Mitochondrial DNA copy number and neurocognitive outcomes in children.

BACKGROUND: Low mitochondria DNA copy number (mtDNAcn) has been linked to cognitive decline. However, the role of mtDNAcn in healthy cognitive development is unclear. We hypothesized early-life mtDNAcn would be associated with children's learning and memory. METHODS: We quantified mtDNAcn in umbilical cord blood and child blood at ages 5-7 from participants in a prospective birth cohort. We administered the Children's Memory Scale (CMS) at ages 9-14 (N = 342) and the Wechsler Intelligence Scale for Children (WISC-IV) at ages 7 and 9 (N = 457). Associations between mtDNAcn tertiles and CMS and WISC were evaluated with linear regression and linear mixed-effects models, respectively. We examined non-linear associations using generalized additive mixed models. RESULTS: Relative to the middle tertile of mtDNAcn, lower childhood mtDNAcn was associated with lower WISC Working Memory (ß = -2.65, 95% CI [-5.24, -0.06]) and Full-Scale IQ (ß = -3.71 [-6.42, -1.00]), and higher CMS Visual Memory (ß = 4.70 [0.47, 8.93]). Higher childhood mtDNAcn was linked to higher CMS Verbal Memory (ß = 7.75 [2.50, 13.01]). In non-linear models, higher childhood mtDNAcn was associated with lower WISC Verbal Comprehension. CONCLUSIONS: Our study provides novel evidence that mtDNAcn measured in childhood is associated with children's neurocognitive performance. mtDNAcn may be a marker of healthy child development. IMPACT: Mitochondrial DNA copy number (mtDNAcn) may serve as a biomarker for early-life neurocognitive performances in the children's population. Both low and high mtDNAcn may contribute to poorer neurocognition, reflected through learning and memory abilities. This research elucidated the importance of investigating mitochondrial biomarkers in healthy populations and facilitated advancements of future studies to better understand the associations between mitochondrial markers and adverse children's health outcomes.

Exposure to chlorpyrifos and pyrethroid insecticides and symptoms of Attention Deficit Hyperactivity Disorder (ADHD) in preschool children from the Odense Child Cohort.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is a common childhood psychiatric disorder with severe and lifelong impact on mental health and socioeconomic achievements. Environmental factors may play a role in the increasing incidens rates. Previous studies on associations between prenatal and childhood exposure to organophosphate and pyrethroid insecticides and ADHD symptoms have yielded mixed findings. OBJECTIVES: To investigate associations between prenatal and childhood exposure to chlorpyrifos and pyrethroids and ADHD symptoms in 5-year-old children from the Odense Child Cohort. METHODS: Spot urine samples from pregnant women in gestational week 28 (n = 614) and offspring at 5 years of age (n = 814) were collected and analyzed for the specific metabolite of chlorpyrifos, TCPY (3,5,6-trichloro-2-pyridinol), as well as the generic pyrethroid metabolite, 3-PBA (3-phenoxybenzoic acid). Offspring ADHD symptoms were assessed at age 5 years using the parent reported "ADHD scale" from the "Child Behavior Checklist 1½-5" (n = 1114). Associations between insecticide exposure variables and an ADHD score ≥90th percentile were analyzed using logistic regression for all children and stratified by sex. RESULTS: Most pregnant women had detectable concentrations of 3-PBA (93%) and TCPY (91%) with median concentrations of 0.20 µg/L and 1.62 µg/L, respectively. In children, 3-PBA and TCPY concentrations were detectable in 88% and 82% of the samples, and the median concentrations were 0.17 and 1.16 µg/L. No statistically significant associations were observed between insecticide metabolites and an ADHD score ≥90th percentile at age 5. CONCLUSION: In this relatively large Danish birth cohort study with mainly low dietary insecticide exposure, we found no statistically significant associations between prenatal or childhood exposure to chlorpyrifos or pyrethroids, and excess ADHD-symptom load, in 5-year-old children. Prospective studies with multiple urine samples across vulnerable windows of neurodevelopment is warranted to improve assessment of safe exposure levels, which is particularly relevant for pyrethroids, since their use is increasing.

Rhinorrhea and watery eyes in infancy and risk of attention-deficit hyperactivity disorder in school-age children.

