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Background: Prenatal exposures to xenobiotics during the masculinization programming window are suggested to impact male fecundity later in life. Frequently used nitrosatable drugs, such as penicillins and beta2-agonists, contain amines or amides that may form teratogenic compounds in reaction with nitrite., Objectives: We explored whether maternal nitrosatable drug use during gestation was associated with biomarkers of male fecundity in adulthood; moreover, the potential modifiable effect of nitrate and vitamin intake was investigated., Method: We performed a cohort study in the Fetal Programming of Semen Quality cohort that includes semen characteristics, reproductive hormone concentrations, and measures of testis size on 1058 young adult sons in the Danish National Birth Cohort. Information on maternal use of nitrosatable drugs was obtained from questionnaires and interviews around gestational weeks 11 and 16. A multivariable negative binomial regression model was used to obtain relative differences in biomarkers of male fecundity for those whose mothers used nitrosatable drugs compared to those without such maternal use. In sub-analyses, the exposure was categorized according to nitrosatable drug type: secondary amine, tertiary amine, or amide. We investigated dose dependency by examining the number of weeks with intake and explored potential effect modification by low versus high maternal nitrate and vitamin intake from diet and nitrate concentration in drinking water. We added selection weights and imputed values of missing covariates to limit the risk of selection bias., Results: In total, 19.6% of the study population were born of mothers with an intake of nitrosatable drugs at least once during early pregnancy. Relative differences in biomarkers related to male fecundity between exposed and unexposed participants were negligible. Imputation of missing covariates did not fundamentally alter the results. Furthermore, no sensitive subpopulations were detected., Conclusions: The results suggest that maternal use of nitrosatable drugs does not have a harmful influence on the male fecundity of the offspring., (© 2024 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Background: A large body of data shows that fetal brain development is vulnerable to disruption by air pollution experienced by the mother during pregnancy, adversely affecting cognitive and psychomotor capabilities during childhood (De Asis-Cruz et al., Biol Psychiatry 7:480-90, 2022; Morgan ZEM et al., Environ Health 22:11, 2023). This study has sought to identify gestational windows of susceptibility to prenatal exposure to air pollution., Methods: 470 African American and Latina mother/child pairs participated in a prospective cohort study based in the low-income communities of Northern Manhattan and the South Bronx, New York City. Gestational exposure to respirable particulate matter (PM 2.5 ) and nitrogen dioxide (NO 2 ) was assessed through validated models in relation to cognitive and motor development assessed at ages 1, 2, and 3 years using the Bayley-II Scales. Multiple linear regression models and distributed lag models (DLM) were used to identify critical windows of exposure by trimester and week of pregnancy., Results: By linear regression, average exposures to NO 2 during the first and second trimesters and the entire pregnancy were significantly and negatively associated with the mental developmental index (MDI) at age 1. Average exposures to PM 2.5 during the second trimester and the entire pregnancy were also significantly, inversely associated with age 1 MDI. No significant associations were found between these exposures and MDI at age 2. NO 2 exposure during the first trimester was significantly negatively associated with MDI at age 3. Using DLM, exposures to NO 2 at lags 29-30 weeks (within the first trimester) and PM 2.5 at lags 17-18 weeks (second trimester) were significantly and inversely associated with MDI at age 1. Significant, inverse associations were found between exposures to NO 2 at lag 29 weeks and PM 2.5 at lags 27-29 weeks and children's MDI at age 3. No significant associations were found between psychomotor index (PDI) and prenatal exposures to NO 2 or PM 2.5 at ages 1, 2 or 3., Conclusions: Our finding that prenatal exposure to air pollution in the first and second trimesters was associated with lower scores for cognitive development at ages 1 and 3 is of concern because of the potential consequences of these outcomes for long-term functioning. They underscore the need for stronger policies to protect pregnant individuals and offspring, particularly during vulnerable, early life-stage of development., (© 2024. The Author(s).)

Background: Exposure to ambient air pollution is a top risk factor contributing to the global burden of disease. Pregnant persons and their developing fetuses are particularly susceptible to adverse health outcomes associated with air pollution exposures. During pregnancy, the thyroid plays a critical role in fetal development, producing thyroid hormones that are associated with brain development. Our objective is to systematically review recent literature that investigates how prenatal exposure to air pollution affects maternal and fetal thyroid function., Methods: Following the Navigation Guide Framework, we systematically reviewed peer-reviewed journal articles that examined prenatal exposures to air pollution and outcomes related to maternal and fetal thyroid function, evaluated the risk of bias for individual studies, and synthesized the overall quality and strength of the evidence., Results: We found 19 studies that collected data on pregnancy exposure windows spanning preconception to full term from 1999 to 2020 across nine countries. Exposure to fine particulate matter (PM 2.5 ) was most frequently and significantly positively associated with fetal/neonatal thyroid hormone concentrations, and inversely associated with maternal thyroid hormone concentrations. To a lesser extent, traffic-related air pollutants, such as nitrogen dioxide (NO 2 ) had significant effects on fetal/neonatal thyroid function but no significant effects on maternal thyroid function. However, the body of literature is challenged by risk of bias in exposure assessment methods and in the evaluation of confounding variables, and there is an inconsistency amongst effect estimates. Thus, using the definitions provided by the objective Navigation Guide Framework, we have concluded that there is limited, low quality evidence pertaining to the effects of prenatal air pollution exposure on maternal and fetal thyroid function., Conclusion: To improve the quality of the body of evidence, future research should seek to enhance exposure assessment methods by integrating personal monitoring and high-quality exposure data (e.g., using spatiotemporally resolved satellite observations and statistical modeling) and outcome assessment methods by measuring a range of thyroid hormones throughout the course of pregnancy., (© 2024. The Author(s).)

Background: The gut microbiome is central to human health, but the potential impact of ozone (O 3 ) exposure on its establishment in early life has not been thoroughly examined. Therefore, this study aimed to investigate the relationship between prenatal O 3 exposure and the variations of the human gut microbiome during the first two years of life., Design: A cohort study design was used. Pregnant women in the third trimester were recruited from an obstetric clinic, and long-term follow-ups were conducted after delivery. The gut microbiome was analyzed using the 16 S rRNA V3-V4 gene regions. Functional pathway analyses of gut microbial communities in neonates were performed using Tax4fun. The average concentrations of ambient O 3 and other air pollutants from pregnancy to delivery were calculated using the China High Air Pollutants (CHAP) dataset, based on the permanent residential addresses of participants. Multiple linear regression and mixed linear models were utilized to investigate the associations between prenatal O 3 exposure and gut microbiome features., Results: Prenatal O 3 exposure did not significantly affect the gut microbial alpha diversity of mothers and neonates. However, it was found to be positively associated with the gut microbial alpha diversity in 24-month-old infants. Prenatal O 3 exposure explained 13.1 % of the variation in neonatal gut microbial composition. After controlling for potential covariates, prenatal O 3 exposure was associated with neonatal-specific gut microbial taxa and functional pathways. Furthermore, the mixed linear models showed that prenatal O 3 exposure was negatively associated with variations of Streptococcus (p-value = 0.001, q-value = 0.005), Enterococcus (p-value = 0.001, q-value = 0.005), Escherichia-Shigella (p-value = 0.010, q-value = 0.025), and Bifidobacterium (p-value = 0.003, q-value = 0.010)., Conclusions: This study is the first to examine the effects of prenatal O 3 exposure on gut microbial homeostasis and variations. It demonstrates that prenatal O 3 exposure is associated with variations in certain aspects of the gut microbiome. These findings provide novel insights into the dynamics and establishment of the human microbiome during the first two years of life., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

