Gestational Age Newborns (ELGAN) Study is a longitudinal study of children born < 28 weeks gestation. At age 15, six hundred and seventy adolescents completed the Mini-International Neuropsychiatric Interview for Children and Adolescents (MINI-KID), the Youth Self Report, a disability scale of participation in social roles and cognitive testing. Parents completed a family psychiatric history questionnaire. RESULTS: The most prevalent psychiatric disorders were anxiety, attention deficit hyperactivity disorder (ADHD) and major depression. More girls met criteria for anxiety than boys. Though 66% of participants did not meet criteria for a psychiatric disorder, 15% met criteria for one, 9% for two and 8% for ≥ 3 psychiatric disorders. Those with ≥ 2 psychiatric disorders were more likely to have repeated a grade, to have an individualized educational program (IEP) and to have a lower Non-Verbal IQ than those with no psychiatric disorders. Those with any psychiatric disorder were more likely to use psychotropic medications, to have greater cognitive and functional impairment, and to have mothers who were single, on public health insurance and had less than a high school education. Finally, a positive family psychiatric history was identified more frequently among adolescents with ≥ 3 psychiatric disorders. CONCLUSION: Among adolescents born extremely preterm anxiety, major depression and ADHD were the most prevalent psychiatric disorders at age 15. Adolescents with > 1 psychiatric disorder were at increased risk for multiple functional and participatory challenges.

High throughput screening (HTS) programs have demonstrated that the Vitamin D receptor (VDR) is activated and/or antagonized by a wide range of structurally diverse chemicals. In this study, we examined the Tox21 qHTS data set generated against VDR for reproducibility and concordance and elucidated functional insights into VDR-xenobiotic interactions. Twenty-one potential VDR agonists and 19 VDR antagonists were identified from a subset of >400 compounds with putative VDR activity and examined for VDR functionality utilizing select orthogonal assays. Transient transactivation assay (TT) using a human VDR plasmid and Cyp24 luciferase reporter construct revealed 20/21 active VDR agonists and 18/19 active VDR antagonists. Mammalian-2-hybrid assay (M2H) was then used to evaluate VDR interactions with co-activators and co-regulators. With the exception of a select few compounds, VDR agonists exhibited significant recruitment of co-regulators and co-activators whereas antagonists exhibited considerable attenuation of recruitment by VDR. A unique set of compounds exhibiting synergistic activity in antagonist mode and no activity in agonist mode was identified. Cheminformatics modeling of VDR-ligand interactions were conducted and revealed selective ligand VDR interaction. Overall, data emphasizes the molecular complexity of ligand-mediated interactions with VDR and suggest that VDR transactivation may be a target site of action for diverse xenobiotics.