Adverse Neurobehavioral Outcomes Research Articles

Exposure in utero to SGAs not linked to adverse neurobehavioral outcomes

Prenatal exposure to second‐generation antipsychotics (SGAs) did not increase risk of adverse childhood developmental or behavioral outcomes compared with antipsychotic‐unexposed children, a study examining preschool‐aged children has found. This was one of the largest studies to date that examined neurobehavioral outcomes in children exposed prenatally to SGAs, the investigators reported. Study results were published online March 13, 2024, in the Journal of Clinical Psychiatry.

In Utero Exposure to Alcohol and Tobacco and Electroencephalogram Power During Childhood

Prenatal alcohol exposure (PAE) and prenatal tobacco exposure (PTE) are risk factors associated with adverse neurobehavioral and cognitive outcomes. To quantify long-term associations of PAE and PTE with brain activity in early and middle childhood via electroencephalography (EEG). This cohort study included participants enrolled in the Safe Passage Study (August 2007 to January 2015), from which a subset of 649 participants were followed up in the Environmental Influences on Child Health Outcomes Program. From September 2018 through November 2022, EEG recordings were obtained at ages 4, 5, 7, 9, or 11 years. Data were analyzed from November 2022 to November 2023. Maternal self-reported consumptions of alcohol and tobacco during pregnancy were captured at the recruitment interview and at up to 3 visits during pregnancy (20-24, 28-32, and ≥34 weeks' gestation). Classifications of PAE (continuous drinking, quit-early drinking, and nondrinking) and PTE (continuous smoking, quit-early smoking, and nonsmoking) were previously obtained. EEG band powers (theta, alpha, beta, gamma) were extracted from the EEG recordings. Linear regression models were used to estimate the associations of PAE and PTE with EEG estimates. The final sample included 649 participants (333 [51.3%] female) aged 4, 5, 7, 9, or 11 years. Children whose mothers were in the quit-early drinking cluster had increased alpha power (0.116 [95% CI, 0.023 to 0.209] μV2; P = .02) compared with individuals without PAE. The magnitude of this increase was approximately double for children exposed to continuous drinking (0.211 [95% CI, 0.005 to 0.417] μV2; P = .04). Children whose mothers were in the continuous smoking cluster had decreased beta power (-0.031 [95% CI, -0.059 to -0.003] μV2; P = .03) and gamma power (-0.020 [95% CI, -0.039 to -0.000] μV2; P = .04) compared with the nonsmoking cluster. In exploratory sex-stratified models, male participants in the quit-early PAE cluster had greater EEG power in the alpha band (0.159 [95% CI, 0.003 to 0.315] μV2; P = .04) compared with those with no PAE, and the difference was approximately double for male participants with continuous PAE (0.354 [95% CI, 0.041 to 0.667] μV2; P = .03). Male participants in the continuous PTE cluster had decreased beta (-0.048 [95% CI, -0.090 to - 0.007] μV2; P = .02) and gamma (-0.032 [95% CI, -0.061 - 0.002] μV2; P = .04) power compared with those with no PTE. These findings suggest that even low levels of PAE and PTE were associated with long-term alterations of brain activity.

Secular trends in blood lead concentrations of school-age children in Montevideo, Uruguay from 2009 to 2019

Lead exposure continues to be a public health problem globally, yet very few countries perform systematic biomonitoring or surveillance of children's blood lead levels (BLLs). Secular trends in children's BLLs have not been well characterized outside North America and Europe. In 2009–19, we conducted a series of non-representative cross-sectional surveys in Montevideo, Uruguay, enrolling children living in areas of the city with known or suspected lead contamination. Lead was measured with atomic absorption spectrometry on fasting venous blood samples. Of the 856 children representing independent (non-sibling) observations, 759 had BLL measures. Other missing data were imputed. Using linear and logistic regression models, we estimated the covariate-adjusted year to year difference in mean BLL and the likelihood of having BLL ≥5 and BLL ≥3.5 μg/dL. At the start of the study, mean ± SD BLL was 4.8 ± 2.6 μg/dL, and at the end 1.4 ± 1.4 μg/dL. The prevalence of BLL ≥5 and BLL ≥3.5 μg/dL also differed markedly between 2009 and 2019 (30.8% vs. 2.7% and 53.8% vs. 5.8%). Similarly, where 80.8% of children had BLL ≥2 μg/dL in 2011, in 2019 that number was 19.3%. The estimated year to year difference in BLL was ∼0.3 μg/dL. Despite this progress, pediatric lead exposure remains a problem in Montevideo. In years 2015–19, between 19 and 48% of school children had BLL ≥2 μg/dL, a level at which adverse neurobehavioral outcomes continue to be reported in the literature. Continued prevention and risk-reduction efforts are needed in Montevideo, including systematic surveillance of BLLs in all children.