There has been an increasing use of cannabis during pregnancy in recent years. Studies have indicated that THC exposure in utero may increase the risk of attention deficits and memory impairments in adolescence. The goal of the present study is to investigate the effects of vaporized THC exposure during pregnancy on offspring memory and attention performance in early and late adolescence. Pregnant dams were exposed to vaporized THC (10 mg or 40 mg) daily from gestational day 2 until labor. Pups were given either a standard or a high-fat diet at weaning and tested in early and late adolescence in two memory tests, the Novel Object Recognition (NOR) test and the Morris Water Maze (MWM) test, and a test of attention, the Object-Based Attention (OBA) test. Rats exposed to low-dose THC showed significantly decreased object exploration in both the NOR and OBA tests, indicating decreased attention. Object exploration time in OBA was significantly lower in females than males. Additionally, post hoc analysis of MWM tests showed some differences in learning patterns for HD THC offspring in early adolescence, possibly due to diet interaction, but ultimate performance was not impacted. While there are existing studies examining prenatal exposure to THC in rodents, this is the first to our knowledge examining memory and attention in adolescence following vaporized THC exposure in utero, and we find indications that prenatal THC exposure may lead to attention deficits and altered memory performance., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rationale Clinical research has shown that prenatal exposure to nicotine may result in increased obesity risk later in life. Preclinical research has corroborated this finding, but few studies have investigated inhaled nicotine or the interaction with diet on obesity risk. Objective The aim of this study was to investigate the effects of prenatal nicotine exposure on both direct and indirect obesity measures, with both sex and diet as factors. Methods Pregnant rats were exposed to either vehicle or nicotine vapor (24 mg/mL or 59 mg/mL) throughout the entire gestational period. Offspring from each treatment group were given either a normal diet or a high fat diet starting at postnatal day 22. Caloric intake, body weight, spontaneous locomotion, sleep/wake activity, and voluntary exercise were measured throughout adolescence. Pregnancy weight gain and pup birthweights were collected to further measure developmental effects of prenatal nicotine exposure. Results Both maternal weight gain during pregnancy and pup weight at birth were decreased with prenatal nicotine exposure. Early adolescent males showed increased spontaneous activity in the open field following prenatal nicotine exposure compared to vehicle counterparts, particularly those given high-fat diet. Additionally, high dose nicotine prenatal treated males ran significantly less distance on the running wheel in late adolescence compared to vehicle counterparts, in the normal diet group only. Conclusion The results presented here show decreased birthweight, hyperactivity, and decreased voluntary exercise in adolescence following prenatal nicotine exposure in dose, sex, and diet dependent manners, which could lead to increased obesity risk in adulthood., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Epidemiological, experimental, and ecological data have indicated the controversial effect of in utero chronic low dose rate (<6 mGy/h) with accumulative low (≤100 mGy) or high (>100 mGy) dose radiation exposure. Our main goal of this study was to examine if different low dose rates of chronic pre- and/or post-natal radiation exposure with accumulative high doses could induce hippocampal cellular, mRNA, and miRNA changes leading to neuropsychiatric disorders. The comprehensive mouse phenotypic traits, organ weight, pathological, and blood mRNA and miRNA changes were also studied. Using different approaches including SmithKline, Harwell, Imperial College, Royal Hospital, Phenotype Assessment (SHIRPA), neurobehavioral tests, pathological examination, immunohistochemistry, mRNA and miRNA sequencing, and real-time quantitative polymerase chain reaction (qRT-PCR) validation, we found that in prenatally irradiated (100 mGy/d for 18 days with an accumulative dose of 1.8 Gy) 1-year-old mice, no cellular changes, including immature neurons in the subgranular zone, mature neurons and glial cells in the hilus of the dentate gyrus and development of cognitive impairment, neuropsychiatric disorders, occurred. However, a significant reduction in body weight and mass index (BMI) was indicated by the SHIRPA test. A reduced exploratory behavior was shown by an open field test. Organ weights showed significant reductions in the testes, kidneys, heart, liver and epididymides with no abnormal pathology. mRNA and miRNA sequencing and qRT-PCR validation revealed the upregulation of Rubcnl and Abhd14b, and downregulation of Hspa1b, P4ha1, and Banp genes in both the hippocampus and blood of mice prenatally irradiated with 100 mGy/d. Meanwhile, downregulation of miR-448-3p and miR1298-5p in the hippocampus, miR-320-3p, miR-423-5p, miR-486b-5p, miR-486b-3p, miR-423-3p, miR-652-3p, miR-324-3p, miR-181b-5p, miR-let-7b, and miR-6904-5p in the blood was induced. The target scan revealed that Rubcnl is one of the miR-181b-5p targets in the blood. We, therefore, concluded that prenatal chronic irradiation with a low dose rate of 100 mGy/d and accumulative dose of 1.8 Gy or below might not induce significant adverse health effects on the offspring. Further study of different low dose rate radiation exposures with accumulative high doses may provide threshold doses for authorities or regulators to set new radiation safety guidelines to replace those extrapolated from acute high dose/dose rate irradiation to reduce unnecessary emergency evacuation or spending once a nuclear accident or leakage occurs.

Background: Metal(oid)s have been cross-sectionally associated with lung function outcomes in childhood but there is limited data on their combined effects starting in utero. Child sex may further modify these effects., Objective: Examine associations between in utero and early life exposure to metals assessed via novel dentine biomarkers and childhood lung function and explore effect modification by child sex., Methods: Analyses included 291 children enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, a longitudinal birth cohort study in Mexico City. Weekly dentine levels of arsenic (As), cadmium (Cd), cobalt (Co), copper (Cu), manganese (Mn), nickel (Ni), and lead (Pb) were measured from 15 weeks pre-birth to 15 weeks post birth in deciduous children's teeth. Lung function was tested at ages 8-14 years and then modeled as age, height and sex adjusted z-scores. Associations were modeled using lagged weighted quantile sum (LWQS) regression to evaluate the potential for a time-varying mixture effect adjusting for maternal age and education at enrollment and exposure to environmental tobacco smoke in pregnancy. Models were also stratified by sex., Results: We identified a window of susceptibility at 12-15 weeks pre-birth in which the metal mixture was associated with lower FVC z-scores in children aged 8-14 years. Cd and Mn were the largest contributors to the mixture effect (70 %). There was also some evidence of effect modification by sex, in which the mean weights and weighted correlations over the identified window was more evident in males when compared to females. In the male stratum, Cd, Mn and additionally Pb also dominated the mixture association., Conclusions: Prenatal metal(oid) exposure was associated with lower lung function in childhood. These findings underscore the need to consider both mixtures and windows of susceptibility to fully elucidate effects of prenatal metal(oid) exposure on childhood lung function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: We investigated the individual and interaction effects of maternal plasma 𝛂- and ϒ-tocopherol levels (vitamin E isomers) on child asthma and wheeze at age 8-9., Methods: Mother-child dyads were enrolled between 2006 and 2011 into the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) prenatal cohort. Maternal second-trimester samples were analyzed for tocopherol and lipid concentrations. We assessed child asthma/wheeze using the International Study of Asthma and Allergies in Childhood (ISAAC) and other self-reported Ent wheeze. In multivariable logistic regression analyses, we assessed associations between vitamin E isomers and child asthma/wheeze outcomes (n = 847 mother-child dyads) and tested for prespecified interaction terms., Results: Median cholesterol-corrected tocopherol levels (interquartile range (IQR)) were 5.0 (4.3-5.7) and 0.8 (0.7-0.9) (umol/mmol) for 𝛂- and ϒ-tocopherol, respectively. Associations between 𝛂-tocopherol and asthma outcome variables were inverse but not statistically significant. In contrast, for ϒ-tocopherol, associations were in the positive direction, but also nonsignificant. Interactions analysis between tocopherols did not reach statistical significance for any outcome. Among children of women with a history of asthma, the likelihood of ever asthma in the child appears to be decreasing with increasing maternal 𝛂-tocopherol levels, whereas this trend was not observed among those without a history of asthma (p-interaction = .05)., Conclusion: We observed no associations for prenatal 𝛂- or ϒ-tocopherol concentrations with child asthma/wheeze. We detected some evidence of effect modification by maternal asthma history in associations between 𝛂-tocopherol and child asthma., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Introduction: Epigenetic marks are key biomarkers linking the prenatal environment to health and development. However, DNA methylation associations and persistence of marks for prenatal exposure to multiple Endocrine Disrupting Chemicals (EDCs) in human populations have not been examined in great detail., Methods: We measured Bisphenol-A (BPA), triclosan, benzophenone-3 (BP3), methyl-paraben, propyl-paraben, and butyl-paraben, as well as 11 phthalate metabolites, in two pregnancy urine samples, at approximately 13 and 26 weeks of gestation in participants of the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study (N = 309). DNA methylation of cord blood at birth and child peripheral blood at ages 9 and 14 years was measured with 450K and EPIC arrays. Robust linear regression was used to identify differentially methylated probes (DMPs), and comb-p was used to identify differentially methylated regions (DMRs) in association with pregnancy-averaged EDC concentrations. Quantile g-computation was used to assess associations of the whole phenol/phthalate mixture with DMPs and DMRs., Results: Prenatal BPA exposure was associated with 1 CpG among males and Parabens were associated with 10 CpGs among females at Bonferroni-level significance in cord blood. Other suggestive DMPs (unadjusted p-value < 1 × 10 -6 ) and several DMRs associated with the individual phenols and whole mixture were also identified. A total of 10 CpG sites at least suggestively associated with BPA, Triclosan, BP3, Parabens, and the whole mixture in cord blood were found to persist into adolescence in peripheral blood., Conclusions: We found sex-specific associations between prenatal phenol exposure and DNA methylation, particularly with BPA in males and Parabens in females. Additionally, we found several DMPs that maintained significant associations with prenatal EDC exposures at age 9 and age 14 years., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Early life exposure to organophosphate (OP) pesticides is linked with adverse neurodevelopment and brain function in children. However, we have limited knowledge of how these exposures affect functional connectivity, a measure of interaction between brain regions. To address this gap, we examined the association between early life OP pesticide exposure and functional connectivity in adolescents., Methods: We administered functional near-infrared spectroscopy (fNIRS) to 291 young adults with measured prenatal or childhood dialkylphosphates (DAPs) in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study, a longitudinal study of women recruited during pregnancy and their offspring. We measured DAPs in urinary samples collected from mothers during pregnancy (13 and 26 weeks) and children in early life (ages 6 months, 1, 2, 3, and 5 years). Youth underwent fNIRS while they performed executive function and semantic language tasks during their 18-year-old visit. We used covariate-adjusted regression models to estimate the associations of prenatal and childhood DAPs with functional connectivity between the frontal, temporal, and parietal regions, and a mediation model to examine the role of functional connectivity in the relationship between DAPs and task performance., Results: We observed null associations of prenatal and childhood DAP concentrations and functional connectivity for the entire sample. However, when we looked for sex differences, we observed an association between childhood DAPs and functional connectivity for the right interior frontal and premotor cortex after correcting for the false discovery rate, among males, but not females. In addition, functional connectivity appeared to mediate an inverse association between DAPs and working memory accuracy among males., Conclusion: In CHAMACOS, a secondary analysis showed that adolescent males with elevated childhood OP pesticide exposure may have altered brain regional connectivity. This altered neurofunctional pattern in males may partially mediate working memory impairment associated with childhood DAP exposure., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Maternal exposure to elevated levels of steroid hormones during pregnancy is associated with the development of chronic conditions in offspring that manifest in adulthood. However, the effects of progesterone (P4) administration during early pregnancy on fetal development and subsequent offspring behavior remain poorly understood. In this study, we aimed to investigate the effects of P4 treatment during early pregnancy on the transcript abundance in the fetal brain and assess the behavioral consequences in the offspring during adolescence and adulthood. Using RNA-seq analysis, we examined the impact of P4 treatment on the fetal brain transcriptome in a dosage-dependent manner. Our results revealed differential regulation of genes involved in neurotransmitter transport, synaptic transmission, and transcriptional regulation. Specifically, we observed bidirectional regulation of transcription factors (TFs) by P4 at different doses, highlighting the critical role of these TFs in neurodevelopment. To assess behavioral outcomes, we conducted open field and elevated plus maze tests. Offspring treated with low-dose P4 (LP4) displayed increased exploratory behavior during both adolescence and adulthood. In contrast, the high-dose P4 (HP4) group exhibited impaired exploration and heightened anxiety-like behaviors compared to the control mice. Moreover, in a novel object recognition test, HP4-treated offspring demonstrated impaired object recognition memory during both developmental stages. Additionally, both LP4 and HP4 groups showed reduced social interaction in the three-chamber test. These results suggest that prenatal exposure to P4 exerts a notable influence on the expression of genes associated with neurodevelopment and may induce alterations in behavioral characteristics in progeny, highlighting the need to monitor progesterone levels during pregnancy for long-term impacts on fetal brain development and behavior., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Maternal bisphenol A (BPA) exposure has been reported to cause learning and memory deficits in born offspring. However, little is known that this impairment is potentially caused by epigenetic modulation on the development of NMDA receptor subunits. This study investigates the effect of prenatal BPA exposure on the hippocampal miR-19a and miR-539, which are responsible for regulating NMDA receptor subunits as well as learning and memory functions. Pregnant Sprague Dawley rats were orally administered with 5 mg/kg/day of BPA from pregnancy day 1 (PD1) until gestation day 21 (GD21), while control mothers received no BPA. The mothers were observed daily until GD21 for either a cesarean section or spontaneous delivery. The male offspring were sacrificed when reaching GD21 (fetus), postnatal days 7, 14, 21 (PND7, 14, 21) and adolescent age 35 (AD35) where their hippocampi were dissected from the brain. The expression of targeted miR-19a, miR-539, GRIN2A, and GRIN2B were determined by qRT-PCR while the level of GluN2A and GluN2B were estimated by western blot. At AD35, the rats were assessed with neurobehavioral tests to evaluate their learning and memory function. The findings showed that prenatal BPA exposure at 5 mg/kg/day significantly reduces the expression of miR-19a, miR-539, GRIN2A, and GRIN2B genes in the male rat hippocampus at all ages. The level of GluN2A and GluN2B proteins is also significantly reduced when reaching adolescent age. Consequently, the rats showed spatial and fear memory impairments when reaching AD35. In conclusion, prenatal BPA exposure disrupts the role of miR-19a and miR-539 in regulating the NMDA receptor subunit in the hippocampus which may be one of the causes of memory and learning impairment in adolescent rats., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Tramadol is a novel centrally acting analgesic. Despite, its implementation during pregnancy may impair neuronal survival and synaptic development in neonatal cerebella. The current investigation assessed the histological and ultrastructural alterations in postnatal cortical cerebellar neuronal development induced by prenatal tramadol. 30 offsprings were divided to control group I: fifteen pups born to mothers given saline from D10 till D21 of gestation. Tramadol-treated group II: fifteen pups born to mothers received tramadol HCL (50 mg/kg/day) from D10 till D21 of gestation. Pups were categorized into three subgroups (a, b, and c) and offered for sacrifice on the seventh, fourteenth and twenty-first post-natal days. Light microscopic examination revealed the overcrowding and signs of red degeneration affecting purkinje cell layer. Neurodegenerative signs of both purkinje and granule cell neurons were also confirmed by TEM in form of chromatin condensation, dilated Golgi channels, disrupted endoplasmic reticulum, marked infolding of the nuclear envelope and decrease in granule cell precursors. In addition, the astrocytic processes and terminal nerve axons appeared with different degrees of demyelination and decreased number of oligodendrocytes and degenerated mitochondria. Furthermore, group II exhibited an increase in P53 immune expression. The area percentage of apoptotic cells detected by TUNEL assay was significantly increased. Besides to the significant decrease of Ki67 immunoreactivity in the stem neuronal cell progenitors. Quantitative PCR results showed a significant decline in micro RNA7 gene expression in tramadol treated groups resulting in affection of multiple target genes in P53 signaling pathways, improper cortical size and defect in neuronal development., (© 2024. The Author(s).)