Increased parasympathetic nervous system (PNS) activity is associated with attention-deficit/hyperactivity disorder (ADHD) inattentive symptoms, but not hyperactive-impulsive symptoms, and may contribute to inattentive subtype etiology. Guided by prior work linking infant rhinorrhea and watery eyes without a cold (RWWC) to PNS dysregulation, we examined associations between infant RWWC and childhood ADHD symptoms in a longitudinal cohort of Black and Latinx children living in the context of economic disadvantage (N = 301 youth: 158 females, 143 males). Infant RWWC predicted higher inattentive (relative risk [RR] 2.16, p < .001) but not hyperactive-impulsive (RR 1.53, p = .065) ADHD symptoms (DuPaul scale), administered to caregivers at child age 8-14 years. Stratified analyses revealed that these associations were present in females but not males, who were three times more likely to have higher ADHD current total symptoms if they had infant RWWC than if they did not. Additionally, associations between RWWC and inattention symptoms were observed only in females. RWWC may thus serve as a novel risk marker of ADHD inattentive-type symptoms, especially for females.

Examining the impact of prenatal maternal internalizing symptoms and socioeconomic status on children's frontal alpha asymmetry and psychopathology.

Prenatal maternal internalizing psychopathology (depression and anxiety) and socioeconomic status (SES) have been independently associated with higher risk for internalizing and externalizing problems in children. However, the pathways behind these associations are not well understood. Numerous studies have linked greater right frontal alpha asymmetry to internalizing problems; however, findings have been mixed. Several studies have also linked maternal internalizing psychopathology to children's frontal alpha asymmetry. Additionally, emerging studies have linked SES to children's frontal alpha asymmetry. To date, only a limited number of studies have examined these associations within a longitudinal design, and the majority have utilized relatively small samples. The current preregistered study utilizes data from a large prospective study of young children (N = 415; Meanage  = 7.27 years; Rangeage  = 5-11 years) to examine the association between prenatal maternal internalizing symptoms, children's frontal alpha asymmetry, and behavior problems. Prenatal maternal internalizing symptoms did not predict children's frontal alpha asymmetry, and there was no association between frontal alpha asymmetry and behavior problems. However, mothers' internalizing symptoms during pregnancy predicted children's internalizing and externalizing outcomes. Non-preregistered analyses showed that lower prenatal maternal SES predicted greater child right frontal alpha asymmetry and internalizing problems. Additional non-preregistered analyses did not find evidence for frontal alpha asymmetry as a moderator of the relation between prenatal maternal internalizing psychopathology and SES to children's behavior problems. Future research should examine the impact of SES on children's frontal alpha asymmetry in high-risk samples.

Anesthesia and Developing Brains: Unanswered Questions and Proposed Paths Forward.

Anesthetic agents disrupt neurodevelopment in animal models, but evidence in humans is mixed. The morphologic and behavioral changes observed across many species predicted that deficits should be seen in humans, but identifying a phenotype of injury in children has been challenging. It is increasingly clear that in children, a brief or single early anesthetic exposure is not associated with deficits in a range of neurodevelopmental outcomes including broad measures of intelligence. Deficits in other domains including behavior, however, are more consistently reported in humans and also reflect findings from nonhuman primates. The possibility that behavioral deficits are a phenotype, as well as the entire concept of anesthetic neurotoxicity in children, remains a source of intense debate. The purpose of this report is to describe consensus and disagreement among experts, summarize preclinical and clinical evidence, suggest pathways for future clinical research, and compare studies of anesthetic agents to other suspected neurotoxins.

Prenatal exposure to air pollution and maternal stress predict infant individual differences in reactivity and regulation and socioemotional development.

BACKGROUND: Humans are ubiquitously exposed to air pollutants including polycyclic aromatic hydrocarbons (PAH). Although most studies of prenatal exposures have focused on psychopathology in childhood or adolescence, the effects of air pollutants on early emerging individual differences in reactivity and regulation are of growing concern. Our study is the first to report effects of prenatal exposure to PAH and maternal stress on infant reactivity and regulation. METHODS: Participants included 153 infants (74 girls and 79 boys). Prenatal exposure to PAH was measured via personal air monitoring during the third trimester of pregnancy. Maternal perceived stress was measured via self-report. We assessed infant orienting/regulation (OR), surgency (SE), and negative affectivity (NA) at 4 months using the Infant Behavior Questionnaire. We measured infant socioemotional outcomes at 12 months using the Brief Infant-Toddler Social & Emotional Assessment Questionnaire. RESULTS: Infants with higher prenatal PAH exposure and of mothers with higher stress had lower OR at 4 months, which predicted lower competence at 12 months. Infants with higher prenatal PAH exposure had lower SE at 4 months, which predicted more behavioral problems at 12 months. Prenatal exposure to PAH had no effects on infant NA at 4 months, although NA was associated with greater behavioral problems at 12 months. CONCLUSIONS: Infant reactivity and regulation, as early makers of child psychopathology, can facilitate timely and targeted screening and possibly prevention of disorders caused, in part, by environmental pollution. A multifaceted approach to improve environmental quality and reduce psychosocial stress is necessary to improve the developmental outcomes of children and most specially children from disadvantaged communities that disproportionately experience these environmental exposures.