Air pollution exposure and social responsiveness in childhood: The cincinnati combined childhood cohorts.

Autism Spectrum Disorder (ASD) affects about 1 in 44 children and environmental exposures may contribute to disease onset. Air pollution has been associated with adverse neurobehavioral outcomes, yet little research has examined its association with autistic-like behaviors. Therefore, our objective was to examine the association between exposure to air pollution, including NO2 and PM2.5, during pregnancy and the first year of life to ASD-like behaviors during childhood. Participants (n=435) enrolled in the Cincinnati Childhood Allergy and Air Pollution Study and the Health Outcomes and Measures of the Environment Study were included in the analysis. Daily exposures to NO2 and PM2.5 at the residential addresses of participants were estimated using validated spatiotemporal models and averaged to obtain prenatal and first year exposure estimates. ASD-like behaviors were assessed via the Social Responsiveness Scale (SRS) questionnaire at age 12. Linear regression models adjusting for confounders were applied to estimate the association between pollutants and SRS scores. After adjusting for covariates, the association between NO2 and PM2.5 and SRS scores remained positive but were no longer statistically significant. Prenatal and first year exposure to NO2 were associated with total SRS T-scores with an estimated 0.4 point increase (95% CI: -0.7, 1.6) per 5.2ppb increase in NO2 exposure and 0.7 point (95% CI: -0.3, 1.6) per 4.2ppb increase in NO2 exposure, respectively. For PM2.5, a 2.6μg/m3 increase in prenatal exposure was associated with a 0.1 point increase (95% CI: -1.1, 1.4) in SRS Total T-scores and a 1.3μg/m3 increase first year of life was associated with a 1 point increase (95% CI: -0.2, 2.3). In summary, exposure to NO2 and PM2.5 during pregnancy and the first year of life were not significantly associated with higher autistic-like behaviors measured with SRS scores after adjustment of covariates. Additional research is warranted given prior studies suggesting air pollution contributes to ASD.

Low to Moderate Prenatal Alcohol Exposure and Neurodevelopmental Outcomes: A Narrative Review and Methodological Considerations.

Although abstinence is recommended in pregnancy, many pregnancies are exposed to alcohol. Observational studies of the effects of low to moderate prenatal alcohol exposure (PAE) and neurodevelopmental outcomes have yielded inconsistent results, with some studies finding an increased risk of adverse neurobehavioral and cognitive outcomes, and other studies finding no changes or reduced risk of the same outcomes. The purpose of this narrative review is to summarize these inconsistencies and apply a methodological framework to discuss how different parameters contribute to the findings. The authors also provide recommendations on how to advance future research in this area. The PubMed, Web of Science, and Embase databases were searched, along with reference lists of selected systematic reviews and meta-analyses. Search terms used were (infant or child or children or adolescent or offspring) AND (low or light or mild or moderate or low-to-moderate) AND (drinking or alcohol or drinks) AND (pregnancy or prenatal or fetal) AND (neurodevelopment or behavioral or psychological or cognitive or developmental) NOT (mice or rat or fish or animal) NOT (meta-analysis or review). Peer-reviewed original research studies were included if they analyzed associations between an exposure defined and characterized as low/light or moderate PAE with offspring neurodevelopmental outcomes. Animal studies, studies that did not provide clear cutoff points to classify PAE categories, studies lacking an abstinence control group, and studies that did not present a multivariable-adjusted measure of association were excluded. The searches identified 2,422 papers, with 36 papers meeting eligibility criteria. These studies were carried out across nine countries and included samples ranging from approximately 500 to 40,000 participants. Cognitive, academic, socioemotional, and behavioral outcomes were assessed from infancy through age 19. When the findings from the selected articles were summarized by geographic region, exposure definition, or neurodevelopmental outcome, no consistent observations or patterns emerged between low to moderate PAE and offspring outcomes. Although some studies found positive (i.e., beneficial) associations between low to moderate PAE and outcomes (primarily outcomes related to cognition) and others found negative (i.e., detrimental) associations (primarily for behavioral outcomes), most findings were null (i.e., showed no effect of PAE). The heterogeneity in study results is likely due to methodological issues, including residual confounding, effect measure modification, and exposure misclassification that make synthesis of studies difficult. Alternative study designs, including longitudinal trajectory analysis, sibling design, negative controls, and instrumental variable analyses, may reduce biases and are discussed. To date, the consequences of light to moderate levels of PAE on neurodevelopment remain unresolved; studies that advance methodological rigor will be important contributions to the field.