Introduction: Studies indicate that ∼7% of pregnant individuals in North America consume cannabis in pregnancy. Pre-clinical studies have established that maternal exposure to Δ 9 -tetrahydrocannabinol (THC; major psychoactive component in cannabis) leads to fetal growth restriction and impaired cardiac function in offspring. However, the effects of maternal exposure to cannabidiol (CBD; major non-euphoric constituent) on cardiac outcomes in offspring remain unknown. Therefore, our objective is to investigate the functional and underlying molecular impacts in the hearts of offspring exposed to CBD in pregnancy. Methods: Pregnant Wistar rats were exposed to either 3 or 30 mg/kg CBD or vehicle control i.p. daily from gestational day 6 to term. Echocardiography was used to assess cardiac function in male and female offspring at postnatal day (PND) 21. Furthermore, quantitative polymerase chain reaction (qPCR), immunoblotting, and bulk RNA-sequencing (RNA-seq) were performed on PND21 offspring hearts. Results: Despite no differences in the heart-to-body weight ratio, both doses of CBD led to reduced cardiac function exclusively in male offspring at 3 weeks of age. Underlying this, significant alterations in the expression of the endocannabinoid system (ECS; e.g., decreased cannabinoid receptor 2) were observed. In addition, bulk RNA-seq data demonstrated transcriptional pathways significantly enriched in mitochondrial function/metabolism as well as development. Conclusion: Collectively, we demonstrated for the first time that gestational exposure to CBD, a constituent perceived as safe, leads to early sex-specific postnatal cardiac deficits and alterations in the cardiac ECS in offspring.

Attention deficit hyperactivity disorder (ADHD), a prevalent neurodevelopmental disorder in children, originates from a multifaceted interplay of genetic, neurological, and environmental factors. Recent studies have increasingly concentrated on environmental determinants, notably air pollution, and their impact on the risk of developing ADHD. Additionally, previous research has often conflated clinically diagnosed ADHD cases with instances of mere ADHD-like symptoms, a methodology that can introduce bias and obscure the true relationship between environmental factors and ADHD. To address this oversight, our systematic review meticulously investigates the relationship between both prenatal and postnatal exposures to particular air pollutants and strictly clinically diagnosed ADHD. Our comprehensive review encompassed 801 studies from PubMed, Cochrane Library, Web of Science, and Embase databases, out of which eight met our rigorous inclusion criteria. The Newcastle-Ottawa Scale (NOS) was utilized to gauge quality and bias. Our review found substantiated the connection between prenatal exposure to PM 2.5 and NO x and a heightened risk of ADHD, while exposure to PM 10 during the prenatal stage was not associated with ADHD. These findings hint at varied health impacts from different particulate matters and the prospect of gender-specific susceptibilities to such exposures. We also identified an association between postnatal exposure to PM 2.5 , PM 10 , and NO 2 and an increased ADHD risk, underlining the potential neurodevelopmental harms from early exposure to these pollutants. These relationships, seemingly intricate and potentially dose-dependent, underscore the need for more detailed scrutiny. The unique value of our review is in its detailed exploration of the association between specific air pollution exposures and clinically diagnosed ADHD. Our findings offer much-needed clarity in this complex domain and emphasize the importance of future research to standardize exposure and outcome metrics, probe potential mechanisms, and reduce bias and heterogeneity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhao, He, Wang and Liu.)

Background: Studies on cognitive and neurodevelopmental outcomes have shown inconsistent results regarding the association with prenatal exposure to perfluoroalkyl substance (PFAS) and organochlorines. Assessment of mixture effects of correlated chemical exposures that persist in later life may contribute to the unbiased evaluation and understanding of dose-response associations in real-life exposures., Methods: For a subset of the 4th Flemish Environment and Health Study (FLEHS), concentrations of four PFAS and six organochlorines were measured in respectively 99 and 153-160 cord plasma samples and 15 years later in adolescents' peripheral serum by Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS). Sustained and selective attention were measured at 14-15 years with the Continuous Performance Test (CPT) and Stroop Test as indicators of potential neurodevelopmental deficits. Quantile g-computation was applied to assess the joint associations between prenatal exposure to separate and combined groups of PFAS and organochlorines and performance in the CPT and Stroop Test at adolescence. Subsequently, individual effects of each chemical compound were analyzed in mixed effects models with two sets of covariates. Analytical data at birth and at the time of cognitive assessment allowed for off-setting postnatal exposure., Results: In mixtures analysis, a simultaneous one-quantile increase in the natural log-transformed values of PFAS and organochlorines combined was associated with a decrease in the mean reaction time (RT) and the reaction time variability (RTV) in the CPT (β = -15.54, 95% CI:-29.64, -1.45, and β = -7.82, 95% CI: -14.97, -0.67 respectively) and for the mixture of PFAS alone with RT (β = -11.94, 95% CI: -23.29, -0.60). In the single pollutant models, these results were confirmed for the association between perfluorohexanesulfonate (PFHxS) with RT (β = -17.95, 95% CI = -33.35, -2.69) and hexachlorobenzene with RTV in the CPT (β = -5.78, 95% CI: -10.39, -0.76). Furthermore, the participants with prenatal exposure above the limit of quantification for perfluorononanoic acid (PFNA) had a significantly shorter RT and RTV in the CPT (β = -23.38, 95% CI: -41.55, -5.94, and β = -9.54, 95% CI: -19.75, -0.43, respectively)., Conclusion: Higher prenatal exposure to a PFAS mixture and a mixture of PFAS and organochlorines combined was associated with better sustained and selective attention during adolescence. The associations seemed to be driven by PFHxS and were not linked to exposure levels at the time of assessment., (Copyright © 2024. Published by Elsevier GmbH.)