Prenatal exposure to air pollution is associated with altered brain structure, function, and metabolism in childhood.

BACKGROUND: Prenatal exposure to air pollution disrupts cognitive, emotional, and behavioral development. The brain disturbances associated with prenatal air pollution are largely unknown. METHODS: In this prospective cohort study, we estimated prenatal exposures to fine particulate matter (PM2.5 ) and polycyclic aromatic hydrocarbons (PAH), and then assessed their associations with measures of brain anatomy, tissue microstructure, neurometabolites, and blood flow in 332 youth, 6-14 years old. We then assessed how those brain disturbances were associated with measures of intelligence, ADHD and anxiety symptoms, and socialization. RESULTS: Both exposures were associated with thinning of dorsal parietal cortices and thickening of postero-inferior and mesial wall cortices. They were associated with smaller white matter volumes, reduced organization in white matter of the internal capsule and frontal lobe, higher metabolite concentrations in frontal cortex, reduced cortical blood flow, and greater microstructural organization in subcortical gray matter nuclei. Associations were stronger for PM2.5 in boys and PAH in girls. Youth with low exposure accounted for most significant associations of ADHD, anxiety, socialization, and intelligence measures with cortical thickness and white matter volumes, whereas it appears that high exposures generally disrupted these neurotypical brain-behavior associations, likely because strong exposure-related effects increased the variances of these brain measures. CONCLUSIONS: The commonality of effects across exposures suggests PM2.5 and PAH disrupt brain development through one or more common molecular pathways, such as inflammation or oxidative stress. Progressively higher exposures were associated with greater disruptions in local volumes, tissue organization, metabolite concentrations, and blood flow throughout cortical and subcortical brain regions and the white matter pathways interconnecting them. Together these affected regions comprise cortico-striato-thalamo-cortical circuits, which support the regulation of thought, emotion, and behavior.

Prenatal exposure to organophosphate and pyrethroid insecticides and the herbicide 2,4-dichlorophenoxyacetic acid and size at birth in urban pregnant women.

BACKGROUND: Organophosphate insecticides and the herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D) are used to protect crops or control weeds. Pyrethroids are used to manage pests both in agriculture and in residences, and to reduce the transmission of insect-borne diseases. Several studies have reported inverse associations between exposure to organophosphates (as a larger class) and birth outcomes but these associations have not been conclusive for pyrethroids or 2,4-D, specifically. We aimed to investigate the association between birth outcomes and urinary biomarkers of pyrethroids, organophosphates and 2,4-D among healthy pregnant women living in New York City. METHODS: We quantified urinary biomarkers of 2,4-D and of organophosphate and pyrethroid insecticides from 269 women from two cohorts: a) Thyroid Disruption And Infant Development (TDID) and b) Sibling/Hermanos cohort (S/H). We used weighted quantile sum regression and multivariable linear regression models to evaluate the associations between a mixture of urinary creatinine-adjusted biomarker concentrations and birth outcomes of length, birthweight and head circumference, controlling for covariates. We also used linear regression models and further classified biomarkers concentrations into three categories (i: non-detectable; ii: between the limit of detection and median; and iii: above the median) to investigate single pesticides' association with these birth outcomes. Covariates considered were delivery mode, ethnicity, marital status, education, income, employment status, gestational age, maternal age and pre-pregnancy BMI. Analyses were conducted separately for each cohort and stratified by child sex within each cohort. RESULTS: In TDID cohort, we found a significant inverse association between weighted quantile sum of mixture of pesticides and head circumference among boys. We found that the urinary biomarkers of organophosphate chlorpyrifos, TCPy, and 2,4-D had the largest contribution to the overall mixture effect in the TDID cohort among boys (b = -0.57, 95%CI: -0.92, -0.22) (weights = 0.81 and 0.16 respectively) but not among girls. In the multivariable linear regression models, we found that among boys, for each log unit increase in 3,5,6-trichloro-2-pyridinol (TCPy, metabolite of organophosphate chlorpyrifos) in maternal urine, there was a -0.56 cm decrease in head circumference (95%CI: -0.92, -0.19). Among boys in the TDID cohort, 2,4-D was associated with smaller head circumference in the second (b = -1.57; 95%CI: -2.74, -0.39) and third (b = -1.74, 95%CI: -2.98, -0.49) concentration categories compared to the first. No associations between pyrethroid and organophosphate biomarkers and birth outcomes were observed in girls analyzed in WQS regression or individually in linear regression models in TDID cohort. In the S/H cohort, head circumference increased with higher concentrations of 3-phenoxybenzoic acid (3-PBA, a biomarker of several pyrethroids) (b = 0.53, 95%CI: 0.03, 1.04) among boys and head circumference was lower among girls in the high compared to low category of 2,4-D (b = -2.27, 95%CI: - 3.98, -0.56). Birth length was also positively associated with the highest concentration of 2,4-D compared to the lowest among boys (b = 4.01, 95%CI: 0.02,8.00). CONCLUSIONS: Weighted quantile sum of pesticides was negatively associated with head circumference among boys in one cohort. Nonetheless, due to directional homogeneity assumption in WQS no positive associations were detected. In linear regression models with individual pesticides, concentrations of TCPy were inversely associated with head circumference in boys and higher concentrations of 2,4-D was inversely associated with head circumference among girls; 2,4-D concentrations were also associated with higher birth length among boys. Concentrations of 3-PBA was positively associated with head circumference among boys.