Low Doses of Bisphenol A Disrupt Neuronal Differentiation of Human Neuronal Stem/Progenitor Cells.

Bisphenol A (BPA) is an endocrine disrupting chemical. Human epidemiological studies have suggested that adverse neurobehavioral outcomes are induced by fetal exposure to BPA. The remarkable differences in the corticogenesis between human and agyrencephalic mammals are an increase in the intermediate progenitor cells (IPCs) and a following increase in the subplate thickness. It is uncertain whether low doses of BPA (low-BPA) affect human early corticogenesis when basal progenitor cells (BPs) produce IPCs resulting in amplified neurogenesis. In this study, human-derived neuronal stem/progenitor cells were exposed to low-BPA or the vehicle only, and the resultant cell type-specific molecular changes and morphology were analyzed. We focused on stem cells immunoreactive for SOX2, BPs for NHLH1, and immature neurons for DCX. SOX2-positive cells significantly decreased at day in vitro (DIV) 4 and 7, whereas NHLH1-positive cells tended to be higher, while DCX-positive cells significantly increased at DIV7 when exposed to 100 nM of BPA compared with the vehicle. Morphologically DCX-positive cells showed a decrease in unipolar cells and an increase in multipolar cells when exposed to 100 nM of BPA compared with the vehicle. These results provide insights into the in vivo effect of low-BPA on neuronal differentiation in the human fetal corticogenesis.

Health Effects of Pesticide Exposure in Latin American and the Caribbean Populations: A Scoping Review.

Background:Multiple epidemiological studies have shown that exposure to pesticides is associated with adverse health outcomes. However, the literature on pesticide-related health effects in the Latin American and the Caribbean (LAC) region, an area of intensive agricultural and residential pesticide use, is sparse. We conducted a scoping review to describe the current state of research on the health effects of pesticide exposure in LAC populations with the goal of identifying knowledge gaps and research capacity building needs.Methods:We searched PubMed and SciELO for epidemiological studies on pesticide exposure and human health in LAC populations published between January 2007 and December 2021. We identified 233 publications from 16 countries that met our inclusion criteria and grouped them by health outcome (genotoxicity, neurobehavioral outcomes, placental outcomes and teratogenicity, cancer, thyroid function, reproductive outcomes, birth outcomes and child growth, and others).Results:Most published studies were conducted in Brazil (37%, ) and Mexico (20%, ), were cross-sectional in design (72%, ), and focused on farmworkers (45%, ) or children (21%, ). The most frequently studied health effects included genotoxicity (24%, ) and neurobehavioral outcomes (21%, ), and organophosphate (OP) pesticides were the most frequently examined (26%, ). Forty-seven percent () of the studies relied only on indirect pesticide exposure assessment methods. Exposure to OP pesticides, carbamates, or to multiple pesticide classes was consistently associated with markers of genotoxicity and adverse neurobehavioral outcomes, particularly among children and farmworkers.Discussion:Our scoping review provides some evidence that exposure to pesticides may adversely impact the health of LAC populations, but methodological limitations and inconsistencies undermine the strength of the conclusions. It is critical to increase capacity building, integrate research initiatives, and conduct more rigorous epidemiological studies in the region to address these limitations, better inform public health surveillance systems, and maximize the impact of research on public policies. https://doi.org/10.1289/EHP9934

Human placental microRNAs dysregulated by cadmium exposure predict neurobehavioral outcomes at birth.

