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BACKGROUND: Prenatal fish intake is a key source of omega-3 (ω-3) polyunsaturated fatty acids needed for brain development, yet intake is generally low, and studies addressing associations with autism spectrum disorder (ASD) and related traits are lacking. OBJECTIVE: This study aimed to examine associations of prenatal fish intake and ω-3 supplement use with both autism diagnosis and broader autism-related traits. METHODS: Participants were drawn from 32 cohorts in the Environmental influences on Child Health Outcomes Cohort Consortium. Children were born between 1999 and 2019 and part of ongoing follow-up with data available for analysis by August 2022. Exposures included self-reported maternal fish intake and ω-3/fish oil supplement use during pregnancy. Outcome measures included parent report of clinician-diagnosed ASD and parent-reported autism-related traits measured by the Social Responsiveness Scale (SRS)-second edition (n = 3939 and v3609 for fish intake analyses, respectively; n = 4537 and n = 3925 for supplement intake analyses, respectively). RESULTS: In adjusted regression models, relative to no fish intake, fish intake during pregnancy was associated with reduced odds of autism diagnosis (odds ratio: 0.84; 95% confidence interval [CI]: 0.77, 0.92), and a modest reduction in raw total SRS scores (β: -1.69; 95% CI: -3.3, -0.08). Estimates were similar across categories of fish consumption from any or less than once per week to more than twice per week. For ω-3 supplement use, relative to no use, no significant associations with autism diagnosis were identified, whereas a modest relation with SRS score was suggested (β: 1.98; 95% CI: 0.33, 3.64). CONCLUSIONS: These results extend previous work by suggesting that prenatal fish intake, but not ω-3 supplement use, may be associated with lower likelihood of both autism diagnosis and related traits. Given the low-fish intake in the United States general population and the rising autism prevalence, these findings suggest the need for better public health messaging regarding guidelines on fish intake for pregnant individuals.

BACKGROUND: Motor function is critical for childrens health, yet remains an understudied neurodevelopmental domain. Exposure to metals has been linked with motor function, but no study has examined the joint effects of metal mixtures. METHODS: We evaluated cross-sectional associations between a metal mixture and motor function among 569 adolescents (10-14 years old) living near the ferroalloy industry. Concentrations of blood lead, hair manganese, hair copper, and hair chromium were quantified using inductively coupled plasma mass spectrometry. Neuropsychologists administered multiple fine motor function assessments: pursuit aiming, finger tapping, visual reaction time (VRT), and subtests from the Luria Nebraska battery. We estimated associations between motor function and the metal mixture using quantile-based g-computation and multivariable linear regression, adjusting for child age, sex, and socioeconomic status. We explored sex-specific associations in stratified models. RESULTS: Associations between the metal mixture and motor function were mostly null but were modified by sex. We observed a beneficial association among females: a quartile increase in all metals in the mixture was associated with a 2.6% faster average response time on the VRT (95% confidence interval [CI] = -4.7%, -0.5%), driven by Cu and Cr. In contrast, this association was adverse among males (ß = 1.5% slower response time [95% CI = -0.7%, 3.9%]), driven by Cu and Mn. CONCLUSIONS: Results suggest that males may be more susceptible to the adverse effects of metal exposure on motor function during adolescence than females. Future studies, particularly prospective study designs, are warranted to further understand the associations of metal mixtures with motor function.

Zika virus (ZIKV) infection during pregnancy causes severe neurological and ocular abnormalities in infants, yet no vaccine or antivirals are available. Our transcriptomic analysis of ZIKV-infected retinal pigment epithelial (RPE) cells revealed alterations in the cholesterol pathway. Thus, we investigated the functional roles of ATP binding cassette transporter G1 (ABCG1) and sterol response element binding protein 2 (SREPB-2), two key players in cholesterol metabolism, during ocular ZIKV infection. Our in vitro data showed that increased ABCG1 activity via liver X receptors (LXRs), reduced ZIKV replication, while ABCG1 knockdown increased replication with elevated intracellular cholesterol. Conversely, inhibiting SREBP-2 or its knockdown reduced ZIKV replication by lowering cholesterol levels. In vivo, LXR agonist or SREBP-2 inhibitor treatment mitigated ZIKV-induced chorioretinal lesions in mice, concomitant with decreased expression of inflammatory mediators and increased activation of antiviral response genes. In summary, our study identifies ABCG1's antiviral role and SREBP-2's proviral effects in ocular ZIKV infection, offering cholesterol metabolism as a potential target to develop antiviral therapies.