Prenatal exposure to air pollution is associated with childhood inhibitory control and adolescent academic achievement.

BACKGROUND: Prenatal air pollution exposure is associated with reductions in self-regulation and academic achievement. Self-regulation has been separately linked with academic achievement. Understudied, however, are the contributions of pollution exposure to inhibitory control, a facet of self-regulation, and whether pollution-related inhibitory control deficits are associated with impairment in academic achievement. METHODS: Participants were recruited from a prospective birth cohort. Measures of prenatal airborne polycyclic aromatic hydrocarbons (PAH) during the third trimester of pregnancy, inhibitory control (NEPSY Inhibition) at mean age = 10.4 years, and Woodcock-Johnson Tests of Achievement-III at mean age = 13.7 were available for N = 200 participants. Multiple linear regression examined sex-dependent and sex independent associations among prenatal PAH, childhood inhibitory control, and academic achievement during adolescence, and whether childhood inhibitory control mediated associations between prenatal PAH and academic achievement during adolescence, controlling for ethnicity, maternal country of birth, language of prenatal interview, maternal marital status, maternal years of education, material hardship, quality of home caregiving environment, and early life stress. RESULTS: Across all participants, higher prenatal PAH was significantly associated with worse spelling skills (WJ-III Spelling, ß = -0.16, 95%Confidence Interval [CI]: 0.30, -0.02, p = .02). Trend level associations between higher prenatal PAH and worse reading comprehension (WJ-III Passage Comprehension, ß = -0.13, 95%CI: 0.28, 0.01, p = .07) and math skills (WJ-III Broad Math, ß = -0.11, 95%CI: 0.25, 0.03, p = .11) were detected. Across all participants, higher PAH was significantly associated with worse inhibitory control (ß = -0.15, 95%CI: 0.29,-0.01 p = .03). Better inhibitory control was significantly associated with better reading comprehension (WJ-III Passage Comprehension, ß = 0.22, 95%CI: 0.09, 0.36, p < .002) and math skills (WJ-III Broad Math Index, ß = 0.32, 95%CI: 0.19, 0.45, p < .001), and trend level associations with better spelling skills (WJ-III Spelling, ß = 0.12, 95%CI: 0.02, 0.26, p = .10). Inhibitory control significantly mediated PAH-related achievement effects for Passage Comprehension (ß = -0.61, 95%CI: 1.49, -0.01) and Broad Math Index (ß = -1.09, 95%CI: 2.36, -0.03). CONCLUSIONS: Higher prenatal PAH exposure and lower childhood inhibitory control were associated with worse spelling, passage comprehension, and math in adolescence. Notably, childhood inhibitory control mediated PAH exposure-related effects on achievement in adolescents. Identifying these potential exposure-related phenotypes of learning problems may promote interventions that target inhibitory control deficits rather than content specific deficits.

Maturation of Brain Microstructure and Metabolism Associates with Increased Capacity for Self-Regulation during the Transition from Childhood to Adolescence.

