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Early life metal exposure dysregulates cellular bioenergetics in children with regressive autism spectrum disorder.

ABSTRACT: Neurodevelopmental regression (NDR) is a subtype of autism spectrum disorder (ASD) that manifests as loss of previously acquired developmental milestones. Early life dysregulation of nutritional metals and/or exposure to toxic metals have been associated with ASD, but the underlying biological mechanisms by which metals influence neurodevelopment remain unclear. We hypothesize that metals influences neurodevelopment through dysregulation of bioenergetics. Prenatal and early postnatal metal exposures were measured using validated tooth-matrix biomarkers in 27 ASD cases (13 with NDR) and 7 typically-developing (TD) controls. Mitochondrial respiration and glycolysis were measured in peripheral blood mononuclear cells using the Seahorse XF96. Children with ASD demonstrated lower prenatal and postnatal Copper (Cu) and prenatal Nickel concentrations and Copper-to-Zinc (Cu/Zn) ratio as compared with TD children. Children with ASD and NDR showed greater metal-related disruption of cellular bioenergetics than children with ASD without NDR. For children with ASD and NDR mitochondrial respiration decreased as prenatal Manganese concentration increased and increased as prenatal Zinc concentration increased; glycolysis decreased with increased exposure to prenatal Manganese and Lead and postnatal Manganese. For children with ASD without a history of NDR, glycolysis increased with increased postnatal exposure to Tin. Language and communication scores in children with ASD were positively related to prenatal Cu exposure and Cu/Zn ratio. This study suggests that prenatal nutritional metals may be important for neurodevelopment in children with ASD, and that exposure to toxic metals and differences in nutritional metal exposures is associated with dysregulation of cellular bioenergetics, particularly in the NDR subtype of ASD.

SUBMITTER: Frye RE

PROVIDER: S-EPMC7341836 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Early life metal exposure dysregulates cellular bioenergetics in children with regressive autism spectrum disorder.

Frye Richard E RE Cakir Janet J Rose Shannon S Delhey Leanna L Bennuri Sirish C SC Tippett Marie M Palmer Raymond F RF Austin Christine C Curtin Paul P Arora Manish M

Translational psychiatry 20200707 1

Neurodevelopmental regression (NDR) is a subtype of autism spectrum disorder (ASD) that manifests as loss of previously acquired developmental milestones. Early life dysregulation of nutritional metals and/or exposure to toxic metals have been associated with ASD, but the underlying biological mechanisms by which metals influence neurodevelopment remain unclear. We hypothesize that metals influences neurodevelopment through dysregulation of bioenergetics. Prenatal and early postnatal metal expos ...[more]

PMID: 32636364

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Project description:BACKGROUND:Ambient air pollution and maternal diabetes may affect common biological pathways underlying adverse neurodevelopmental effects. However, joint effects of maternal diabetes and air pollution on autism spectrum disorder (ASD) have not been studied. OBJECTIVE:We evaluated whether prenatal and early-life air pollution exposure interacts with maternal diabetes status to affect ASD risk. METHODS:This retrospective cohort study included 246,420 singleton children born in Kaiser Permanente Southern California hospitals in 1999-2009. Children were followed from birth until age 5, during which 2471 ASD cases were diagnosed. Ozone (O3), particulate matter?<?2.5??m (PM2.5) and <10??m in aerodynamic diameter, and nitrogen dioxide measured at regulatory air monitoring stations were interpolated to estimate exposures during preconception and each pregnancy trimester, and first year of life at each child's birth address. Hazard ratios (HRs) for ASD were estimated adjusting for birth year, KPSC service areas, and relevant maternal and child characteristics. For each exposure window, interactions were tested between pollutants and a 4-category maternal diabetes variable (none, GDM???24 and <24?weeks' gestation, and pre-existing type 2 diabetes). For an exposure window with statistically significant global interaction between pollutant and diabetes (p?<?0.05), pollutant-associated HRs were estimated separately for each category of maternal diabetes. RESULTS:There were associations of ASD with preconception, first and third trimesters, and first year of life PM2.5, but not with other pollutants. There were, however, interactions of maternal diabetes with first trimester and first year of life O3. Increased ASD risk was associated with first trimester O3 among mothers with GDM?<?24?weeks' gestation [adjusted HR 1.50 per 15.7?ppb O3 (95% CI: 1.08-2.09)]. No O3 associations with ASD were observed in other categories of maternal diabetes. CONCLUSIONS:GDM onset early in pregnancy may increase children's susceptibility to prenatal O3-associated ASD risk. These novel findings merit further investigation.