BACKGROUND: Manganese (Mn) plays a significant role in both human health and global industries. Epidemiological studies of exposed populations demonstrate a dose-dependent association between Mn and neuromotor effects ranging from subclinical effects to a clinically defined syndrome. However, little is known about the relationship between early life Mn biomarkers and adolescent postural balance. OBJECTIVES: This study investigated the associations between childhood and adolescent Mn biomarkers and adolescent postural balance in participants from the longitudinal Marietta Communities Actively Researching Exposures Study (CARES) cohort. METHODS: Participants were recruited into CARES when they were 7-9 y old, and reenrolled at 13-18 years of age. At both time points, participants provided samples of blood, hair, and toenails that were analyzed for blood Mn and lead (Pb), serum cotinine, hair Mn, and toenail Mn. In adolescence, participants completed a postural balance assessment. Greater sway indicates postural instability (harmful effect), whereas lesser sway indicates postural stability (beneficial effect). Multivariable linear regression models were conducted to investigate the associations between childhood and adolescent Mn biomarkers and adolescent postural balance adjusted for age, sex, height--weight ratio, parent/caregiver intelligence quotient, socioeconomic status, blood Pb, and serum cotinine. RESULTS: CARES participants who completed the adolescent postural balance assessment (n=123) were 98% White and 54% female and had a mean age of 16 y (range: 13-18 y). In both childhood and adolescence, higher Mn biomarker concentrations were significantly associated with greater adolescent sway measures. Supplemental analyses revealed sex-specific associations; higher childhood Mn biomarker concentrations were significantly associated with greater sway in females compared with males. DISCUSSION: This study found childhood and adolescent Mn biomarkers were associated with subclinical neuromotor effects in adolescence. This study demonstrates postural balance as a sensitive measure to assess the association between Mn biomarkers and neuromotor function. https://doi.org/10.1289/EHP13381, Introduction Manganese (Mn) is an element that exists ubiquitously in the environment, often in combination with other elements. (1) Mn plays a significant role in both human health and global [...]

BACKGROUND: The developing fetal brain is sensitive to many environmental exposures. However, the independent and joint effects of prenatal exposure to metals and micronutrients on child cognition are not well understood. OBJECTIVES: Our aim was to evaluate associations of first-trimester (∼10 wk) maternal erythrocyte concentrations of mixtures of nonessential and essential metals and micronutrients with early (∼3 y) and mid-childhood (∼8 y) cognitive test scores in Project Viva, a prebirth cohort in Boston, Massachusetts, USA. METHODS: We measured concentrations of five essential metals (Cu, Mg, Mn, Se, Zn) and two micronutrients (vitamin B12 and folate), together termed the nutrient mixture, as well as six nonessential metals (As, Ba, Cd, Cs, Hg, Pb), together termed the neurotoxic mixture, in first-trimester (∼10 wk) maternal erythrocytes (metals) or plasma (micronutrients). We assessed visual-motor function and receptive vocabulary in early childhood (∼3 y), and visual-motor function, visual memory, and fluid and crystallized intelligence in mid-childhood (∼8 y). We employed adjusted quantile g-computation and linear regression to estimate mixture and individual component associations, respectively. RESULTS: Analyses included 900 mother-child pairs (74% college graduates; 52% male children). In mixture analyses, a quartile increase in the nutrient mixture was associated with a mean difference in early childhood receptive vocabulary score of 1.58 points [95% confidence interval (CI): 0.06, 3.10], driven by Zn and Se. A quartile increase in the neurotoxic mixture was associated with a mean difference in mid-childhood visual-motor score of -3.01 points (95% CI: -5.55, -0.47), driven by Ba and Cs. Linear regressions supported quantile g-computation findings for mixture component contributions. DISCUSSION: Maternal circulating concentrations of several essential (Zn and Se) and nonessential (Ba and Cs) metals were associated with some domains of child cognition. In this folate-replete cohort, first-trimester circulating concentrations of known neurotoxic metals, such as Pb, were not associated with child cognition. https://doi.org/10.1289/EHP12016.

