A Mixture of Urinary Phthalate Metabolite Concentrations During Pregnancy and Offspring Social Responsiveness Scale Scores.

BACKGROUND: Phthalates are a group of chemicals with ubiquitous exposure worldwide. Exposures to phthalates during pregnancy may play a role in autism spectrum disorder (ASD) etiology by disrupting hormone levels or directly impacting fetal neurodevelopment. However, there is little research quantifying the aggregate effect of phthalates on child ASD-related behaviors. METHODS: We used data from two prospective pregnancy and birth cohorts-the Health Outcomes and Measures of the Environment (HOME) and the Early Autism Risk Longitudinal Investigation (EARLI). HOME is a general population cohort while participants in EARLI were at higher familial risk for ASD. Using quantile g-computation and linear regression models, we assessed the joint and individual associations of a mixture of six phthalate metabolites during pregnancy with child ASD-related traits measured by Social Responsiveness Scale (SRS) scores at ages 3-8 years. RESULTS: Our analyses included 271 participants from HOME and 166 participants from EARLI. There were imprecise associations between the phthalate mixture and SRS total raw scores in HOME (difference in SRS scores per decile increase in every phthalate = 1.3; 95% confidence interval [CI] = -0.2, 2.8) and EARLI (difference in SRS scores per decile increase in every phthalate = -0.9; 95% CI = -3.5, 1.7). CONCLUSIONS: The cohort-specific effect sizes of the pthalates-SRS associations were small and CIs were imprecise. These results suggest that if there are associations between phthalate metabolites during pregnancy and child SRS scores, they may differ across populations with different familial liabilities. Further studies with larger sample sizes are warranted.

Exposure to heavy metals in utero and autism spectrum disorder at age 3: a meta-analysis of two longitudinal cohorts of siblings of children with autism.

BACKGROUND: Autism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder. Risk is attributed to genetic and prenatal environmental factors, though the environmental agents are incompletely characterized. METHODS: In Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies Learning Early Signs (MARBLES), two pregnancy cohorts of siblings of children with ASD, urinary metals concentrations during two pregnancy time periods (< 28 weeks and ≥ 28 weeks of gestation) were measured using inductively coupled plasma mass spectrometry. At age three, clinicians assessed ASD with DSM-5 criteria. In an exposure-wide association framework, using multivariable log binomial regression, we examined each metal for association with ASD status, adjusting for gestational age at urine sampling, child sex, age at pregnancy, race/ethnicity and education. We meta-analyzed across the two cohorts. RESULTS: In EARLI (n = 170) 17% of children were diagnosed with ASD, and 44% were classified as having non-neurotypical development (Non-TD). In MARBLES (n = 231), 21% were diagnosed with ASD, and 14% classified as Non-TD. During the first and second trimester period (< 28 weeks), having cadmium concentration over the level of detection was associated with 1.69 (1.08, 2.64) times higher risk of ASD, and 1.29 (0.95, 1.75)times higher risk of Non-TD. A doubling of first and second trimester cesium concentration was marginally associated with 1.89 (0.94, 3.80) times higher risk of ASD, and a doubling of third trimester cesium with 1.69 (0.97, 2.95) times higher risk of ASD. CONCLUSION: Exposure in utero to elevated levels of cadmium and cesium, as measured in urine collected during pregnancy, was associated with increased risk of developing ASD.

Gestational thyroid hormones and autism-related traits in the EARLI and HOME studies.

Thyroid hormones are essential for neurodevelopment. Few studies have considered associations with quantitatively measured autism spectrum disorder (ASD)-related traits, which may help elucidate associations for a broader population. Participants were drawn from two prospective pregnancy cohorts: the Early Autism Risk Longitudinal Investigation (EARLI), enrolling pregnant women who already had a child with ASD, and the Health Outcomes and Measures of the Environment (HOME) Study, following pregnant women from the greater Cincinnati, OH area. Gestational thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were measured in mid-pregnancy 16 (±3) weeks gestation serum samples. ASD-related traits were measured using the Social Responsiveness Scale (SRS) at ages 3-8 years. The association was examined using quantile regression, adjusting for maternal and sociodemographic factors. 278 participants (132 from EARLI, 146 from HOME) were included. TSH distributions were similar across cohorts, while FT4 levels were higher in EARLI compared to HOME. In pooled analyses, particularly for those in the highest SRS quantile (95th percentile), higher FT4 levels were associated with increasing SRS scores (ß = 5.21, 95% CI = 0.93, 9.48), and higher TSH levels were associated with decreasing SRS scores (ß = -6.94, 95% CI = -11.04, -2.83). The association between TSH and SRS remained significant in HOME for the 95% percentile of SRS scores (ß = -6.48, 95% CI = -12.16, -0.80), but not EARLI. Results for FT4 were attenuated when examined in the individual cohorts. Our results add to evidence that gestational thyroid hormones may be associated with ASD-related outcomes by suggesting that relationships may differ across the distribution of ASD-related traits and by familial likelihood of ASD.