Children ages 9-12 years face increasing social and academic expectations that require mastery of their thoughts, emotions, and behavior. Little is known about the development of neural pathways integral to these improving capacities during the transition from childhood to adolescence. Among 234 healthy, inner-city male and female youth (species Homo sapiens) 9-12 years of age followed by the Columbia Center for Children's Environmental Health, we acquired diffusion tensor imaging, multiplanar chemical shift imaging, and cognitive measures requiring self-regulation. We found that increasing age was associated with increased fractional anisotropy and decreased apparent diffusion coefficient, most prominently in the frontal and cingulate cortices, striatum, thalamus, deep white matter, and cerebellum. Additionally, we found increasing age was associated with increased N-acetyl-l-aspartate (NAA) in the anterior cingulate and insular cortices, and decreased NAA in posterior cingulate and parietal cortices. Age-associated changes in microstructure and neurometabolite concentrations partially mediated age-related improvements in performance on executive function tests. Together, these findings suggest that maturation of key regions within cortico-striatal-thalamo-cortical circuits subserve the emergence of improved self-regulatory capacities during the transition from childhood to adolescence.SIGNIFICANCE STATEMENT Few imaging studies of normal brain development have focused on a population of inner-city, racial/ethnic minority youth during the transition from childhood to adolescence, a period when self-regulatory capacities rapidly improve. We used DTI and MPCSI to provide unique windows into brain maturation during this developmental epoch, assessing its mediating influences on age-related improvement in performance on self-regulatory tasks. Our findings suggest that rapid maturation of cortico-striato-thalamo-cortical circuits, represented as progressive white-matter maturation (increasing FA and increasing NAA, Ch, Cr concentrations accompanying advancing age) in frontal regions and related subcortical projections and synaptic pruning (decreasing NAA, Ch, Cr, Glx) in posterior regions, support age-related improvements in executive functioning and self-regulatory capacities in youth 9-12 years of age.

Prenatal exposure to polycyclic aromatic hydrocarbons modifies the effects of early life stress on attention and Thought Problems in late childhood.

BACKGROUND: Risk for childhood psychopathology is complex and multifactorial, implicating direct and interacting effects of familial and environmental factors. The role of environmental neurotoxicants in psychiatric risk is of growing concern, including polycyclic aromatic hydrocarbons (PAH), common in air pollution. Prenatal PAH exposure is linked to adverse physical, behavioral, and cognitive outcomes as well as increasing psychiatric risk. It is unclear whether environmental exposures, like PAH, magnify the effects of exposure to early life stress (ELS), a critical risk factor for psychopathology. The current work aimed to test potential interactions between prenatal PAH exposure and psychosocial/socioeconomic stress on psychiatric symptoms in school-age children. METHODS: Data were from the Columbia Center for Children's Environmental Health Mothers and Newborns longitudinal birth cohort study. Prenatal PAH exposure was ascertained though air monitoring during pregnancy and maternal PAH-DNA adducts at delivery. Mothers reported on ELS (child age 5) and on child psychiatric symptoms across childhood (child age 5, 7, 9, and 11) using the Child Behavior Checklist (CBCL). RESULTS: Significant prenatal airborne PAH × ELS interactions (FDR-corrected) predicted CBCL Attention (ß = 0.22, t(307) = 3.47, p < .001, pfdr  = .003) and Thought Problems T-scores (ß = 0.21, t(307) = 3.29, p = .001, pfdr  = .004) at age 11 (n = 319). Relative to those with lower exposure, children with higher prenatal PAH exposure exhibited stronger positive associations between ELS and CBCL Attention and Thought Problem T-scores. This interaction was also significant examining convergent ADHD measures (Conners, DuPaul) and examining maternal PAH-DNA adducts (ß = 0.29, t(261) = 2.48, p = .01; n = 273). A three-way interaction with assessment wave indicated that the PAH × ELS interaction on Attention Problems was stronger later in development (ß = 0.03, t(1,601) = 2.19, p = .03; n = 477). CONCLUSIONS: Prenatal exposure to PAH, a common neurotoxicant in air pollution, may magnify or sustain the effects of early life psychosocial/socioeconomic stress on psychiatric outcomes later in child development. This work highlights the critical role of air pollution exposure on child mental health.

Report of prenatal maternal demoralization and material hardship and infant rhinorrhea and watery eyes.