Prenatal cadmium (Cd) exposure has been implicated in both placental toxicity and adverse neurobehavioral outcomes. Placental microRNAs (miRNAs) may function to developmentally program adverse pregnancy and newborn health outcomes in response to gestational Cd exposure. In a subset of the Rhode Island Child Health Study (RICHS, n = 115) and the New Hampshire Birth Cohort Study (NHBCS, = 281), we used small RNA sequencing and trace metal analysis to identify Cd-associated expression of placental miRNAs using negative binomial generalized linear models. We predicted mRNAs targeted by Cd-associated miRNAs and relate them to neurobehavioral outcomes at birth through the integration of transcriptomic data and summary scores from the NICU Network Neurobehavioral Scale (NNNS). Placental Cd concentrations are significantly associated with the expression level of five placental miRNAs in NHBCS, with similar effect sizes in RICHS. These miRNA target genes overrepresented in nervous system development, and their expression is correlated with NNNS metrics suggestive of atypical neurobehavioral outcomes at birth. Gestational Cd exposure is associated with the expression of placental miRNAs. Predicted targets of these miRNAs are involved in nervous system development and may also regulate placental physiology, allowing their dysregulation to modify developmental programming of early life health outcomes. This research aims to address the poor understanding of the molecular mechanisms governing adverse pregnancy and newborn health outcomes in response to Gestational cadmium (Cd) exposure. Our results outline a robust relationship between Cd-associated placental microRNA expression and NICU Network Neurobehavioral Scales (NNNS) at birth indicative of atypical neurobehavior. This study utilized healthy mother-infant cohorts to describe the role of Cd-associated dysregulation of placental microRNAs as a potential mechanism by which adverse neurobehavioral outcomes are developmentally programmed.

Structural and pragmatic language in young children with sex chromosome trisomy (XXX, XXY, XYY): Predictive value for neurobehavioral problems one year later

Objective: To investigate pragmatic language abilities in young children with an increased risk for adverse neurobehavioral and neurocognitive outcomes due to an extra X or Y chromosome (sex chromosome trisomy; SCT) and to investigate to what degree early structural and pragmatic language abilities are predictive of neurobehavioral problems one year later. Method: In total, 72 children with SCT and 71 controls aged 3-7 years were included. Language assessments included parent-reported pragmatic language skills and direct assessment of structural language abilities. Parent-reported behavioral outcomes were measured one year after the initial language assessment. Results: Children with SCT demonstrated weaker pragmatic language skills compared to controls. These differences were not driven by karyotype, time of diagnosis, or ascertainment bias and irrespective of the presence of structural language impairment. Odds of having pragmatic difficulties was 23 times higher in the SCT group, with 25% of the children not meeting age-expectations. In addition, language, in particular pragmatic language, was an important predictor for later affective, oppositional defiant, pervasive developmental, attention deficit, and social-emotional problems in young children with SCT. Conclusions: This study is one of the first studies that directly illustrates the relationship between language and behavioral outcomes in children with SCT. Our results stress the importance to closely monitor pragmatic language in addition to structural language in clinical care of children with SCT, as pragmatic language abilities could serve as an early marker for children at risk for developing behavioral problems.

Using High-Throughput Screening to Evaluate Perturbations Potentially Linked to Neurobehavioral Outcomes: A Case Study Using Publicly Available Tools on FDA Batch-Certified Synthetic Food Dyes.

There is growing evidence from human and animal studies indicating an association between exposure to synthetic food dyes and adverse neurobehavioral outcomes in children. However, data gaps persist for potential mechanisms by which the synthetic food dyes could elicit neurobehavioral impacts. We developed an approach to evaluate seven US FDA-batch-certified food dyes using publicly available high-throughput screening (HTS) data from the US EPA's Toxicity Forecaster to assess potential underlying molecular mechanisms that may be linked to neurological pathway perturbations. The dyes were screened through 270 assays identified based on whether they had a neurological-related gene target and/or were mapped to neurodevelopmental processes or neurobehavioral outcomes, and were conducted in brain tissue, targeted specific hormone receptors, or targeted oxidative stress and inflammation. Some results provided support for neurological impacts found in human and animal studies, while other results showed a lack of correlation with in vivo findings. The azo dyes had a range of activity in assays mapped to G-protein-coupled receptors and were active in assays targeting dopaminergic, serotonergic, and opioid receptors. Assays mapped to nuclear receptors (androgen, estrogen, and thyroid hormone) also exhibited activity with the food dyes. Other molecular targets included the aryl hydrocarbon receptor, acetylcholinesterase, and monoamine oxidase. The Toxicological Prioritization Index tool was used to visualize the results of the Novascreen assays. Our results highlight certain limitations of HTS assays but provide insight into potential underlying mechanisms of neurobehavioral effects observed in in vivo animal toxicology studies and human clinical studies.

