Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and associations with attention-deficit/hyperactivity disorder and autism spectrum disorder in children

Background Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) may be a risk factor for neurodevelopmental deficits and disorders, but evidence is inconsistent. Objectives We investigated whether prenatal exposure to PFAS were associated with childhood diagnosis of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD). Methods This study was based on the Norwegian Mother, Father and Child Cohort Study and included n = 821 ADHD cases, n = 400 ASD cases and n = 980 controls. Diagnostic cases were identified by linkage with the Norwegian Patient Registry. In addition, we used data from the Medical Birth Registry of Norway. The study included the following PFAS measured in maternal plasma sampled mid-pregnancy: Perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptanesulfonic acid (PFHpS), and perfluorooctane sulfonate (PFOS). Relationships between individual PFAS and ADHD or ASD diagnoses were examined using multivariable adjusted logistic regression models. We also tested for possible non-linear exposure-outcome associations. Further, we investigated the PFAS mixture associations with ASD and ADHD diagnoses using a quantile-based g-computation approach. Results Odds of ASD was significantly elevated in PFOA quartile 2 [OR = 1.71 (95% CI: 1.20, 2.45)] compared to quartile 1, and PFOA appeared to have a non-linear, inverted U-shaped dose-response relationship with ASD. PFOA was also associated with increased odds of ADHD, mainly in quartile 2 [OR = 1.54 (95% CI: 1.16, 2.04)] compared to quartile 1, and displayed a non-linear relationship in the restricted cubic spline model. Several PFAS (PFUnDA, PFDA, and PFOS) were inversely associated with odds of ADHD and/or ASD. Some of the associations were modified by child sex and maternal education. The overall PFAS mixture was inversely associated with ASD [OR = 0.76 (95% CI: 0.64, 0.90)] as well as the carboxylate mixture [OR = 0.79 (95% CI: 0.68, 0.93)] and the sulfonate mixture [OR = 0.84 (95% CI: 0.73, 0.96)]. Conclusion Prenatal exposure to PFOA was associated with increased risk of ASD and ADHD in children. For some PFAS, as well as their mixtures, there were inverse associations with ASD and/or ADHD. However, the inverse associations reported herein should not be interpreted as protective effects, but rather that there could be some unresolved confounding for these relationships. The epidemiologic literature linking PFAS exposures with neurodevelopmental outcomes is still inconclusive, suggesting the need for more research to elucidate the neurotoxicological potential of PFAS during early development

Association between gestational levels of toxic metals and essential elements and cerebral palsy in children

IntroductionCerebral palsy (CP) is the most common motor disability in childhood, but its causes are only partly known. Early-life exposure to toxic metals and inadequate or excess amounts of essential elements can adversely affect brain and nervous system development. However, little is still known about these as perinatal risk factors for CP. This study aims to investigate the associations between second trimester maternal blood levels of toxic metals, essential elements, and mixtures thereof, with CP diagnoses in children.MethodsIn a large, population-based prospective birth cohort (The Norwegian Mother, Father, and Child Cohort Study), children with CP diagnoses were identified through The Norwegian Patient Registry and Cerebral Palsy Registry of Norway. One hundred forty-four children with CP and 1,082 controls were included. The relationship between maternal blood concentrations of five toxic metals and six essential elements and CP diagnoses were investigated using mixture approaches: elastic net with stability selection to identify important metals/elements in the mixture in relation to CP; then logistic regressions of the selected metals/elements to estimate odds ratio (OR) of CP and two-way interactions among metals/elements and with child sex and maternal education. Finally, the joint effects of the mixtures on CP diagnoses were estimated using quantile-based g-computation analyses.ResultsThe essential elements manganese and copper, as well as the toxic metal Hg, were the most important in relation to CP. Elevated maternal levels of copper (OR = 1.40) and manganese (OR = 1.20) were associated with increased risk of CP, while Hg levels were, counterintuitively, inversely related to CP. Metal/element interactions that were associated with CP were observed, and that sex and maternal education influenced the relationships between metals/elements and CP. In the joint mixture approach no significant association between the mixture of metals/elements and CP (OR = 1.00, 95% CI = [0.67, 1.50]) was identified.ConclusionUsing mixture approaches, elevated levels of copper and manganese measured in maternal blood during the second trimester could be related to increased risk of CP in children. The inverse associations between maternal Hg and CP could reflect Hg as a marker of maternal fish intake and thus nutrients beneficial for foetal brain development

Association between gestational levels of toxic metals and essential elements and cerebral palsy in children