BACKGROUND: Previously, we found that reported infant rhinorrhea and watery eyes without a cold (RWWC) predicted school age exercise-induced wheezing, emergency department visits, and respiratory-related hospitalizations for asthma. These findings appeared independent of infant wheezing and allergy. Overall, we theorize that prenatal material hardship and psychosocial distress can induce infant dysregulation in the autonomic nervous system leading to infant RWWC and school age exercise-induced wheezing. OBJECTIVE: To test the hypotheses that indicators of prenatal stress and measures of maternal demoralization, which can alter infant autonomic nervous system responses, would predict infant RWWC. METHODS: In a prospective birth cohort of urban children (n = 578), pregnant women were queried in the third trimester about material hardship and maternal demoralization using validated instruments. Child RWWC was queried every 3 months in infancy. RESULTS: Notably, 44% of the mothers reported not being able to afford at least one of the basic needs of daily living during pregnancy, and children of those mothers were more likely to have infant RWWC (P < .001). The children had an increased risk of RWWC with increasing maternal demoralization during pregnancy (P < .001). In models controlling for sex, race and ethnicity, maternal asthma, maternal allergy, smoker in the home (pre- or postnatal), prenatal pesticide exposure, and older siblings, RWWC was predicted by mother's report of material hardship (relative risk, 1.22; P = .021) and maternal demoralization (relative risk, 1.14; P = .030). CONCLUSION: These results suggest an association between material hardship and psychological distress during pregnancy and RWWC in infancy, further supporting a link between infant autonomic dysregulation and RWWC.

Prenatal lead exposure impacts cross-hemispheric and long-range connectivity in the human fetal brain.

Lead represents a highly prevalent metal toxicant with potential to alter human biology in lasting ways. A population segment that is particularly vulnerable to the negative consequences of lead exposure is the human fetus, as exposure events occurring before birth are linked to varied and long-ranging negative health and behavioral outcomes. An area that has yet to be addressed is the potential that lead exposure during pregnancy alters brain development even before an individual is born. Here, we combine prenatal lead exposure information extracted from newborn bloodspots with the human fetal brain functional MRI data to assess whether neural network connectivity differs between lead-exposed and lead-naïve fetuses. We found that neural connectivity patterns differed in lead-exposed and comparison groups such that fetuses that were not exposed demonstrated stronger age-related increases in cross-hemispheric connectivity, while the lead-exposed group demonstrated stronger age-related increases in posterior cingulate cortex (PCC) to lateral prefrontal cortex (PFC) connectivity. These are the first results to demonstrate metal toxicant-related alterations in human fetal neural connectivity. Remarkably, the findings point to alterations in systems that support higher-order cognitive and regulatory functions. Objectives for future work are to replicate these results in larger samples and to test the possibility that these alterations may account for significant variation in future child cognitive and behavioral outcomes.

Prenatal and childhood exposure to phthalates and motor skills at age 11 years.

BACKGROUND: Previous reports suggest that prenatal phthalate exposure is associated with lower scores on measures of motor skills in infants and toddlers. Whether these associations persist into later childhood or preadolescence has not been studied. METHODS: In a follow up study of 209 inner-city mothers and their children the concentrations of mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), monoisobutyl phthalate (MiBP), monomethyl phthalate (MEP), mono-carboxy-isooctyl phthalate (MCOP), and four di-2-ethylhexyl phthalate metabolites (ΣDEHP) were measured in spot urine sample collected from the women in late pregnancy and from their children at ages 3, 5, and 7 years. The Bruininks-Oseretsky Test of Motor Proficiency short form (BOT-2) was administered at child age 11 to assess gross and fine motor skills. RESULTS: The total number of children included in the study was 209. Of the 209 children, 116(55.5%) were girls and 93 were (45%) boys. Among girls, prenatal MnBP(b=-2.09; 95%CI: [-3.43, -0.75]), MBzP (b=-1.14; [95%CI: -2.13, -0.14]), and MiBP(b=-1.36; 95%CI: [-2.51, -0.21] and MEP(b=-1.23 [95%CI: -2.36, -0.11]) were associated with lower total BOT-2 composite score. MnBP (b= -1.43; 95% CI: [-2.44, -0.42]) was associated with lower fine motor scores and MiBP(b = -0.56; 95% CI: [-1.12, -0.01]) and MEP (b = -0.60; 95% CI: [-1.14, -0.06])was associated with lower gross motor scores. Among boys, prenatal MBzP (b = -0.79; 95% CI: [-1.40, -0.19]) was associated with lower fine motor composite score. The associations between MEP measured at age 3 and the BOT-2 gross motor, fine motor and total motor score differed by sex. In boys, there was an inverse association between ΣDEHP metabolites measured in childhood at ages 3 (b = -1.30; 95% CI: [-2.34, -0.26]) and 7 years (b = -0.96; 95% CI: [-1.79, -0.13]), and BOT-2 fine motor composite scores. CONCLUSIONS: Higher prenatal exposure to specific phthalates was associated with lower motor function among 11- year old girls while higher postnatal exposure to ΣDEHP metabolites was associated with lower scores among boys. As lower scores on measures of motor development have been associated with more problems in cognitive, socioemotional functioning and behavior, the findings of this study have implications related to overall child development.