IFNγ-Producing γ/δ T Cells Accumulate in the Fetal Brain Following Intrauterine Inflammation.

Intrauterine inflammation impacts prenatal neurodevelopment and is linked to adverse neurobehavioral outcomes ranging from cerebral palsy to autism spectrum disorder. However, the mechanism by which a prenatal exposure to intrauterine inflammation contributes to life-long neurobehavioral consequences is unknown. To address this gap in knowledge, this study investigates how inflammation transverses across multiple anatomic compartments from the maternal reproductive tract to the fetal brain and what specific cell types in the fetal brain may cause long-term neuronal injury. Utilizing a well-established mouse model, we found that mid-gestation intrauterine inflammation resulted in a lasting neutrophil influx to the decidua in the absence of maternal systemic inflammation. Fetal immunologic changes were observed at 72-hours post-intrauterine inflammation, including elevated neutrophils and macrophages in the fetal liver, and increased granulocytes and activated microglia in the fetal brain. Through unbiased clustering, a population of Gr-1+ γ/δ T cells was identified as the earliest immune cell shift in the fetal brain of fetuses exposed to intrauterine inflammation and determined to be producing high levels of IFNγ when compared to γ/δ T cells in other compartments. In a case-control study of term infants, IFNγ was found to be elevated in the cord blood of term infants exposed to intrauterine inflammation compared to those without this exposure. Collectively, these data identify a novel cellular immune mechanism for fetal brain injury in the setting of intrauterine inflammation.

Role of endocrine disrupting chemicals in children's neurodevelopment

Environmental stressors, like endocrine disrupting chemicals (EDC), are considered important contributors to the increased rates of neurodevelopmental dysfunctions. Considering the cumulative research on adverse neurodevelopmental effects associated with prenatal exposure to EDC, the purpose of this study was to review the available limited literature about the effects of postnatal exposure to EDC on child neurodevelopment and behaviour. Despite widespread children's exposure to EDC, there are a limited number of epidemiological studies on the association of this exposure with neurodevelopmental disorders, in particular in the postnatal period. The available research suggests that postnatal EDC exposure is related to adverse neurobehavioral outcomes in children; however the underlying mechanisms of action remain unclear. Timing of exposure is a key factor determining potential neurodevelopmental consequences, hence studying the impact of multiple EDC co-exposure in different vulnerable life periods could guide the identification of sensitive subpopulations. Most of the reviewed studies did not take into account sex differences in the EDC effects on children neurodevelopment. We believe that the inclusion of sex in the study design should be considered as the role of EDC on children neurodevelopment are likely sex-specific and should be taken into consideration when determining susceptibility and potential mechanisms of action.

Evaluation of aqueous dimethyl trisulfide as an antidote to a highly lethal cyanide poisoning in a large swine model

Background Cyanide is a rapid acting, lethal, metabolic poison and remains a significant threat. Current FDA-approved antidotes are not amenable or efficient enough for a mass casualty incident. Objective The objective of this study is to evaluate short and long-term efficacy of intramuscular aqueous dimethyl trisulfide (DMTS) on survival and clinical outcomes in a swine model of cyanide exposure. Methods Anesthetized swine were instrumented and acclimated until breathing spontaneously. Potassium cyanide infusion was initiated and continued until 5 min after the onset of apnea. Subsequently, animals were treated with intramuscular DMTS (n = 11) or saline control (n = 10). Laboratory values and DMTS blood concentrations were assessed at various time points and physiological parameters were monitored continuously until the end of the experiment unless death occurred. A subset of animals treated with DMTS (n = 5) were survived for 7 days to evaluate muscle integrity by repeat biopsy and neurobehavioral outcomes. Results Physiological parameters and time to apnea were similar in both groups at baseline and at time of treatment. Survival in the DMTS-treated group was 90% and 30% in saline controls (p = 0.0034). DMTS-treated animals returned to breathing at 12.0 ± 10.4 min (mean ± SD) compared to 22.9 ± 7.0 min (mean ± SD) in the 3 surviving controls. Blood collected prior to euthanasia showed improved blood lactate concentrations in the DMTS treatment group; 5.47 ± 2.65 mmol/L vs. 9.39 ± 4.51 mmol/L (mean ± SD) in controls (p = 0.0310). Low concentrations of DMTS were detected in the blood, gradually increasing over time with no elimination phase observed. There was no mortality, histological evidence of muscle trauma, or observed adverse neurobehavioral outcomes, in DMTS-treated animals survived to 7 days. Conclusion Intramuscular administration of aqueous DMTS improves survival following cyanide poisoning with no observed long-term effects on muscle integrity at the injection site or adverse neurobehavioral outcomes.