Maternal prenatal distress can participate in the programming of offspring development, in which exposure to altered maternal long-term cortisol levels as measured by hair cortisol concentrations (HCC) may contribute. Yet, studies investigating whether and how maternal prenatal HCC associates with problems in child socioemotional development are scarce. Furthermore, questions remain regarding the timing and potential sex-specificity of fetal exposure to altered cortisol levels and whether there are interactions with maternal prenatal distress, such as depressive symptoms. The subjects were drawn from those FinnBrain Birth Cohort families that had maternal reports of child socioemotional problems (the Brief Infant-Toddler Social and Emotional Assessment [BITSEA] at 2 years and/or the Strengths and Difficulties Questionnaire [SDQ] at 5 years) as follows: HCC1 population: maternal mid-pregnancy HCC measured at gestational week 24 with 5 cm segments to depict cortisol levels from the previous five months (n = 321); and HCC2 population: end-of-pregnancy HCC measured 1-3 days after childbirth (5 cm segment; n = 121). Stepwise regression models were utilized in the main analyses and a sensitivity analysis was performed to detect potential biases. Negative associations were observed between maternal HCC2 and child BITSEA Total Problems at 2 years but not with SDQ Total difficulties at 5 years, and neither problem score was associated with HCC1. In descriptive analyses, HCC2 was negatively associated with Internalizing problems at 2 years and SDQ Emotional problems at 5 years. A negative association was observed among 5-year-old girls between maternal HCC1 and SDQ Total Difficulties and the subscales of Conduct and Hyperactivity/inattentive problems. When interactions were also considered, inverse associations between HCC2 and BITSEA Internalizing and Dysregulation Problems were observed in subjects with elevated prenatal depressive symptoms. It was somewhat surprising that only negative associations were observed between maternal HCC and child socioemotional problems. However, there are previous observations of elevated end-of-pregnancy cortisol levels associating with better developmental outcomes. The magnitudes of the observed associations were, as expected, mainly modest. Future studies with a focus on the individual changes of maternal cortisol levels throughout pregnancy as well as studies assessing both maternal and child HPA axis functioning together with child socioemotional development are indicated., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Air pollutants, such as fine particulate matter (PM 2.5 ), nitrogen dioxide (NO 2 ), and ozone (O 3 ), have been associated with adverse birth outcomes, including low birth weight, often exhibiting sex-specific effects. However, the modifying effect of placental telomere length (TL), reflecting cumulative lifetime oxidative stress in mothers, remains unexplored., Method: Using data from a Northeastern U.S. birth cohort (n = 306), we employed linear regression and weighted quantile sum models to assess trimester-average air pollution exposures and birth weight for gestational age (BWGA) z-scores. Placental TL, categorized by median split, was considered as an effect modifier. Interactions among air pollutants, placental TL, infant sex, and BWGA z-score were evaluated., Results: Without placental TL as a modifier, only 1 st trimester O 3 was significantly associated with BWGA z-scores (coefficient: 0.33, 95% CI: 0.03, 0.63). In models considering TL interactions, a significant modifying effect was observed between 3 rd trimester NO 2 and BWGA z-scores (interaction p-value = 0.02). Specifically, a one interquartile range (1-IQR) increase in 3 rd trimester NO 2 was linked to a 0.28 (95% CI: 0.06, 0.52) change in BWGA z-score among shorter placental TL group, with no significant association among longer TL group. Among male infants, there were significant associations between 3 rd trimester PM 2.5 exposure and BWGA z-scores in the longer TL group (coefficient: -0.34, 95% CI: -0.61, -0.02), and between 1 st trimester O 3 exposure and BWGA z-scores among males in the shorter TL group (coefficient: 0.59, 95% CI: 0.06, 1.08). For females, only a negative association in 2 nd trimester mixture model was observed within the longer TL group (coefficient: -0.10, 95% CI: -0.21, -0.01)., Conclusion: These findings highlight the need to consider the complex interactions among prenatal air pollutant exposures, placental TL, and fetal sex to better elucidate those at greatest risk for adverse birth outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Preclinical studies have found that chronic ∆9-tetrahydrocannabinol (THC) treatment is directly associated with weight gain when introduced during adolescence and adulthood, but the effect of prenatal THC is unclear. Clinical studies have demonstrated prenatal exposure to THC is a prospective predictor of increased health risks associated with obesity. Our study aims to examine prenatal THC impact on obesity risks in males and females throughout adolescence using a clinically relevant inhalation model., Methods: Pregnant rats were exposed to one of the following from gestational day 2 through birth: 10 mg THC, 40 mg THC, or air. Daily 10-min inhalations were conducted in each animal from 0900 to 1200. Offspring from each treatment group were given either a high-fat diet (HFD) or a normal diet (ND). Food and bodyweights were collected daily, while circadian activity, locomotion, and exercise were measured periodically (PND 21-60). Pregnancy weight gain and birth weight were collected to determine early-life developmental effects., Results: Rats prenatally treated with low-dose THC (LDTHC) generally had lower dark-cycle activity compared with control counterparts, but this altered activity was not observed at the higher dose of THC (HDTHC). In terms of open-field activity, THC doses displayed a general increase in locomotion. In addition, the LDTHC male rats in the ND showed significantly greater exploratory behavior. Prenatal THC had dose-dependent effects on maternal weight gain and birth weight., Conclusions: Overall, our findings indicate there are some activity-related and developmental effects of prenatal THC, which may be related to obesity risks later in life., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Purpose of Review: To consolidate information on the obesogenic and cardiometabolic effects of prenatal exposure to cannabis., Recent Findings: A PubMed search strategy updated from January 1, 2014, through 14 June 2023, produced a total of 47 epidemiologic studies and 12 animal studies. Prenatal exposure to cannabis is consistently associated with small for gestational age and low birth weight. After birth, these offspring gain weight rapidly and have increased adiposity and higher glucose (fat mass percentage) in childhood. More preclinical and prospective studies are needed to deepen our understanding of whether these associations vary by sex, dose, timing, and composition of cannabis (e.g., ratio of delta-Δ9-tetrahydrocannabinol [Δ9-THC] to cannabidiol [CBD]). Addressing these gaps may help to solidify causality and identify intervention strategies. Based on the available data, clinicians and public health officials should continue to caution against cannabis use during pregnancy to limit its potential obesogenic and adverse cardiometabolic effects on the offspring., (© 2023. The Author(s).)

Background: It is plausible that exposure to cannabis in-utero could be associated with an increased risk of neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD) symptoms and autism spectrum disorder (ASD) during childhood and adolescence; however, mixed results have been reported. This study investigated whether there is an association between prenatal cannabis use and ADHD symptoms and ASD in offspring using a systematic review and meta-analysis methodology., Methods: A systematic literature search was conducted in PubMed/Medline, Scopus, EMBASE, Web of Science, Psych-Info, and Google Scholar to identify relevant studies. The study protocol has been preregistered in the Prospective Register of Systematic Reviews (PROSPERO) (CRD42022345001), and the Newcastle-Ottawa Quality Assessment Scale (NOS) was used to assess the methodological quality of included studies. An inverse variance weighted random effect meta-analysis was conducted to pool the overall effect estimates from the included studies., Results: Fourteen primary studies, consisting of ten on ADHD and four on ASD, with a total of 203,783 participants, were included in this study. Our meta-analysis underscores an increased risk of ADHD symptoms and/or disorder [β = 0.39: 95 % CI (0.20-0.58), I 2  = 66.85 %, P = 0.001)] and ASD [RR = 1.30: 95 % CI (1.03-1.64), I 2  = 45.5 %, P = 0.14] associated with in-utero cannabis exposure in offspring compared to their non-exposed counterparts. Additionally, our stratified analysis highlighted an elevated risk of ADHD symptoms [β = 0.54: 95 % CI (0.26-0.82)] and a marginally significant increase in the risk of diagnostic ADHD among exposed offspring compared to non-exposed counterparts [RR = 1.13, 95 % CI (1.01, 1.26)]., Conclusion: This study indicated that maternal prenatal cannabis exposure is associated with a higher risk of ADHD symptoms and ASD in offspring., Competing Interests: Declaration of competing interest All authors have no conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: While prenatal exposure to alkylphenols (APs) has been demonstrated to be associated with neurodevelopmental impairments in animals, the evidence from epidemiological studies remains limited and inconclusive. This study aimed to explore the link between AP exposure during pregnancy and the intelligence quotient (IQ) of preschool children., Methods: A total of 221 mother-child pairs from the Guangxi Zhuang Birth Cohort were recruited. Nonylphenol (NP), 4-tert-octylphenol (4-T-OP), 4-n-nonylphenol (4-N-NP), and 4-n-octylphenol were measured in maternal serum in early pregnancy. Childhood IQ was evaluated by the Fourth Edition of Wechsler Preschool and Primary Scale of the Intelligence at 3 to 6 years of age. The impact of APs on childhood IQ were evaluated by generalized linear models (GLMs), restricted cubic spline (RCS), and Bayesian kernel machine regression (BKMR)., Results: In GLMs, prenatal exposure to NP and the second tertile of 4-T-OP exhibited an inverse association with full-scale IQ (FSIQ) (β = -2.38; 95% CI: -4.59, -0.16) and working memory index (WMI) (β = -5.24; 95% CI: -9.58, -0.89), respectively. Prenatal exposure to the third tertile of 4-N-NP showed a positive association with the fluid reasoning index (β = 4.95; 95% CI: 1.14, 8.77) in total children, as well as in girls when stratified by sex. A U-shaped relationship between maternal 4-T-OP and WMI was noted in total children and girls by RCS (all P nonlinear < 0.05). The combined effect primarily driven by NP, of maternal AP mixtures at concentrations above the 50th percentile exhibited an inverse trend on FSIQ in total children and girls in BKMR., Conclusions: Prenatal exposure to various APs affects IQ in preschool children, and there may be nonmonotonic and sex-specific effects. Further investigation across the population is required to elucidate the potential neurotoxic effects of APs., (© 2024. The Author(s).)