BACKGROUND: Early-life environmental exposures during critical windows (CWs) of development can impact life course health. Exposure to neuroactive metals such as manganese (Mn) during prenatal and early postnatal CWs may disrupt typical brain development, leading to persistent behavioral changes. Males and females may be differentially vulnerable to Mn, presenting distinctive CWs to Mn exposure. METHODS: We used magnetic resonance imaging to investigate sex-specific associations between early-life Mn uptake and intrinsic functional connectivity in adolescence. A total of 71 participants (15-23 years old; 53% female) from the Public Health Impact of Manganese Exposure study completed a resting-state functional magnetic resonance imaging scan. We estimated dentine Mn concentrations at prenatal, postnatal, and early childhood periods using laser ablation-inductively coupled plasma-mass spectrometry. We performed seed-based correlation analyses to investigate the moderating effect of sex on the associations between Mn and intrinsic functional connectivity adjusting for age and socioeconomic status. RESULTS: We identified significant sex-specific associations between dentine Mn at all time points and intrinsic functional connectivity in brain regions involved in cognitive and motor function: 1) prenatal: dorsal striatum, occipital/frontal lobes, and middle frontal gyrus; 2) postnatal: right putamen and cerebellum; and 3) early childhood: putamen and occipital, frontal, and temporal lobes. Network associations differed depending on exposure timing, suggesting that different brain networks may present distinctive CWs to Mn. CONCLUSIONS: These findings suggest that the developing brain is vulnerable to Mn exposure, with effects lasting through late adolescence, and that females and males are not equally vulnerable to these effects. Future studies should investigate cognitive and motor outcomes related to these associations.

BACKGROUND: Biomarker concentrations of metals are associated with neurodevelopment, and these associations may be modified by nutritional status (e.g., iron deficiency). No prior study on associations of metal mixtures with neurodevelopment has assessed effect modification by iron status. OBJECTIVES: We aimed to quantify associations of an industry-relevant metal mixture with verbal learning and memory among adolescents, and to investigate the modifying role of iron status on those associations. METHODS: We used cross-sectional data from 383 Italian adolescents (10-14 years) living in proximity to ferroalloy industry. Verbal learning and memory was assessed using the California Verbal Learning Test for Children (CVLT-C), and metals were quantified in hair (manganese, copper, chromium) or blood (lead) using inductively coupled plasma mass spectrometry. Serum ferritin, a proxy for iron status, was measured using immunoassays. Covariate-adjusted associations of the metal mixture with CVLT subtests were estimated using Bayesian Kernel Machine Regression, and modification of the mixture associations by ferritin was examined. RESULTS: Compared to the 50th percentile of the metal mixture, the 90th percentile was associated with a 0.12 standard deviation [SD] (95% CI = -0.27, 0.50), 0.16 SD (95% CI = -0.11, 0.44), and 0.11 SD (95% CI = -0.20, 0.43) increase in the number of words recalled for trial 5, long delay free, and long delay cued recall, respectively. For an increase from its 25th to 75th percentiles, copper was beneficially associated the recall trials when other metals were fixed at their 50th percentiles (for example, trial 5 recall: β = 0.31, 95% CI = 0.14, 0.48). The association between copper and trial 5 recall was stronger at the 75th percentile of ferritin, compared to the 25th or 50th percentiles. CONCLUSIONS: In this metal mixture, copper was beneficially associated with neurodevelopment, which was more apparent at higher ferritin concentrations. These findings suggest that metal associations with neurodevelopment may depend on iron status, which has important public health implications.