Exposure to multiple pesticides and neurobehavioral outcomes among smallholder farmers in Uganda

BackgroundMultiple epidemiological studies have shown that exposure to single pesticide active ingredients or chemical groups is associated with adverse neurobehavioral outcomes in farmers. In agriculture, exposure to multiple pesticide active ingredients is the rule, rather than exception. Therefore, occupational studies on neurobehavioral effects of pesticides should account for potential co-exposure confounding. MethodsWe conducted a cross-sectional study of 288 Ugandan smallholder farmers between September and December 2017. We collected data on self-reported use of pesticide products during the 12 months prior to survey and estimated yearly exposure-intensity scores for 14 pesticide active ingredients using a semi-quantitative exposure algorithm. We administered 11 neurobehavioral tests to assess five neurobehavioral domains. We implemented a Bayesian Model-Averaging (BMA) approach to examine the association between exposure to multiple pesticides and neurobehavioral outcomes, while accounting for multiple testing. We applied two levels of inference to determine (1) which neurobehavioral outcomes were associated with overall pesticide exposure (marginal inclusion probability (MIP) for covariate-only models <0.5) and (2) which specific pesticide active ingredients were associated with these outcomes (MIP for models where active ingredient was included >0.5). ResultsSeventy-two percent of farmers reported use of pesticide products that contained at least one of 14 active ingredients, while the applicators used in median three different active ingredients (interquartile range (IQR) 4) in the 12 months prior to the study. The most widely used active ingredients were glyphosate (79%), cypermethrin (60%), and mancozeb (55%). We found that overall pesticide exposure was associated with impaired visual memory (Benton Visual Retention Test (BVRT)), language (semantic verbal fluency test), perceptual-motor function (Finger tapping test), and complex attention problems (Trail making A test and digit symbol test). However, when we looked at the associations for individual active ingredients, we only observed a positive association between glyphosate exposure and impaired visual memory (-0.103 [95% Bayesian Credible Interval (BCI)] [-0.24, 0] units in BVRT scores per interquartile range (IQR) increase in annual exposure to glyphosate, relative to a median [IQR] of 6 [3] units in BVRT across the entire study population). ConclusionsWe found that overall pesticide exposure was associated with several neurobehavioral outcome variables. However, when we examined individual pesticide active ingredients, we observed predominantly null associations, except for a positive association between glyphosate exposure and impaired visual memory. Additional epidemiologic studies are needed to evaluate glyphosate’s neurotoxicity, while accounting for co-pollutant confounding.

The association of prenatal exposure to intensive traffic with early preterm infant neurobehavioral development as reflected by the NICU Network Neurobehavioral Scale (NNNS)

Introduction: Traffic-related air pollution has been shown to be neurotoxic to the developing fetus and in term-born infants during early childhood. It is unknown whether there is an increased risk of adverse neurobehavioral outcome in preterm infants exposed to higher levels of air pollution during the fetal period. Objective: To assess the association between prenatal exposure to traffic-related air pollution on early preterm infant neurobehavior. Methods: Air pollution exposure was estimated by two methods: density of major roads and density of vehicle-miles traveled (VMT), each at multiple buffering areas around residential addresses. We examined the association between prenatal exposure to traffic-related air pollution and performance on the Neonate Intensive Care Unit (NICU) Network Behavioral Scale (NNNS), a measure of neurobehavioral outcome in infancy for 240 preterm neonates enrolled in the NICU-Hospital Exposures and Long-Term Health cohort. Linear regression analysis was conducted for exposure and individual NNNS subscales. Latent profile analysis (LPA) was applied to classify infants into distinct NNNS phenotypes. Multinomial logistic regression analysis was conducted between exposure and LPA groups. Covariates included gestational age, birth weight z-score, post-menstrual age at NNNS assessment, socioeconomic status, race, delivery type, maternal smoking status, and medical morbidities during the NICU stay. Results: Among all 13 NNNS subscales, hypotonia was significantly associated with VMT (104 vehicle-mile/km2) in 150m (β=0.01, P-value&lt;0.001), 300m (β=0.01, P-value=0.003), and 500m (β=0.01, P-value=0.002) buffering areas, as well as with road density in a 500m buffering area (β=0.03, P-value=0.03). We identified three NNNS phenotypes by LPA. Among them, high density of major roads within 150m, 300m, and 500m buffers of the residential address was significantly associated with the same phenotype (P&lt;0.05). Conclusion: Prenatal exposure to intensive air pollution emitted from major roads may impact early neurodevelopment of preterm infants. Motor development may be particularly sensitive to air pollution-related toxicity.