Introduction Cerebral palsy (CP) is the most common motor disability in childhood, but its causes are only partly known. Early-life exposure to toxic metals and inadequate or excess amounts of essential elements can adversely affect brain and nervous system development. However, little is still known about these as perinatal risk factors for CP. This study aims to investigate the associations between second trimester maternal blood levels of toxic metals, essential elements, and mixtures thereof, with CP diagnoses in children. Methods In a large, population-based prospective birth cohort (The Norwegian Mother, Father, and Child Cohort Study), children with CP diagnoses were identified through The Norwegian Patient Registry and Cerebral Palsy Registry of Norway. One hundred forty-four children with CP and 1,082 controls were included. The relationship between maternal blood concentrations of five toxic metals and six essential elements and CP diagnoses were investigated using mixture approaches: elastic net with stability selection to identify important metals/elements in the mixture in relation to CP; then logistic regressions of the selected metals/elements to estimate odds ratio (OR) of CP and two-way interactions among metals/elements and with child sex and maternal education. Finally, the joint effects of the mixtures on CP diagnoses were estimated using quantile-based g-computation analyses. Results The essential elements manganese and copper, as well as the toxic metal Hg, were the most important in relation to CP. Elevated maternal levels of copper (OR = 1.40) and manganese (OR = 1.20) were associated with increased risk of CP, while Hg levels were, counterintuitively, inversely related to CP. Metal/element interactions that were associated with CP were observed, and that sex and maternal education influenced the relationships between metals/elements and CP. In the joint mixture approach no significant association between the mixture of metals/elements and CP (OR = 1.00, 95% CI = [0.67, 1.50]) was identified. Conclusion Using mixture approaches, elevated levels of copper and manganese measured in maternal blood during the second trimester could be related to increased risk of CP in children. The inverse associations between maternal Hg and CP could reflect Hg as a marker of maternal fish intake and thus nutrients beneficial for foetal brain development

Organophosphorus Pesticide Exposure at 17 Weeks’ Gestation and Odds of Offspring Attention-Deficit/Hyperactivity Disorder Diagnosis in the Norwegian Mother, Father, and Child Cohort Study

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

Prenatal Exposure to Organophosphorus Pesticides and Preschool ADHD in the Norwegian Mother, Father and Child Cohort Study

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

(Table 1) Circulating levels of TT3 and TT4, and age, length, girth, and estimated body mass in polar bears (Ursus maritimus) from East Greenland 1999-2001

We investigated the multivariate relationships between adipose tissue residue levels of 48 individual organohalogen contaminants (OHCs) and circulating thyroid hormone (TH) levels in polar bears (Ursus maritimus) from East Greenland (1999-2001, n = 62), using projection to latent structure (PLS) regression for four groupings of polar bears; subadults (SubA), adult females with cubs (AdF_N), adult females without cubs (AdF_S) and adult males (AdM). In the resulting significant PLS models for SubA, AdF_N and AdF_S, some OHCs were especially important in explaining variations in circulating TH levels: polybrominated diphenylether (PBDE)-99, PBDE-100, PBDE-153, polychlorinated biphenyl (PCB)-52, PCB-118, cis-nonachlor, trans-nonachlor, trichlorobenzene (TCB) and pentachlorobenzene (QCB), and both negative and positive relationships with THs were found. In addition, the models revealed that DDTs had a positive influence on total 3,5,3'-triiodothyronine (TT3) in AdF_S, and that a group of 17 higher chlorinated ortho-PCBs had a positive influence on total 3,5,3',5'-tetraiodothyronine (thyroxine, TT4) in AdF_N. TH levels in AdM seemed less influenced by OHCs because of non-significant PLS models. TH levels were also influenced by biological factors such as age, sex, body size, lipid content of adipose tissue and sampling date. When controlling for biological variables, the major relationships from the PLS models for SubA, AdF_N and AdF_S were found significant in partial correlations. The most important OHCs that influenced TH levels in the significant PLS models may potentially act through similar mechanisms on the hypothalamic-pituitary-thyroid (HPT) axis, suggesting that both combined effects by dose and response addition and perhaps synergistic potentiation may be a possibility in these polar bears. Statistical associations are not evidence per se of biological cause-effect relationships. Still, the results of the present study indicate that OHCs may affect circulating TH levels in East Greenland polar bears, adding to the "weight of evidence" suggesting that OHCs might interfere with thyroid homeostasis in polar bears

Neonatal thyroid‐stimulating hormone and association with attention‐deficit/hyperactivity disorder