Prepregnancy obesity is associated with cognitive outcomes in boys in a low-income, multiethnic birth cohort.

BACKGROUND: Maternal obesity and high gestational weight gain (GWG) disproportionally affect low-income populations and may be associated with child neurodevelopment in a sex-specific manner. We examined sex-specific associations between prepregnancy BMI, GWG, and child neurodevelopment at age 7. METHODS: Data are from a prospective low-income cohort of African American and Dominican women (n = 368; 44.8% male offspring) enrolled during the second half of pregnancy from 1998 to 2006. Neurodevelopment was measured using the Wechsler Intelligence Scale for Children (WISC-IV) at approximately child age 7. Linear regression estimated associations between prepregnancy BMI, GWG, and child outcomes, adjusting for race/ethnicity, marital status, gestational age at delivery, maternal education, maternal IQ and child age. RESULTS: Overweight affected 23.9% of mothers and obesity affected 22.6%. At age 7, full-scale IQ was higher among girls (99.7 ± 11.6) compared to boys (96.9 ± 13.3). Among boys, but not girls, prepregnancy overweight and obesity were associated with lower full-scale IQ scores [overweight ß: - 7.1, 95% CI: (- 12.1, - 2.0); obesity ß: - 5.7, 95% CI: (- 10.7, - 0.7)]. GWG was not associated with full-scale IQ in either sex. CONCLUSIONS: Prepregnancy overweight and obesity were associated with lower IQ among boys, but not girls, at 7 years. These findings are important considering overweight and obesity prevalence and the long-term implications of early cognitive development.

Combined effects of prenatal exposure to polycyclic aromatic hydrocarbons and material hardship on child ADHD behavior problems.

IMPORTANCE: Polycyclic aromatic hydrocarbons (PAH) are carcinogenic and neurotoxic combustion by-products commonly found in urban air. Exposure to PAH is disproportionately high in low income communities of color who also experience chronic economic stress. OBJECTIVE: In a prospective cohort study in New York City (NYC) we previously found a significant association between prenatal PAH exposure and Attention Deficit Hyperactivity Disorder (ADHD) behavior problems at age 9. Here, we have evaluated the joint effects of prenatal exposure to PAH and prenatal/childhood material hardship on ADHD behavior problems. MATERIALS AND METHODS: We enrolled nonsmoking African-American and Dominican pregnant women in New York City between 1998 and 2006 and followed their children through 9 years of age. As a biomarker of prenatal PAH exposure, PAH-DNA adducts were measured in maternal blood at delivery and were dichotomized at the limit of detection (to indicate high vs. low exposure). Maternal material hardship (lack of adequate food, housing, utilities, and clothing) was self-reported prenatally and at multiple time points through child age 9. Latent variable analysis identified four distinct patterns of hardship. ADHD behavior problems were assessed using the Conners Parent Rating Scale- Revised. Analyses adjusted for relevant covariates. RESULTS: Among 351 children in our sample, across all hardship groups, children with high prenatal PAH exposure (high adducts) generally had more symptoms of ADHD (higher scores) compared to those with low PAH exposure. The greatest difference was seen among the children with hardship persisting from pregnancy through childhood. Although the interactions between high PAH exposure and hardship experienced at either period ("persistent" hardship or "any" hardship) were not significant, we observed significant differences in the number of ADHD symptoms between children with high prenatal PAH exposure and either persistent hardship or any hardship compared to the others. These differences were most significant for combined high PAH and persistent hardship: ADHD Index (p < 0.008), DSM-IV Inattentive (p = 0.006), DSM-IV Hyperactive Impulsive problems (p = 0.033), and DSM-IV Index Total (p = 0.009). CONCLUSION: The present findings add to existing evidence that co-exposure to socioeconomic disadvantage and air pollution in early life significantly increases the risk of adverse neurodevelopmental outcomes. They suggest the need for multifaceted interventions to protect pregnant mothers and their children.

Maternal prenatal urinary phthalate metabolite concentrations and visual recognition memory among infants at 27 weeks.