BACKGROUND: Prenatal nonessential metals may contribute to postnatal adiposity, whereas essential metals may have metabolic benefits. We evaluated joint and individual associations between prenatal metals and childhood adiposity. METHODS: We measured concentrations of six nonessential (arsenic, barium, cadmium, cesium, lead, and mercury) and four essential (magnesium, manganese, selenium, and zinc) metals in first trimester maternal blood from a prebirth cohort. We collected anthropometric measures in early childhood, mid-childhood, and early adolescence including subscapular+tricep skinfold thickness (mm) (N = 715-859), waist circumference (cm) (N = 717-882), and body mass index (BMI) (z-score) (N = 716-875). We measured adiposity in mid-childhood and early adolescence using bone densitometry total- and trunk- fat mass index (kg/m 2 ) (N = 511-599). We estimated associations using adjusted quantile g-computation and linear regression. RESULTS: The nonessential metal mixture was associated with higher total (β = 0.07, 95% CI = 0.01, 0.12) and trunk fat mass index (β = 0.12, CI = 0.02, 0.22), waist circumference (β = 0.01, CI = 0.00, 0.01), and BMI (β = 0.24, CI = 0.07, 0.41) in mid-childhood, and total fat mass index (β = 0.07, CI = 0.01, 0.14), and BMI (β = 0.19, CI = 0.02, 0.37) in early adolescence. The essential metal mixture was associated with lower early adolescence total-(β = -0.11, CI = -0.17, -0.04) and trunk- fat mass index (β = -0.13, CI = -0.21, -0.05), subscapular+tricep skinfold thickness (β = -0.02, CI = -0.03, -0.00), waist circumference (β = -0.003, CI = -0.01, -0.00), and BMI (β = -0.16, CI = -0.28, -0.04). Cadmium and cesium were individually associated with childhood adiposity at different timepoints. CONCLUSIONS: Prenatal first-trimester essential metals were associated with lower childhood adiposity, whereas nonessential metals were associated with higher adiposity into adolescence.

BackgroundIn the United States, disparities in gestational age at birth by maternal race, ethnicity, and geography are theorized to be related, in part, to differences in individual- and neighborhood-level socioeconomic status (SES). Yet, few studies have examined their combined effects or whether associations vary by maternal race and ethnicity and United States Census region.MethodsWe assembled data from 34 cohorts in the Environmental influences on Child Health Outcomes (ECHO) program representing 10,304 participants who delivered a liveborn, singleton infant from 2000 through 2019. We investigated the combined associations of maternal education level, neighborhood deprivation index (NDI), and Index of Concentration at the Extremes for racial residential segregation (ICERace) on gestational weeks at birth using linear regression and on gestational age at birth categories (preterm, early term, post-late term relative to full term) using multinomial logistic regression.ResultsAfter adjustment for NDI and ICERace, gestational weeks at birth was significantly lower among those with a high school diploma or less (-0.31 weeks, 95% CI: -0.44, -0.18), and some college (-0.30 weeks, 95% CI: -0.42, -0.18) relative to a master's degree or higher. Those with a high school diploma or less also had an increased odds of preterm (aOR 1.59, 95% CI: 1.20, 2.10) and early term birth (aOR 1.26, 95% CI: 1.05, 1.51). In adjusted models, NDI quartile and ICERace quartile were not associated with gestational weeks at birth. However, higher NDI quartile (most deprived) associated with an increased odds of early term and late term birth, and lower ICERace quartile (least racially privileged) associated with a decreased odds of late or post-term birth. When stratifying by region, gestational weeks at birth was lower among those with a high school education or less and some college only among those living in the Northeast or Midwest. When stratifying by race and ethnicity, gestational weeks at birth was lower among those with a high school education or less only for the non-Hispanic White category.ConclusionIn this study, maternal education was consistently associated with shorter duration of pregnancy and increased odds of preterm birth, including in models adjusted for NDI and ICERace.