Background: Although previous studies have shown an association between prenatal exposure to perfluorinated and polyfluoroalkyl substances (PFAS) and neurodevelopmental disorders in children, the results have been inconsistent. We summarize studies on the association between prenatal PFAS exposure and neurodevelopment in children in order to better understand the relationship., Objective: We conducted a meta-analysis of prenatal PFAS exposure and developmental outcomes associated with intellectual, executive function and behavioral difficulty in children to explore the relationship between prenatal exposure to perfluorinated and polyfluoroalkyl substances (PFAS) and neurodevelopmental disorders in children., Methods: We searched for articles published up to August 3, 2023, included and quantified original studies on PFAS and child Intelligence Quotient (IQ), executive function and behavioral difficulty during pregnancy, and systematically summarized articles that could not be quantified., Conclusion: There is evidence of sex-specific relationship between PFAS exposure and children's PIQ. We found that PFOS [β = -1.56, 95% CI = -2.96, - 0.07; exposure = per 1 ln (ng/ml) increase], PFOA [β = -1.87, 95% CI = -3.29, - 0.46; exposure = per 1 ln (ng/ml) increase], PFHxS [β = -2.02, 95% CI = -3.23, - 0.81; exposure = per 1 ln (ng/ml) increase] decreased performance IQ in boys, but PFOS [β = 1.56, 95% CI = 0.06, 3.06; exposure = per 1 ln (ng/ml) increase] increased performance IQ in girls. PFAS are associated with executive function impairments in children, but not related to behavioral difficulty in children., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Early life exposure to organophosphate (OP) pesticides has been linked with poorer neurodevelopment from infancy to adolescence. In our Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort, we previously reported that residential proximity to OP use during pregnancy was associated with altered cortical activation using functional near infrared spectroscopy (fNIRS) in a small subset (n = 95) of participants at age 16 years., Methods: We administered fNIRS to 291 CHAMACOS young adults at the 18-year visit. Using covariate-adjusted regression models, we estimated associations of prenatal and childhood urinary dialkylphosphates (DAPs), non-specific OP metabolites, with cortical activation in the frontal, temporal, and parietal regions of the brain during tasks of executive function and semantic language., Results: There were some suggestive associations for prenatal DAPs with altered activation patterns in both the inferior frontal and inferior parietal lobes of the left hemisphere during a task of cognitive flexibility (β per ten-fold increase in DAPs = 3.37; 95% CI: -0.02, 6.77 and β = 3.43; 95% CI: 0.64, 6.22, respectively) and the inferior and superior frontal pole/dorsolateral prefrontal cortex of the right hemisphere during the letter retrieval working memory task (β = -3.10; 95% CI: -6.43, 0.22 and β = -3.67; 95% CI: -7.94, 0.59, respectively). We did not observe alterations in cortical activation with prenatal DAPs during a semantic language task or with childhood DAPs during any task., Discussion: We observed associations of prenatal OP concentrations with mild alterations in cortical activation during tasks of executive function. Associations with childhood exposure were null. This is reasonably consistent with studies of prenatal OPs and neuropsychological measures of attention and executive function found in CHAMACOS and other birth cohorts., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Asa Bradman reports a relationship with The Organic Center that includes: board membership., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Lead (Pb) has become a major environmental contaminant. There are several ways in which lead can enter the human body and cause toxic effects on human health. This review focuses on the impact of lead toxicity at prenatal and early life stages and its effect on neurodevelopment. Lead exposure to the developing foetus targets foetal neural stem cells. Hence, it has detrimental effects on developing neural and glial cells, adversely influencing cognition and behaviour. Lead has a profound influence on the movement of calcium ions (Ca 2+ ), which can be attributed to most of the mechanisms by which lead affects neurodevelopment. There is no known safe threshold of lead exposure for children. Lead can affect foetal neurodevelopment leading to various neurological disorders, and neurotoxic effects on behavioural and cognitive outcomes. In this review, we discuss prenatal and early-life lead exposure, its mechanism, and consequences for neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease in later stages of life. This review further highlights the importance of lead exposure during pregnancy and lactation periods as well as early development of the child in understanding the extent of lead-induced neurological damage to the foetus/children and the associated future risks., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Acute leukemia is the most common pediatric cancer, with an incidence peak at 2-5 years of age. Despite the medical advances improving survival rates, children suffer from significant side effects of treatments as well as its high social and economic impact. The frequent prenatal origin of this developmental disease follows the two-hit carcinogenesis model established in the 70s: a first hit in prenatal life with the creation of genetic fusion lesions or aneuploidy in hematopoietic progenitor/stem cells, and usually a second hit in the pediatric age that converts the preleukemic clone into clinical leukemia. Previous research has mostly focused on postnatal environmental factors triggering the second hit., Summary: There is scarce evidence on prenatal risk factors associated with the first hit. Mainly retrospective case-control studies suggested several environmental and lifestyle determinants as risk factors. If these associations could be confirmed, interventions focused on modifying prenatal factors might influence the subsequent risk of leukemia during childhood and reveal unexplored research avenues for the future. In this review, we aim to comprehensively summarize the currently available evidence on prenatal risk factors for the development of childhood leukemia. According to the findings of this review, parental age, ethnicity, maternal diet, folate intake, alcohol consumption, X-ray exposure, pesticides, perinatal infections, and fetal growth may have a significant role in the appearance of preleukemic lesions during fetal life. Other factors such as socioeconomic status, consumption of caffeinated beverages, and smoking consumption have been suggested with inconclusive evidence. Additionally, investigating the association between prenatal factors and genetic lesions associated with childhood leukemia at birth is crucial. Prospective studies evaluating the link between lifestyle factors and genetic alterations could provide indirect evidence supporting new research avenues for leukemia prevention. Maternal diet and lifestyle factors are modifiable determinants associated with adverse perinatal outcomes that could be also related to preleukemic lesions., Key Messages: Parental age, ethnicity, maternal diet, folate intake, alcohol consumption, X-ray exposure, pesticides, perinatal infections, and fetal growth may have a significant role in the appearance of preleukemic lesions during fetal life. Dedicating efforts to studying maternal lifestyle during pregnancy and its association with genetic lesions leading to childhood leukemia could lead to novel prevention strategies., (© 2024 S. Karger AG, Basel.)

Acetaminophen is currently the only analgesic considered safe for use throughout pregnancy, but recent studies indicate that prenatal exposure to acetaminophen may be related to poorer neurodevelopmental outcomes. Multiple studies have suggested that it may be associated with attention problems, but few have examined this association by trimester of exposure. The Illinois Kids Development Study is a prospective birth cohort located in east-central Illinois. Exposure data were collected between December 2013 and March 2020, and 535 newborns were enrolled during that period. Mothers reported the number of times they took acetaminophen at six time points across pregnancy. When children were 2, 3, and 4 years of age, caregivers completed the Child Behavior Checklist for ages 1.5-5 years (CBCL). Associations of acetaminophen use during pregnancy with scores on the Attention Problems and ADHD Problems syndrome scales, the Internalizing and Externalizing Behavior composite scales, and the Total Problems score were evaluated. Higher acetaminophen exposure during the second trimester of fetal development was associated with higher Attention Problems, ADHD Problems, Externalizing Behavior, and Total Problems scores at ages 2 and 3. Higher second trimester exposure was only associated with higher Externalizing Behavior and Total Problems scores at 4 years. Higher cumulative exposure across pregnancy was associated with higher Attention Problems and ADHD Problems scores at ages 2 and 3. Findings suggest that prenatal acetaminophen exposure, especially during the second trimester, may be related to problems with attention in early childhood., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Senior author serves on Neurotoxicology and Teratology Editorial Advisory Board - S.L.S., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Because of the legalization of Cannabis in many jurisdictions and the trend of increasing Δ 9 -tetrahydrocannabinol (THC) content in Cannabis products, an urgent need exists to understand the impact of Cannabis use during pregnancy on fetal neurodevelopment and behavior. To this end, we exposed female Sprague Dawley rats to Cannabis smoke daily from gestational day 6 to 20 or room air. Maternal reproductive parameters, offspring behavior, and gene expression in the offspring amygdala were assessed. Body temperature was decreased in dams following smoke exposure and more fecal boli were observed in the chambers before and after smoke exposure in dams exposed to smoke. Maternal weight gain, food intake, gestational length, litter number, and litter weight were not altered by exposure to Cannabis smoke. A significant increase in the male-to-female ratio was noted in the Cannabis -exposed litters. In adulthood, male and female Cannabis smoke-exposed offspring explored the inner zone of an open field significantly less than control offspring. Gestational Cannabis smoke exposure did not affect behavior on the elevated plus maze test or social interaction test in the offspring. Cannabis offspring were better at visual pairwise discrimination and reversal learning tasks conducted in touchscreen-equipped operant conditioning chambers. Analysis of gene expression in the adult amygdala using RNA sequencing revealed subtle changes in genes related to development, cellular function, and nervous system disease in a subset of the male offspring. These results demonstrate that repeated exposure to high-THC Cannabis smoke during gestation alters maternal physiological parameters, sex ratio, and anxiety-like behaviors in the adulthood offspring., Competing Interests: R.B.L. is a member of the Scientific Advisory Board for Shackleford Pharma, which had no input into this research study. The authors declare no other competing financial interests., (Copyright © 2023 Sandini et al.)