BACKGROUND: Prior research has demonstrated inverse associations between maternal prenatal urinary phthalate metabolite concentrations and cognitive development assessed in preschool and school-aged children. While there are a limited number of studies that evaluated these associations during infancy, no study has evaluated whether these associations exist when using the Fagan Test of Infant Intelligence (FTII), which captures novelty preference as a function of visual recognition memory. OBJECTIVE: We evaluated associations between phthalate metabolite concentrations in maternal prenatal urine and cognition in infancy using the FTII at 27 weeks and determine if these associations are sex-specific. METHODS: Mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), monoisobutyl phthalate (MiBP), mono-ethyl phthalate (MEP), mono-3-carboxypropyl phthalate (MCPP) and four di-2-ethylhexyl phthalate metabolites (DEHP) were quantified in urine samples collected from 168 minority women living in urban neighborhoods during their third trimester of pregnancy. The FTII was administered to infants at 27 weeks to measure visual recognition memory and was recorded as the novelty preference score. RESULTS: There were no associations between prenatal phthalate metabolite concentrations and novelty preference score in the full sample. However, there was evidence of effect modification by infant sex. Sex-stratified models demonstrated that compared to girls in the lowest tertile of MBzP concentrations, girls in tertiles 2 and 3 had, on average, 3.98 and 4.65 points lower novelty preference scores (p-value=0.04 and 0.03, respectively). The relationship was similar for ΣDEHP, MiBP, and MEP. Effects among boys were inconsistent and generally not significant. CONCLUSION: Maternal prenatal exposure to some phthalates was negatively associated with visual recognition memory as measured by the FTII among girls at age 27 weeks.

Research Review: Environmental exposures, neurodevelopment, and child mental health - new paradigms for the study of brain and behavioral effects.

BACKGROUND: Environmental exposures play a critical role in the genesis of some child mental health problems. METHODS: We open with a discussion of children's vulnerability to neurotoxic substances, changes in the distribution of toxic exposures, and cooccurrence of social and physical exposures. We address trends in prevalence of mental health disorders, and approaches to the definition of disorders that are sensitive to the subtle effects of toxic exposures. We suggest broadening outcomes to include dimensional measures of autism spectrum disorders, attention-deficit hyperactivity disorder, and child learning capacity, as well as direct assessment of brain function. FINDINGS: We consider the impact of two important exposures on children's mental health: lead and pesticides. We argue that longitudinal research designs may capture the cascading effects of exposures across biological systems and the full-range of neuropsychological endpoints. Neuroimaging is a valuable tool for observing brain maturation under varying environmental conditions. A dimensional approach to measurement may be sensitive to subtle subclinical toxic effects, permitting the development of exposure-related profiles and testing of complex functional relationships between brain and behavior. Questions about the neurotoxic effects of chemicals become more pressing when viewed through the lens of environmental justice. CONCLUSIONS: Reduction in the burden of child mental health disorders will require longitudinal study of neurotoxic exposures, incorporating dimensional approaches to outcome assessment, and measures of brain function. Research that seeks to identify links between toxic exposures and mental health outcomes has enormous public health and societal value.

Longitudinal effects of prenatal exposure to air pollutants on self-regulatory capacities and social competence.

BACKGROUND: We evaluated the influence of prenatal exposure to widespread urban air pollutants on the development of self-regulation and social competence in a longitudinal prospective cohort of children born to nonsmoking minority women in New York City. METHODS: Air pollutant exposure was estimated categorically by level of polycyclic aromatic hydrocarbon (PAH)-DNA adducts in maternal blood collected at delivery, providing a biomarker of maternal exposure to PAH over a 2- to 3-month period. Deficient emotional self-regulation (DESR) was defined as moderate elevations on three specific scales of the child behavior checklist (anxious/depressed, aggressive behavior, and attention problems). We used generalized estimating equations to assess the influence of prenatal exposure to PAH on DESR in children at 3-5, 7, 9, and 11 years of age, adjusted for gender and race/ethnicity. Next, we assessed the association of prenatal exposure to PAH with social competence, as measured by the social responsiveness scale (SRS), the association of impaired self-regulation with social competence, and whether impairment in self-regulation mediated the association of prenatal exposure to PAH with social competence. RESULTS: We detected a significant interaction (at p = .05) of exposure with time, in which the developmental trajectory of self-regulatory capacity was delayed in the exposed children. Multiple linear regression revealed a positive association between presence of PAH-DNA adducts and problems with social competence (p < .04), level of dysregulation and problems with social competence (p < .0001), and evidence that self-regulation mediates the association of prenatal exposure to PAH with social competence (p < .0007). CONCLUSIONS: These data suggest that prenatal exposure to PAH produces long-lasting effects on self-regulatory capacities across early and middle childhood, and that these deficits point to emerging social problems with real-world consequences for high-risk adolescent behaviors in this minority urban cohort.