Project description:ImportanceThe etiology of autism spectrum disorder (ASD) is poorly understood, but prior studies suggest associations with airborne pollutants.ObjectiveTo evaluate the association between prenatal exposures to airborne pollutants and ASD in a large population-based cohort.Design, setting, and participantsThis population-based cohort encompassed nearly all births in Metro Vancouver, British Columbia, Canada, from 2004 through 2009, with follow-up through 2014. Children were diagnosed with ASD using a standardized assessment with the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. Monthly mean exposures to particulate matter with a diameter less than 2.5 µm (PM2.5), nitric oxide (NO), and nitrogen dioxide (NO2) at the maternal residence during pregnancy were estimated with temporally adjusted, high-resolution land use regression models. The association between prenatal air pollution exposures and the odds of developing ASD was evaluated using logistic regression adjusted for child sex, birth month, birth year, maternal age, maternal birthplace, and neighborhood-level urbanicity and income band. Data analysis occurred from June 2016 to May 2018.ExposuresMean monthly concentrations of ambient PM2.5, NO, and NO2 at the maternal residence during pregnancy, calculated retrospectively using temporally adjusted, high-resolution land use regression models.Main outcomes and measuresAutism spectrum disorder diagnoses based on standardized assessment of the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. The hypothesis being tested was formulated during data collection.ResultsIn a cohort of 132 256 births, 1307 children (1.0%) were diagnosed with ASD by the age of 5 years. The final sample size for the PM2.5-adjusted model was 129 439 children, and for NO and NO2, it was 129 436 children; of these, 1276 (1.0%) were diagnosed with ASD. Adjusted odds ratios for ASD per interquartile range (IQR) were not significant for exposure to PM2.5 during pregnancy (1.04 [95% CI, 0.98-1.10] per 1.5 μg/m3 increase [IQR] in PM2.5) or NO2 (1.06 [95% CI, 0.99-1.12] per 4.8 ppb [IQR] increase in NO2) but the odds ratio was significant for NO (1.07 [95% CI, 1.01-1.13] per 10.7 ppb [IQR] increase in NO). Odds ratios for male children were 1.04 (95% CI, 0.98-1.10) for PM2.5; 1.09 (95% CI, 1.02-1.15) for NO; and 1.07 (95% CI, 1.00-1.13) for NO2. For female children, they were for 1.03 (95% CI, 0.90-1.18) for PM2.5; 0.98 (95% CI, 0.83-1.13) for NO; and 1.00 (95% CI, 0.86-1.16) for NO2.Conclusions and relevanceIn a population-based birth cohort, we detected an association between exposure to NO and ASD but no significant association with PM2.5 and NO2.

Project description:BackgroundEvidence from experimental and observational studies suggests that prenatal phthalate exposures may be associated with autism spectrum disorder (ASD). We examined whether prenatal phthalate exposures were associated with an increased risk of ASD.MethodsWe quantified 14 metabolites of eight phthalates in 636 multiple maternal urine samples collected during 2nd and 3rd trimesters of pregnancy from 201 mother-child pairs in MARBLES (Markers of Autism Risk in Babies - Learning Early Signs), a high-risk ASD longitudinal cohort. At 3?years old, children were clinically assessed for ASD and classified into three diagnostic categories: ASD (n?=?46), non-typical development (Non-TD, n?=?55), and typical development (TD, n?=?100). We used multinomial logistic regression to evaluate the association of phthalate metabolite concentrations with ASD and Non-TD.ResultsMost associations of phthalate biomarkers with both ASD and Non-TD were null, with the exception that monoethyl phthalate (MEP) was significantly associated with an increased risk of Non-TD (per 2.72-fold relative increase in concentration: Relative risk ratio (RRR)?=?1.38; 95% confidence interval (CI): 1.01, 1.90). When stratified by prenatal vitamin use during the first month of pregnancy, among mothers who took vitamins, ASD risk was inversely associated with mono-isobutyl phthalate (MiBP, RRR?=?0.44; 95% CI: 0.21, 0.88), mono(3-carboxypropyl) phthalate (MCPP, RRR?=?0.41; 95% CI: 0.20, 0.83) and mono-carboxyisooctyl phthalate (MCOP, RRR?=?0.49; 95% CI: 0.27, 0.88), but among mothers who did not take prenatal vitamins, Non-TD risk was positively associated with MCPP (RRR?=?5.09; 95% CI: 2.05, 12.6), MCOP (RRR?=?1.86; 95% CI: 1.01, 3.39), and mono-carboxyisononyl phthalate (MCNP, RRR?=?3.67; 95% CI: 1.80, 7.48). When stratified by sex, among boys, MEP, monobenzyl phthalate, MCPP, MCNP, and sum of di(2-ethylhexyl) phthalate metabolites (?DEHP) were positively associated with Non-TD risk, but associations with ASD were null. Among girls, associations with both ASD and Non-TD were null.ConclusionsOur study showed that phthalate exposures in mid- to late pregnancy were not associated with ASD in children from this high-risk ASD cohort. Further studies should be conducted in the general population without high-risk genes to confirm our findings.

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Early life metal exposure dysregulates cellular bioenergetics in children with regressive autism spectrum disorder.

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Early life metal exposure dysregulates cellular bioenergetics in children with regressive autism spectrum disorder.

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