Early Life Exposure to Nicotine: Postnatal Metabolic, Neurobehavioral andRespiratory Outcomes and the Development of Childhood Cancers.

Cigarette smoking during pregnancy is associated with numerous obstetrical, fetal, and developmental complications, as well as an increased risk of adverse health consequences in the adult offspring. Nicotine replacement therapy and electronic nicotine delivery systems (e-cigarettes) have been developed as a pharmacotherapy for smoking cessation and are considered safer alternatives for women to smoke during pregnancy. The safety of nicotine replacement therapy use during pregnancy has been evaluated in a limited number of short-term human trials, but there is currently no information on the long-term effects of developmental nicotine exposure in humans. However, animal studies suggest that nicotine alone may be a key chemical responsible for many of the long-term effects associated with maternal cigarette smoking on the offspring and increases the risk of adverse neurobehavioral outcomes, dysmetabolism, respiratory illness, and cancer. This review will examine the long-term effects of fetal and neonatal nicotine exposure on postnatal health.

Anesthesia plus surgery in neonatal period impairs preference for social novelty in mice at the juvenile age

Anesthetic sevoflurane could induce neurotoxicity in developing brain and cause adverse neurobehavioral outcomes in mice, including inattention, social interaction deficit, and learning and memory impairment. However, there is less data on the effect of anesthesia plus surgery on social interaction behavior. Therefore, we investigated whether the combination of anesthesia and surgical stimulation could induce behavioral and biochemical changes in mice. Firstly, the six-day-old mice were received either 3% sevoflurane anesthesia or abdominal surgery under sevoflurane anesthesia. Then, these mice were scheduled to social interaction test in three-chambered social paradigm at one-month-old. In addition, the brain tissues of neonatal mice were harvested at 24 h after treatment, for measuring the levels of OXTR and NMDAR1 in Western blot analysis. We found that neonatal anesthesia with sevoflurane in a clinically-relevant dosage could not induce social interaction deficit. Nevertheless, anesthesia plus surgery was able to impair preference for social novelty in mice. Moreover, anesthesia plus surgery decreased the levels of OXTR in hippocampus and cortex of mice, as well as NMDAR1 in hippocampus. Collectively, these results suggested that anesthesia plus surgery could impair social novelty preference, but not sociability in mice, and that social memory might be more vulnerable than social affiliation in biological property. Furthermore, reduction in the levels of cortex OXTR and hippocampus NMDAR1 could be associated with social recognition memory in mice.

The associations between prenatal exposure to polycyclic aromatic hydrocarbon metabolites, umbilical cord blood mitochondrial DNA copy number, and children’s neurobehavioral development

Exposure to polycyclic aromatic hydrocarbons (PAHs) during pregnancy is a risk factor for adverse neurobehavioral development outcomes. Mitochondrial DNA are sensitive to environmental toxicants due to the limited ability of repairing. The change of mitochondrial DNA copy number (mtDNAcn) might be a biologically mechanism linking PAH exposure and children’s neurobehavioral impairment. Our aims are to explore whether PAH metabolites in maternal urine were associated with children’s neurobehavioral development at 2 years old and umbilical cord blood mtDNAcn, and whether mtDNAcn was a mediator of PAH-related neurobehavioral development. We included 158 non-smoking pregnant women from Taiyuan City, Shanxi Province. Maternal urinary eleven PAH metabolites were detected by high performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). MtDNAcn in cord blood was detected by real time quantitative polymerase chain reaction (RT-PCR). Children’s neurodevelopment was measured by Gesell Developmental Schedules (GDS) when children were two years age. Generalized linear models and restricted cubic spline models were applied to assess the relationships between PAH metabolites in maternal urine and GDS scores and mtDNAcn. A mediation analysis was also conducted. Generalized linear models showed the relationships of sum of PAH metabolites (Σ-OHPAHs) in maternal urine with decreased motor score, and Σ-OHPAHs with increased mtDNAcn (p for trend < 0.05). Urinary levels of Ln (Σ-OHPAHs) increased one unit was related to a 2.08 decreased in motor scores, and Ln (Σ-OHPAHs) increased one unit was related to 0.15 increased in mtDNAcn. Mediation analysis did not find mtDNAcn can be a mediator between PAH metabolites and neurobehavioral development. Our results suggest that prenatal exposure to PAH decreased children’s neurobehavioral development scores and increased mtDNAcn. And reducing exposure to PAH during pregnancy will benefit to improving neurobehavioral development in children.In our present cohort study, sum of PAH metabolites in urine of pregnant women were related with motor score and were positively associated with umbilical cord blood mtDNA copy number.