Exposure to air pollution is associated with DNA methylation changes in sperm.

Exposure to air pollutants has been associated with adverse health outcomes in adults and children who were prenatally exposed. In addition to reducing exposure to air pollutants, it is important to identify their biologic targets in order to mitigate the health consequences of exposure. One molecular change associated with prenatal exposure to air pollutants is DNA methylation (DNAm), which has been associated with changes in placenta and cord blood tissues at birth. However, little is known about how air pollution exposure impacts the sperm epigenome, which could provide important insights into the mechanism of transmission to offspring. In the present study, we explored whether exposure to particulate matter less than 2.5 microns in diameter, particulate matter less than 10 microns in diameter, nitrogen dioxide (NO2), or ozone (O3) was associated with DNAm in sperm contributed by participants in the Early Autism Risk Longitudinal Investigation prospective pregnancy cohort. Air pollution exposure measurements were calculated as the average exposure for each pollutant measured within 4 weeks prior to the date of sample collection. Using array-based genome-scale methylation analyses, we identified 80, 96, 35, and 67 differentially methylated regions (DMRs) significantly associated with particulate matter less than 2.5 microns in diameter, particulate matter less than 10 microns in diameter, NO2, and O3, respectively. While no DMRs were associated with exposure to all four pollutants, we found that genes overlapping exposure-related DMRs had a shared enrichment for gene ontology biological processes related to neurodevelopment. Together, these data provide compelling support for the hypothesis that paternal exposure to air pollution impacts DNAm in sperm, particularly in regions implicated in neurodevelopment.

Health and Education Services During the COVID-19 Pandemic Among Young Children with Autism Spectrum Disorder and Other Developmental Disabilities.

OBJECTIVE: Understanding how the COVID-19 pandemic affected children with disabilities is essential for future public health emergencies. We compared children with autism spectrum disorder (ASD) with those with another developmental disability (DD) and from the general population (POP) regarding (1) missed or delayed appointments for regular health/dental services, immunizations, and specialty services; (2) reasons for difficulty accessing care; and (3) use of remote learning and school supports. METHOD: Caregivers of children previously enrolled in the Study to Explore Early Development, a case-control study of children with ASD implemented during 2017 to 2020, were recontacted during January-June 2021 to learn about services during March-December 2020. Children were classified as ASD, DD, or POP during the initial study and were aged 3.4 to 7.5 years when their caregivers were recontacted during the pandemic. RESULTS: Over half of all children missed or delayed regular health/dental appointments (58.4%-65.2%). More children in the ASD versus DD and POP groups missed or delayed specialty services (75.7%, 58.3%, and 22.8%, respectively) and reported difficulties obtaining care of any type because of issues using telehealth and difficulty wearing a mask. During school closures, a smaller proportion of children with ASD versus another DD were offered live online classes (84.3% vs 91.1%), while a larger proportion had disrupted individualized education programs (50.0% vs 36.2%). CONCLUSION: Minimizing service disruptions for all children and ensuring continuity of specialty care for children with ASD is essential for future public health emergencies. Children may need additional services to compensate for disruptions during the pandemic.

Maternal age is related to offspring DNA methylation: A meta-analysis of results from the PACE consortium.

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5-10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR < 0.05). Eight of these CpGs were located near/in the MTNR1B gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near MTNR1B, at which higher DNAm was associated with greater maternal age (PFDR = 6.92 × 10-8) in newborns. In childhood blood samples, these differences in blood DNAm of MTNR1B CpGs were nominally significant (p < 0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in RTEL1-TNFRSF6B at birth (PFDR < 0.05) and nominally in childhood (p < 0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in YPEL3/BOLA2B in external data was associated with expression of ITGAL, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health.

Prenatal exposure to metals and autism spectrum disorder: Current status and future directions.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with genetic and environmental contributors to etiology. Many metals have the potential to be neurotoxic and their exposures are widespread. The field of metals exposure and ASD research is emerging, and in this review article we assess the current state of the literature, with emphasis on the previous two years. Epidemiology studies are discussed with respect to exposure timing, exposure matrix, and outcome assessment. Toxicology studies are described for exposure dosing and timing, as well as behavioral and molecular outcomes. Further epidemiological and toxicological investigations can identify the timing and importance of metals as ASD risk factors and uncover biological mechanisms for risk mitigation and therapeutic strategies.