Background: Early life exposure to lead, mercury, polychlorinated biphenyls (PCBs), polybromide diphenyl ethers (PBDEs), organophosphate pesticides (OPPs), and phthalates have been associated with lowered IQ in children. In some studies, these neurotoxicants impact males and females differently. We aimed to examine the sex-specific effects of exposure to developmental neurotoxicants on intelligence (IQ) in a systematic review and meta-analysis., Method: We screened abstracts published in PsychINFO and PubMed before December 31st, 2021, for empirical studies of six neurotoxicants (lead, mercury, PCBs, PBDEs, OPPs, and phthalates) that (1) used an individualized biomarker; (2) measured exposure during the prenatal period or before age six; and (3) provided effect estimates on general, nonverbal, and/or verbal IQ by sex. We assessed each study for risk of bias and evaluated the certainty of the evidence using Navigation Guide. We performed separate random effect meta-analyses by sex and timing of exposure with subgroup analyses by neurotoxicant., Results: Fifty-one studies were included in the systematic review and 20 in the meta-analysis. Prenatal exposure to developmental neurotoxicants was associated with decreased general and nonverbal IQ in males, especially for lead. No significant effects were found for verbal IQ, or postnatal lead exposure and general IQ. Due to the limited number of studies, we were unable to analyze postnatal effects of any of the other neurotoxicants., Conclusion: During fetal development, males may be more vulnerable than females to general and nonverbal intellectual deficits from neurotoxic exposures, especially from lead. More research is needed to examine the nuanced sex-specific effects found for postnatal exposure to toxic chemicals., (© 2023. The Author(s).)

Summary: Background. The human microbiome is important due to the impact it has on host immunologic development and allergy-associated diseases. This study aimed to investigate the impact of prenatal exposure to antibiotics on the incidence of atopic dermatitis (AD) in children at 18 months of age. Methods. Mothers were interviewed at baseline, in the maternity ward and by phone questionnaire after 18 months. Demographic data, mode of delivery, yoghurt consumption, antibiotic and other drug use during pregnancy, atopic history, diagnosis of AD and history of infections in the offspring were noted. Results. 385 mothers were interviewed at baseline. 231 (60%) mothers with 236 children responded at follow up. Cesarean section was reported in 116 (50.2%) deliveries while antibiotic use during pregnancy in 55/231 (23.8%) women. 43/236 (18.22%) infants were diagnosed with AD. Intravenous antibiotic use was associated with a 7.7 increased risk of AD diagnosis in the offspring (95%CI 1.23-48.27, p = 0.029). An increased odd for AD was recorded for mothers 30-40 years of age (OR 4.50, 95%CI 1.08-18.7, p = 0.039). No significant association between cesarean section and AD (p = 0.70) was recorded. In multivariate analysis, reported food allergy (OR 8.03, 95%CI 2.30-27.97, p = 0.001) and otitis media episodes in children (OR 3.76, 95%CI 1.60-8.83, p = 0.002) were significantly associated with AD diagnosis. Conclusions. An increased risk of AD was recorded only when antibiotics were given prenatally by intravenous route and in women between 30-40 years of age. Children with food allergy had an increased risk for AD. The relatively high percentage of cesarean sections was not a risk factor for AD.

Maternal-to-fetal transmission of respiratory syncytial virus (RSV) has been shown to occur but whether late prenatal exposure to RSV season influences offspring postnatal RSV-lower respiratory illness (LRI) risk in early life or RSV immune status at birth is unclear. In this study, the duration of third trimester RSV season exposure was determined for 1,094 newborns of the Tucson Children's Respiratory Study (TCRS) and found to show an inverse relation to risk for first RSV-LRI in the first year. Cord blood anti-RSV antibody is related to third trimester RSV season exposure but not to first year RSV-LRI risk. In a separate birth cohort (the Infant Immune Study), supernatants from cord blood mononuclear cells stimulated with the recall antigen, UV-inactivated RSV, were assayed for IFN-γ and IL-4. The frequency of detectable IFN-γ (but not IL-4) was increased for those with at least 2 mo of third trimester RSV season exposure, suggestive of a fetal immune response to RSV. IMPORTANCE Our study found that duration of third trimester exposure to RSV season related inversely to subsequent risk of postnatal RSV-LRI in the first year, thus implicating this exposure as an important factor in reducing risk of postnatal RSV-LRIs, a risk reduction that appears to be independent of maternally transferred anti-RSV antibody level. The increase in frequency of detectable IFN-γ and not IL-4 in response to UV-inactivated RSV in cord blood immune cells for infants with greater third trimester exposure to RSV season is suggestive of a Type-1 immune response to RSV occurring in utero ., Competing Interests: F.D. Martinez reports grants from the National Institutes of Health (NIH)/National Heart, Lung and Blood Institute (HL139054, HL132523, HL130045, HL147016), NIH/National Institute of Allergy and Infectious Diseases (AI135108, AI146131, AI148104), NIH/Office of Director (OD023282) and OM Pharma (UANLID46205). M. Halonen reports grants from the NIH during the conduct of the study. A.L. Wright reports grants from the NIH during the conduct of the study. T.F. Carr reports grants from the NIH, consulting fees from AstraZeneca and Novartis, honoraria from GSK and Regeneron, and editorial fees from Wolters Kluwer Health during the conduct of this study, unrelated to this work. D.A. Stern and A. Spangenberg report salaries paid by NIH grants noted earlier during the conduct of the study. Raffaella Nenna reports no conflict of interest.

Purpose of Review: Recently, several epidemiological studies have investigated whether prenatal exposure to nitrate from drinking water may be harmful to the fetus, even at nitrate levels below the current World Health Organization drinking water standard. The purpose of this review was to give an overview of the newest knowledge on potential health effects of prenatal exposure to nitrate., Recent Findings: We included 13 epidemiological studies conducted since 2017. Nine studies investigated outcomes appearing around birth, and four studies investigated health outcomes appearing in childhood and young adulthood. The reviewed studies showed some indications of higher risk of preterm delivery, lower birth weight, birth defects, and childhood cancer related to prenatal exposure to nitrate. However, the numbers of studies for each outcome were sparse, and some of the results were conflicting. We suggest that there is a need for additional studies and particularly for studies that include information on water consumption patterns, intake of nitrate from diet, and intake of nitrosatable drugs., (© 2023. The Author(s).)

Background: N-nitroso compounds (NOCs) can be formed by endogenous reactions between nitrosatable drugs and nitrite. Animal studies have found that several NOCs are teratogenic, and epidemiological studies report associations between prenatal exposure to nitrosatable drugs and adverse birth outcomes. It is unknown whether prenatal exposure to nitrosatable drugs is harmful to the child's reproductive health, including pubertal development., Objectives: We investigated whether prenatal exposure to nitrosatable drugs was associated with timing of puberty and whether nitrate, nitrite and antioxidant intake modified any association., Methods: The population-based Danish National Birth Cohort (DNBC) Puberty Cohort, which includes 15,819 children, was used to investigate the association between prenatal exposure to nitrosatable drugs and timing of puberty. Around gestational week 11 and gestational week 18, mothers provided information about drug use during pregnancy. The children's self-reported information on onset of pubertal milestones was collected every six months from 11 years of age and throughout puberty. To investigate potential effect modification by nitrite, nitrate and antioxidant intake, information on these factors was obtained from a food frequency questionnaire completed by the mothers in gestational week 25, and information on nitrate concentration in maternal drinking water at her residential address was obtained from monitoring data from public waterworks. Data were analysed using a multivariable regression model for interval-censored data estimating difference in months in timing of puberty between exposure groups., Results: A total of 2,715 children were prenatally exposed to nitrosatable drugs. We did not find an association between prenatal exposure to nitrosatable drugs and timing of puberty. This finding was supported by null-findings in the following sub-analyses investigating: 1. subtypes of nitrosatable drugs (secondary and tertiary amines and amides), 2. dose-dependency (duration of drug intake), 3. effect modification by maternal intake of nitrate, nitrite, and antioxidants. 4. confounding by indication., Conclusions: Prenatal exposure to nitrosatable drugs was not associated with timing of puberty. Nitrosatable drugs are commonly used drugs in pregnancy, and further research is needed to allow firm conclusions on the potential effect of prenatal exposure to nitrosatable drugs on the child's reproductive health., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Phthalates, a group of pervasive endocrine-disrupting chemicals found in plastics and personal care products, have been associated with a wide range of developmental and health outcomes. However, their impact on biomarkers of aging has not been characterized. We tested associations between prenatal exposure to 11 phthalate metabolites on epigenetic aging in children at birth, 7, 9, and 14 years of age. We hypothesized that prenatal phthalate exposure will be associated with epigenetic age acceleration measures at birth and in early childhood, with patterns dependent on sex and timing of DNAm measurement., Methods: Among 385 mother-child pairs from the CHAMACOS cohort, we measured DNAm at birth, 7, 9, and 14 years of age, and utilized adjusted linear regression to assess the association between prenatal phthalate exposure and Bohlin's Gestational Age Acceleration (GAA) at birth and Intrinsic Epigenetic Age Acceleration (IEAA) throughout childhood. Additionally, quantile g-computation was utilized to assess the effect of the phthalate mixture on GAA at birth and IEAA throughout childhood., Results: We found a negative association between prenatal di (2-ethylhexyl) phthalate (DEHP) exposure and IEAA among males at age 7 (-0.62 years; 95% CI:-1.06 to -0.18), and a marginal negative association between the whole phthalate mixture and GAA among males at birth (-1.54 days, 95% CI: -2.79 to -0.28), while most other associations were nonsignificant., Conclusions: Our results suggest that prenatal exposure to certain phthalates is associated with epigenetic aging in children. Additionally, our findings suggest that the influence of prenatal exposures on epigenetic age may only manifest during specific periods of child development, and studies relying on DNAm measurements solely from cord blood or single time points may overlook potential relationships., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Epidemiological evidence for gestational polycyclic aromatic hydrocarbon (PAH) exposure and adverse child cognitive outcomes is mixed; little is known about critical windows of exposure., Objective: We investigated associations between prenatal PAH exposure and child cognition in a large, multi-site study., Methods: We included mother-child dyads from two pooled prospective pregnancy cohorts (CANDLE and TIDES, N = 1,223) in the ECHO-PATHWAYS Consortium. Seven urinary mono-hydroxylated PAH metabolites were measured in mid-pregnancy in both cohorts as well as early and late pregnancy in TIDES. Child intelligence quotient (IQ) was assessed between ages 4-6. Associations between individual PAH metabolites and IQ were estimated with multivariable linear regression. Interaction terms were used to examine effect modification by child sex and maternal obesity. We explored associations of PAH metabolite mixtures with IQ using weighted quantile sum regression. In TIDES, we averaged PAH metabolites over three periods of pregnancy and by pregnancy period to investigate associations between PAH metabolites and IQ., Results: In the combined sample, PAH metabolites were not associated with IQ after full adjustment, nor did we observe associations with PAH mixtures. Tests of effect modification were null except for the association between 2-hydroxynaphthalene and IQ, which was negative in males (β males  = -0.67 [95%CI:-1.47,0.13]) and positive in females (β females  = 0.31 [95%CI:-0.52,1.13])(p interaction  = 0.04). In analyses across pregnancy (TIDES-only), inverse associations with IQ were observed for 2-hydroxyphenanthrene averaged across pregnancy (β = -1.28 [95%CI:-2.53,-0.03]) and in early pregnancy (β = -1.14 [95%CI:-2.00,-0.28])., Significance: In this multi-cohort analysis, we observed limited evidence of adverse associations of early pregnancy PAHs with child IQ. Analyses in the pooled cohorts were null. However, results also indicated that utilizing more than one exposure measures across pregnancy could improve the ability to detect associations by identifying sensitive windows and improving the reliability of exposure measurement. More research with multiple timepoints of PAH assessment is warranted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Studies show associations between prenatal maternal stress (PNMS) and child autism, with little attention paid to PNMS and autism in young adulthood. The broad autism phenotype (BAP), encompassing sub-clinical levels of autism, includes aloof personality, pragmatic language impairment and rigid personality. It remains unclear whether different aspects of PNMS explain variance in different BAP domains in young adult offspring. We recruited women who were pregnant during, or within 3 months of, the 1998 Quebec ice storm crisis, and assessed three aspects of their stress (i.e., objective hardship, subjective distress and cognitive appraisal). At age 19, the young adult offspring ( n = 33, 22F / 11M) completed a BAP self-report. Linear and logistic regressions were implemented to examine associations between PNMS and BAP traits. Up to 21.4% of the variance in BAP total score and in BAP three domains tended to be explained by at least one aspect of maternal stress, For example, 16.8% of the variance in aloof personality tended to be explained by maternal objective hardship; 15.1% of the variance in pragmatic language impairment tended to be explained by maternal subjective distress; 20.0% of the variance in rigid personality tended to be explained by maternal objective hardship and 14.3% by maternal cognitive appraisal. Given the small sample size, the results should be interpreted with caution. In conclusion, this small prospective study suggests that different aspects of maternal stress could have differential effects on different components of BAP traits in young adults.