INTRODUCTION: Adolescent exposure to neurotoxic metals adversely impacts cognitive, motor, and behavioral development. Few studies have addressed the underlying brain mechanisms of these metal-associated developmental outcomes. Furthermore, metal exposure occurs as a mixture, yet previous studies most often consider impacts of each metal individually. In this cross-sectional study, we investigated the relationship between exposure to neurotoxic metals and topological brain metrics in adolescents. METHODS: In 193 participants (53% females, ages: 15-25 years) enrolled in the Public Health Impact of Metals Exposure (PHIME) study, we measured concentrations of four metals (manganese, lead, copper, and chromium) in multiple biological media (blood, urine, hair, and saliva) and acquired resting-state functional magnetic resonance imaging scans. Using graph theory metrics, we computed global and local efficiency (global:GE; local:LE) in 111 brain areas (Harvard Oxford Atlas). We used weighted quantile sum (WQS) regression models to examine association between metal mixtures and each graph metric (GE or LE), adjusted for sex and age. RESULTS: We observed significant negative associations between the metal mixture and GE and LE [βGE = -0.076, 95% CI (-0.122, -0.031); βLE= -0.051, 95% CI (-0.095, -0.006)]. Lead and chromium measured in blood contributed most to this association for GE, while chromium measured in hair contributed the most for LE. DISCUSSION: Our results suggest that exposure to this metal mixture during adolescence reduces the efficiency of integrating information in brain networks at both local and global levels, informing potential neural mechanisms underlying the developmental toxicity of metals. Results further suggest these associations are due to combined joint effects to different metals, rather than to a single metal.

PurposeSARS-CoV-2 RNA has been detected in ocular tissues, but their susceptibility to SARS-CoV-2 infection is unclear. Here, we tested whether SARS-CoV-2 can infect human conjunctival epithelial cells (hCECs) and induce innate immune response.MethodsConjunctival tissue from COVID-19 donors was used to detect SARS-CoV-2 spike and envelope proteins. Primary hCECs isolated from cadaver eyes were infected with the parental SARS-CoV-2 and its beta variant of concern (VOC). Viral genome copy number, and expression of viral entry receptors, TLRs, interferons, and innate immune response genes were determined by qPCR. Viral entry receptors were examined in hCECs and tissue sections by immunostaining. Spike protein was detected in the cell culture supernatant by dot blot.ResultsSpike and envelope proteins were found in conjunctiva from COVID-19 patients. SARS-CoV-2 infected hCECs showed high viral copy numbers at 24-72h post-infection; spike protein levels were the highest at 24hpi. Viral entry receptors ACE2, TMPRSS2, CD147, Axl, and NRP1 were detected in conjunctival tissue and hCECs. SARS-CoV-2 infection-induced receptor gene expression peaked at early time points post-infection, but gene expression of most TLRs peaked at 48 or 72hpi. SARS-CoV-2 infected hCECs showed higher expression of genes regulating antiviral response, RIG-I, interferons (α, β, & λ), ISG15 & OAS2, cytokines (IL6, IL1β, TNFα), and chemokines (CXCL10, CCL5). Compared to the parental strain, beta VOC induced increased viral copy number and innate response in hCECs.ConclusionsConjunctival epithelial cells are susceptible to SARS-CoV-2 infection. Beta VOC is more infectious than the parental strain and evokes a higher antiviral and inflammatory response.

Background: Sensorimotor difficulties significantly interfere with daily activities, and when undiagnosed in early life, they may increase the risk of later life cognitive and mental health disorders. Subtests from the Luria-Nebraska Neuropsychological Battery (LNNB) discriminate sensorimotor impairments predictive of sensorimotor dysfunction. However, scoring the LNNB sensorimotor assessment is highly subjective and time consuming, impeding the use of this task in epidemiologic studies. Aim: To train and validate a novel automated and image-derived scoring approach to the LNNB neuro-motor tasks for use in adolescents and young adults. Methods: We selected 46 adolescents (19.6 +/− 2.3 years, 48% male) enrolled in the prospective Public Health Impact of Metal Exposure (PHIME) study. We visually recorded the administration of five conventional sensorimotor LNNB tasks and developed automated scoring alternatives using a novel mathematical approach combining optic flow fields from recorded image sequences on a frame-by-frame basis. We then compared the conventional and image-derived LNNB task scores using Pearson’s correlations. Finally, we provided the accuracy of the novel scoring approach with Receiver Operating Characteristic (ROC) curves and the area under the ROC curves (AUC). Results: Image-derived LNNB task scores strongly correlated with conventional scores, which were assessed and confirmed by multiple administrators to limit subjectivity (Pearson’s correlation ≥ 0.70). The novel image-derived scoring approach discriminated participants with low motility (