The association of prenatal exposure to intensive traffic with early preterm infant neurobehavioral development as reflected by the NICU Network Neurobehavioral Scale (NNNS)

IntroductionTraffic-related air pollution has been shown to be neurotoxic to the developing fetus and in term-born infants during early childhood. It is unknown whether there is an increased risk of adverse neurobehavioral outcome in preterm infants exposed to higher levels of air pollution during the fetal period. ObjectiveTo assess the association between prenatal exposure to traffic-related air pollution on early preterm infant neurobehavior. MethodsAir pollution exposure was estimated by two methods: density of major roads and density of vehicle-miles traveled (VMT), each at multiple buffering areas around residential addresses. We examined the association between prenatal exposure to traffic-related air pollution and performance on the Neonate Intensive Care Unit (NICU) Network Behavioral Scale (NNNS), a measure of neurobehavioral outcome in infancy for 240 preterm neonates enrolled in the NICU-Hospital Exposures and Long-Term Health cohort. Linear regression analysis was conducted for exposure and individual NNNS subscales. Latent profile analysis (LPA) was applied to classify infants into distinct NNNS phenotypes. Multinomial logistic regression analysis was conducted between exposure and LPA groups. Covariates included gestational age, birth weight z-score, post-menstrual age at NNNS assessment, socioeconomic status, race, delivery type, maternal smoking status, and medical morbidities during the NICU stay. ResultsAmong all 13 NNNS subscales, hypotonia was significantly associated with VMT (104 vehicle-mile/km2) in 150 m (β = 0.01, P-value<0.001), 300 m (β = 0.01, P-value = 0.003), and 500 m (β = 0.01, P-value = 0.002) buffering areas, as well as with road density in a 500 m buffering area (β = 0.03, P-value = 0.03). We identified three NNNS phenotypes by LPA. Among them, high density of major roads within 150 m, 300 m, and 500 m buffers of the residential address was significantly associated with the same phenotype (P < 0.05). ConclusionPrenatal exposure to intensive air pollution emitted from major roads may impact early neurodevelopment of preterm infants. Motor development may be particularly sensitive to air pollution-related toxicity.

Long-term neuropathological and/or neurobehavioral effects of antenatal corticosteroid therapy in animal models: a systematic review

Antenatal corticosteroids (ACSs) are recommended to all women at risk for preterm delivery; currently, there is controversy about the subsequent long-term neurocognitive sequelae. This systematic review summarizes the long-term neurodevelopmental outcomes after ACS therapy in animal models. An electronic search strategy incorporating MeSH and keywords was performed using all known literature databases and in accordance with PRISMA guidance (PROSPERO CRD42019119663). Of the 669 studies identified, eventually 64 were included. The majority of studies utilized dexamethasone at relative high dosages and primarily involved rodents. There was a high risk of bias, mostly due to lack of randomization, allocation concealment, and blinding. The main outcomes reported on was neuropathological, particularly glucocorticoid receptor expression and neuron densities, and neurobehavior. Overall there was an upregulation of glucocorticoid receptors with lower neuron densities and a dysregulation of the dopaminergic and serotonergic systems. This coincided with various adverse neurobehavioral outcomes. In animal models, ACSs consistently lead to deleterious long-term neurocognitive effects. This may be due to the specific agents, i.e., dexamethasone, or the repetitive/higher total dosing used. ACS administration varied significantly between studies and there was a high risk of bias. Future research should be standardized in well-characterized models.