Background: Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) may adversely affect fetal brain development, yet no study has investigated the potential association between prenatal PFAS exposure and infant sleep., Objectives: To explore the associations of prenatal PFAS exposure with infant sleep disturbances during the first year of life in a prospective cohort study., Methods: We recruited 4127 pregnant women from the Shanghai Birth Cohort (SBC) and followed their children from birth to 12 months old. A total of 2366 infants were included in the 6-month analyses, and 2466 infants in the 12-month analyses. Ten PFAS were quantified in blood serum collected in the first trimester. Sleep quality was measured using the Brief Infant Sleep Questionnaire. We used multiple linear regression and multinomial logistic regression to estimate the individual effects of PFAS on sleep outcomes. We utilized a quantile-based g-computation model to determine the joint effects of the PFAS mixture on infant sleep outcomes. Additionally, generalized estimating equation (GEE) models were performed to examine the longitudinal effects of PFAS exposure during pregnancy., Results: In infants aged 6 months, perfluorooctane sulfonate and perfluoroheptanoic acid were associated with a more than 2-fold risk of parent-reported sleep problems as severe. Perfluorodecanoic acid was associated with an increased risk of often or almost always snoring in one-year-old infants (relative risk ratios, 1.79; 95% CI, 1.12-2.86). PFAS mixtures were positively associated with nighttime awakenings both among infants aged 6 months (β, 0.11; 95% CI, 0.04-0.19) and 12 months (β, 0.11; 95% CI, 0.05-0.18). Prenatal exposure to PFAS were associated with longer sleep latency, increased nighttime awakenings, longer nocturnal wakefulness hours, snoring, and earlier sleep-onset time in infants aged 6-12 months, according to GEE models., Conclusions: Our study suggests that prenatal exposure to PFAS may increase the risk of sleep disturbance in infants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Fetal alcohol syndrome (FAS) is a lifelong developmental disability that occurs among individuals with prenatal alcohol exposure (PAE). With improved prediction models, FAS can be diagnosed or treated early, if not completely prevented., Objective: In this study, we sought to compare different machine learning algorithms and their FAS predictive performance among women who consumed alcohol during pregnancy. We also aimed to identify which variables (eg, timing of exposure to alcohol during pregnancy and type of alcohol consumed) were most influential in generating an accurate model., Methods: Data from the collaborative initiative on fetal alcohol spectrum disorders from 2007 to 2017 were used to gather information about 595 women who consumed alcohol during pregnancy at 5 hospital sites around the United States. To obtain information about PAE, questionnaires or in-person interviews, as well as reviews of medical, legal, or social service records were used to gather information about alcohol consumption. Four different machine learning algorithms (logistic regression, XGBoost, light gradient-boosting machine, and CatBoost) were trained to predict the prevalence of FAS at birth, and model performance was measured by analyzing the area under the receiver operating characteristics curve (AUROC). Of the total cases, 80% were randomly selected for training, while 20% remained as test data sets for predicting FAS. Feature importance was also analyzed using Shapley values for the best-performing algorithm., Results: Overall, there were 20 cases of FAS within a total population of 595 individuals with PAE. Most of the drinking occurred in the first trimester only (n=491) or throughout all 3 trimesters (n=95); however, there were also reports of drinking in the first and second trimesters only (n=8), and 1 case of drinking in the third trimester only (n=1). The CatBoost method delivered the best performance in terms of AUROC (0.92) and area under the precision-recall curve (AUPRC 0.51), followed by the logistic regression method (AUROC 0.90; AUPRC 0.59), the light gradient-boosting machine (AUROC 0.89; AUPRC 0.52), and XGBoost (AUROC 0.86; AURPC 0.45). Shapley values in the CatBoost model revealed that 12 variables were considered important in FAS prediction, with drinking throughout all 3 trimesters of pregnancy, maternal age, race, and type of alcoholic beverage consumed (eg, beer, wine, or liquor) scoring highly in overall feature importance. For most predictive measures, the best performance was obtained by the CatBoost algorithm, with an AUROC of 0.92, precision of 0.50, specificity of 0.29, F1 score of 0.29, and accuracy of 0.96., Conclusions: Machine learning algorithms were able to identify FAS risk with a prediction performance higher than that of previous models among pregnant drinkers. For small training sets, which are common with FAS, boosting mechanisms like CatBoost may help alleviate certain problems associated with data imbalances and difficulties in optimization or generalization., (©Sarah Soyeon Oh, Irene Kuang, Hyewon Jeong, Jin-Yeop Song, Boyu Ren, Jong Youn Moon, Eun-Cheol Park, Ichiro Kawachi. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 18.07.2023.)

Background: Prenatal exposure to air pollution increases the risk for psychiatric disorders characterized by internalizing problems. In this study, we examined the roles of shyness and anterior cingulate cortex (ACC) activity in the association between prenatal exposure to polycyclic aromatic hydrocarbons (PAH) and children's internalizing problems at 7-9 years old., Methods: Participants include 53 children (31 girls, 22 boys). Personal air monitoring was conducted over 48 continuous hours during the third trimester of pregnancy to measure 8 PAHs. Mothers reported children's shyness (Emotionality Activity Sociability Temperament Survey) at age 5 and internalizing problems (Child Behavior Checklist) at ages 7-9. ACC activity was measured by fMRI during the Simon Spatial Incompatibility task at ages 7-9., Results: Shyness mediated the association between prenatal PAH exposure and internalizing problems. Higher prenatal PAH exposure predicted increased shyness, which in turn predicted greater internalizing problems. Moreover, left ACC activity during the Simon task moderated the association between prenatal PAH exposure and internalizing problems. Prenatal PAH exposure predicted increased risk for internalizing problems only when children showed heightened left ACC activity during the resolution of cognitive conflict., Conclusions: Our study innovatively synthesizes the fields of developmental psychology and environmental health science to offer new insights into the risk factors for anxiety disorders. Facilitating the development of healthy reactive and regulatory processes may improve the developmental outcomes for children highly exposed to air pollution., (© 2023 Association for Child and Adolescent Mental Health.)