BACKGROUND. Normal brain development is dependent on maternal, fetal and neonatal thyroid function. Measuring neonatal thyroid stimulating hormone (TSH) 48–72 hours after birth screens for congenital hypothyroidism, allowing early treatment to avoid serious impairment. However, even within sub-clinical ranges, disrupted thyroid homeostasis during brain development has been linked to adverse neurodevelopmental outcomes, including attention-deficit/hyperactivity disorder (ADHD). OBJECTIVE. We estimated the association between neonatal TSH within normal ranges and subsequent ADHD diagnosis using a population-based birth cohort. METHOD. Children with a diagnosis of ADHD in the Norwegian Mother, Father and Child Cohort Study (MoBa) were identified through linkage with the Norwegian Patient Registry using ICD-10 codes for hyperkinetic disorders. The study included 405 ADHD cases and 1,092 controls (born 2003–2008) with available neonatal TSH concentrations below 10 mU/L (cut-off for potential congenital hypothyroidism) measured in dried blood spots sampled 48–72 hours after birth. RESULTS. In multivariable, quintile models the relationship appeared to follow a U-shaped pattern with elevated odds ratios (ORs) at lower and higher TSH levels. Among children with TSH in the lowest quintile, odds of ADHD was approximately 1.5-fold higher than children in the middle quintile (OR = 1.60, 95% CI 1.09, 2.34), which was driven by substantially elevated risk among girls, with no association among boys (P(interaction)=0.02; girls OR=3.10, 95% CI 1.53, 6.30; boys OR=1.16, 95% CI 0.73, 1.84). CONCLUSION. ADHD risk appeared to be elevated among newborns with low TSH levels (i.e. with hyperthyroid status), and this association was mainly found among girls. Because our findings are suggestive of increased risk at very low TSH concentrations, where analytical accuracy is low, future studies should employ highly sensitive assays capable of accurate quantitation at very low concentrations. Also, larger studies are needed to investigate these associations at higher neonatal TSH concentrations where data are more widely distributed

Gestational blood levels of toxic metal and essential element mixtures and associations with global DNA methylation in pregnant women and their infants

Background: Pregnant women and their fetuses are exposed to multiple toxic metals that together with variations in essential element levels may alter epigenetic regulation, such as DNA methylation. Objectives: The aim of the study was to investigate the associations between gestational levels of toxic metals and essential elements and mixtures thereof, with global DNA methylation levels in pregnant women and their newborn children. Methods: Using 631 mother-child pairs from a prospective birth cohort (The Norwegian Mother, Father and Child Cohort Study), we measured maternal blood concentration (gestation week ~18) of five toxic metals and seven essential elements. We investigated associations as individual exposures and two-way interactions, using elastic net regression, and total mixture, using quantile g-computation, with blood levels of 5-methylcytocine (5mC) and 5-hydroxymethylcytosine (5hmC) in mothers during pregnancy and their newborn children (cord blood). Multiple testing was adjusted for using the Benjamini and Hochberg false discovery rate (FDR) approach. Results: The most sensitive marker of DNA methylation appeared to be 5mC levels. In pregnant mothers, elastic net regression indicated associations between 5mC and selenium and lead (non-linear), while in newborns results indicated relationships between maternal selenium, cobalt (non-linear) and mercury and 5mC, as well as copper (non-linear) and 5hmC levels. Several possible two-way interactions were identified (e.g. arsenic and mercury, and selenium and maternal smoking in newborns). None of these findings met the FDR threshold for multiple testing. No net effect was observed in the joint (mixture) exposure-approach using quantile g-computation. Conclusion: We identified few associations between gestational levels of several toxic metals and essential elements and global DNA methylation in pregnant mothers and their newborn children. As DNA methylation dysregulation might be a key mechanism in disease development and thus of high importance for public health, our results should be considered as important candidates to investigate in future studies

Gestational blood levels of toxic metal and essential element mixtures and associations with global DNA methylation in pregnant women and their infants

Background Pregnant women and their fetuses are exposed to multiple toxic metals that together with variations in essential element levels may alter epigenetic regulation, such as DNA methylation. Objectives The aim of the study was to investigate the associations between gestational levels of toxic metals and essential elements and mixtures thereof, with global DNA methylation levels in pregnant women and their newborn children. Methods Using 631 mother-child pairs from a prospective birth cohort (The Norwegian Mother, Father and Child Cohort Study), we measured maternal blood concentration (gestation week ~18) of five toxic metals and seven essential elements. We investigated associations as individual exposures and two-way interactions, using elastic net regression, and total mixture, using quantile g-computation, with blood levels of 5-methylcytocine (5mC) and 5-hydroxymethylcytosine (5hmC) in mothers during pregnancy and their newborn children (cord blood). Multiple testing was adjusted for using the Benjamini and Hochberg false discovery rate (FDR) approach. Results The most sensitive marker of DNA methylation appeared to be 5mC levels. In pregnant mothers, elastic net regression indicated associations between 5mC and selenium and lead (non-linear), while in newborns results indicated relationships between maternal selenium, cobalt (non-linear) and mercury and 5mC, as well as copper (non-linear) and 5hmC levels. Several possible two-way interactions were identified (e.g. arsenic and mercury, and selenium and maternal smoking in newborns). None of these findings met the FDR threshold for multiple testing. No net effect was observed in the joint (mixture) exposure-approach using quantile g-computation. Conclusion We identified few associations between gestational levels of several toxic metals and essential elements and global DNA methylation in pregnant mothers and their newborn children. As DNA methylation dysregulation might be a key mechanism in disease development and thus of high importance for public health, our results should be considered as important candidates to investigate in future studies