BackgroundPrenatal exposure to essential and non-essential metals impacts birth and child health, including fetal growth and neurodevelopment. DNA methylation (DNAm) may be involved in pathways linking prenatal metal exposure and health. In the Project Viva cohort, we analyzed the extent to which metals (As, Ba, Cd, Cr, Cs, Cu, Hg, Mg, Mn, Pb, Se, and Zn) measured in maternal erythrocytes were associated with differentially methylated positions (DMPs) and regions (DMRs) in cord blood and tested if associations persisted in blood collected in mid-childhood. We measured metal concentrations in first-trimester maternal erythrocytes, and DNAm in cord blood (N = 361) and mid-childhood blood (N = 333, 6-10 years) with the Illumina HumanMethylation450 BeadChip. For each metal individually, we tested for DMPs using linear models (considered significant at FDR

BackgroundMetal exposure during pregnancy influences maternal and child health. Oxidative stress and inflammation may mediate adverse effects of heavy metals, whereas essential metals may act as antioxidants. Mitochondrial DNA is a prime target for metal-induced oxidative damage. Telomere dysfunction is attributed to imbalances between reactive oxidant species and antioxidants.ObjectivesWe evaluated individual and joint associations of prenatal metals with mitochondrial DNA copy number (mtDNAcn) and telomere length (TL) in maternal and cord blood as biomarkers of inflammation and oxidative stress.MethodsWe measured six nonessential metals (arsenic, barium, cadmium, cesium, lead, mercury) and four essential metals (magnesium, manganese, selenium, zinc) in first-trimester maternal red blood cells in Project Viva, a U.S. prebirth cohort. We measured relative mtDNAcn (n=898) and TL (n=893) in second-trimester maternal blood and mtDNAcn (n=419) and TL (n=408) in cord blood. We used multivariable linear regression and quantile g-computation to estimate associations between prenatal metals and the biomarkers. We used generalized additive models and Bayesian kernel machine regression to examine nonlinearity and interactions.ResultsA 2-fold increase in maternal magnesium was associated with lower maternal [β=-0.07, 95% confidence interval (CI): -0.10, -0.01] and cord blood (β=-0.08, 95% CI: -0.20, -0.01) mtDNAcn. Lead was associated with higher maternal mtDNAcn (β=0.04, 95% CI: 0.01, 0.06). Selenium was associated with longer cord blood TL (β=0.30, 95% CI: 0.01 0.50). An association was observed between the nonessential metal mixture and higher maternal mtDNAcn (β=0.04, 95% CI: 0.01, 0.07). There was a nonlinear relationship between cord blood mtDNAcn and magnesium; maternal mtDNAcn and barium, lead, and mercury; and maternal TL and barium.DiscussionMaternal exposure to metals such as lead, magnesium, and selenium was associated with mtDNAcn and TL in maternal second trimester and cord blood. Future work will evaluate whether these biomarkers are associated with child health. https://doi.org/10.1289/EHP9294.

The concept of the exposome was introduced over 15 years ago to reflect the important role that the environment exerts on health and disease. While originally viewed as a call-to-arms to develop more comprehensive exposure assessment methods applicable at the individual level and throughout the life course, the scope of the exposome has now expanded to include the associated biological response. In order to explore these concepts, a workshop was hosted by the Gunma University Initiative for Advanced Research (GIAR, Japan) to discuss the scope of exposomics from an international and multidisciplinary perspective. This Global Perspective is a summary of the discussions with emphasis on (1) top-down, bottom-up, and functional approaches to exposomics, (2) the need for integration and standardization of LC- and GC-based high-resolution mass spectrometry methods for untargeted exposome analyses, (3) the design of an exposomics study, (4) the requirement for open science workflows including mass spectral libraries and public databases, (5) the necessity for large investments in mass spectrometry infrastructure in order to sequence the exposome, and (6) the role of the exposome in precision medicine and nutrition to create personalized environmental exposure profiles. Recommendations are made on key issues to encourage continued advancement and cooperation in exposomics.