We explored the association between maternal urinary polycyclic aromatic hydrocarbon (PAH) metabolites and thyroid hormones in umbilical cord blood in 120 pairs of pregnant women and newborns. Maternal urinary PAH metabolites were measured using high-performance liquid chromatography with tandem mass spectrometry. Thyroid hormones were measured using a flow fluorescence assay. The dose-response relationship between PAH metabolites and thyroid hormones was analyzed using the generalized linear model and restricted cubic spline model. Results showed that ƩOH PAHs in maternal urine had a negative effect on triiodothyronine (T3). Associations between maternal urinary PAH metabolites and thyroid hormones in umbilical cord blood plasma were observed. Prenatal exposure to PAHs could affect neonatal thyroid hormones, thereby disrupting neonatal thyroid function., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Exposure to perfluoroalkyl substances (PFAS) has been shown to be neurotoxic in experimental studies, but epidemiological evidence linking prenatal PFAS exposure to child neurodevelopment is equivocal and scarce., Objective: To quantify associations between prenatal exposure to legacy PFAS and children's intelligence (IQ) and executive functioning (EF) in a Canadian pregnancy and birth cohort and to determine if these associations differ by child sex., Methods: We measured first-trimester plasma concentrations of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS) in the Maternal-Infant Research on Environmental Chemicals (MIREC) study and assessed children's full-scale (n = 522), performance (n = 517), and verbal (n = 519) IQ using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III). Children's working memory (n = 513) and ability to plan and organize (n = 514) were assessed using a parent-reported questionnaire, the Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P). We quantified associations between individual log2-transformed PFAS exposure and children's IQ and EF using multiple linear regression analyses and evaluated effect modification by child sex. We also used Repeated Holdout Weighted Quantile Sum (WQS) regression models with effect modification by child sex to quantify the effect of combined exposure to all three PFAS chemicals on IQ and EF. All models were adjusted for key sociodemographic characteristics., Results: Geometric mean plasma concentrations (IQR) for PFOA, PFOS and PFHxS were 1.68 (1.10-2.50), 4.97 (3.20-6.20) and 1.09 (0.67-1.60) μg/L respectively. We found evidence of effect modification by child sex in all models examining performance IQ (p < .01). Specifically, every doubling of PFOA, PFOS, and or PFHxS was inversely associated with performance IQ, but only in males (PFOA: B = -2.80, 95% CI: -4.92, -0.68; PFOS: B = -2.64, 95% CI: -4.77, -0.52; PFHxS: B = -2.92, 95% CI: -4.72, -1.12). Similarly, every quartile increase in the WQS index was associated with poorer performance IQ in males (B = -3.16, 95% CI: -4.90, -1.43), with PFHxS contributing the largest weight to the index. In contrast, no significant association was found for females (B = 0.63, 95% CI: -0.99, 2.26). No significant associations were found for EF in either males or females., Conclusions: Higher prenatal PFAS exposure was associated with lower performance IQ in males, suggesting that this association may be sex- and domain-specific., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the impact of prenatal and early childhood antimicrobial use on autism spectrum disorders (ASD)., Data Sources: We searched PubMed and Embase databases for relevant studies from inception to August 2022., Study Selection and Data Extraction: Peer-reviewed, observational studies were all acceptable. Raw data were extracted into a predefined worksheet and quality analysis was performed using the Newcastle-Ottawa Scale., Data Synthesis: Nineteen studies were identified in the meta-analysis. Prenatal antimicrobial exposure was not associated with ASD ( P = 0.06 > 0.05), whereas early childhood antimicrobial exposure was associated with an increased odds ratio of ASD (OR = 1.17, 95% CI = [1.08-1.27], P value < 0.001). The sibling-matched analysis, with a very limited sample size, suggested that neither prenatal ( P = 0.47 > 0.05) nor early childhood ( P = 0.13 > 0.05) antimicrobial exposure was associated with ASD. Medical professionals may need to take the possible association into consideration when prescribing an antimicrobial in children., Conclusions: Early childhood antimicrobial exposure could increase the incidence of ASD. In future studies, it would be necessary to control for confounding factors, such as genetic factors, parenteral age at birth, or low birthweight, to further validate the association.

There are limited studies on the associations between prenatal exposure to constituents of fine particulate matter (PM 2.5 ) and children's intelligence quotient (IQ). Our study aimed to explore the associations between prenatal PM 2.5 and its six constituents and the IQ levels of 6-year-old children. We included 512 mother-child pairs. We used a satellite-based modelling framework to estimate prenatal PM 2.5 and its six constituents (ammonium, sulfate, nitrate, organic carbon, soil dust, and black carbon). We assessed the children's IQ using the short form of the Wechsler Intelligence Scale. Perceptual Reasoning Index (PRI), Verbal Comprehension Index (VCI), and Full Scale IQ (FSIQ) scores were computed. The multiple informant model (MIM) was applied to explore the trimester specific effects of PM 2.5 and its six constituents' exposure on children's PRI, VCI, and FSIQ. To examine whether the duration of breastfeeding and physical activity (PA) could modify the effects of PM 2.5 on children's IQ, we stratified the analyses according to the duration of breastfeeding (≤6 and >6 months) and time of outdoor activities after school (≤2 and >2 h/week). The first trimester PM 2.5 and its five constituents' exposures were inversely associated with FSIQ [β = -1.34, 95 % confidence interval [CI] (-2.71, 0.04) for PM 2.5 ] and PRI [β = -2.18, 95 %CI (-3.80, -0.57) for PM 2.5 ] in children. The associations were magnified among boys and those with less outdoor activities or shorter breastfeeding duration. Our results indicate that prenatal PM 2.5 and several of its main constituents' exposure may disrupt cognitive development in children aged 6 years. More PA and longer breastfeeding duration may alleviate the detrimental effects of prenatal PM 2.5 exposure on children's cognitive function., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Up to 9.5% of the world's population is diagnosed with attention deficit/hyperactivity disorder (ADHD), making it one of the most common childhood disorders. Air pollutants could be considered an environmental risk condition for ADHD, but few studies have specifically investigated the effect of prenatal exposure. The current paper reviews the studies conducted on the association between prenatal air pollutants (PM, NO x , SO 2 , O 3 , CO and PAH) and ADHD development in children. From the 890 studies searched through PubMed, Google Scholar, Scopus, and Web of Science, 15 cohort studies met the inclusion criteria. NOS and WHO guidelines were used for quality and risk of bias assessment. The accumulative sample was 589,400 of children aged 3-15 years. Most studies reported an association between ADHD symptoms and prenatal PAH and PM exposure. Data available on NO 2 and SO 2 were inconsistent, whereas the effect of CO/O 3 is barely investigated. We observed heterogeneity through an odd ratio forest plot, and discrepancies in methodologies across the studies. Eight of the fifteen studies were judged to be of moderate risk of bias in the outcome measurement. In a nutshell, future studies should aim to minimize heterogeneity and reduce bias by ensuring a more representative sample, standardizing exposure and outcome assessments.

Opioid use during pregnancy impacts the health and well-being of two generations: the pregnant person and the child. The factors that increase risk for opioid use in the adult, as well as those that perpetuate risk for the caregiver and child, oftentimes replicate across generations and may be more likely to affect child neurodevelopment than the opioid exposure itself. In this article, we review the prenatal opioid exposure literature with the perspective that this is not a singular event but an intergenerational cascade of events. We highlight several mechanisms of transmission across generations: biological factors, including genetics and epigenetics and the gut-brain axis; parent-child mechanisms, such as prepregnancy experience of child maltreatment, quality of parenting, infant behaviors, neonatal opioid withdrawal diagnosis, and broader environmental contributors including poverty, violence exposure, stigma, and Child Protective Services involvement. We conclude by describing ways in which intergenerational transmission can be disrupted by early intervention., (© 2023 Association for Child and Adolescent Mental Health.)

Prenatal antidepressant exposure has been associated with increased risk for neurodevelopmental disorders in childhood, including autism spectrum disorder (ASD). The current study utilized multi-cohort data from the Environmental influences on Child Health Outcomes (ECHO) program (N = 3129) to test for this association, and determine whether the association remained after adjusting for maternal prenatal depression and other potential confounders. Antidepressants and a subset of selective serotonin reuptake inhibitors (SSRIs) were examined in relation to binary (e.g., diagnostic) and continuous measures of ASD and ASD related traits (e.g., social difficulties, behavior problems) in children 1.5 to 12 years of age. Child sex was tested as an effect modifier. While prenatal antidepressant exposure was associated with ASD related traits in univariate analyses, these associations were statistically non-significant in models that adjusted for prenatal maternal depression and other maternal and child characteristics. Sex assigned at birth was not an effect modifier for the prenatal antidepressant and child ASD relationship. Overall, we found no association between prenatal antidepressant exposures and ASD diagnoses or traits. Discontinuation of antidepressants in pregnancy does not appear to be warranted on the basis of increased risk for offspring ASD., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Prenatal exposure to famine has been linked to increased diabetes risk in adulthood. However, one fundamental issue to be addressed is that the reported famine-diabetes relation may be confounded by the age differences between the exposed and non-exposed groups. We aimed to determine the association between prenatal exposure to the Chinese famine of 1959-1962 and risk of diabetes by applying age well-controlled strategies., Methods: Among 20,535 individuals born in 1955-1966 who participated in the China Health and Nutrition Survey from 1997 to 2015, we constructed age-matched exposed vs. non-exposed groups to investigate the role of prenatal exposure to the Chinese famine of 1959-1962 in relation to diabetes. We also built a hierarchical age-period-cohort (HAPC) model to specifically examine the relation of famine to diabetes risk independent of age., Results: Compared to the age-balanced men in the non-exposed group, the exposed men born in 1961 had a 154% increased risk of diabetes [odds ratio (OR) 2.54 (95% CI 1.07-6.03), P = 0.04). In the HAPC analysis, the predicted probabilities of diabetes peaked in the 1961-birth cohort of men [3.4% (95% CI 2.4%-5.0%)], as compared to the average probability of diabetes (reference) of 1.8% for men overall. Neither analytical strategy revealed any strong relation between famine exposure and diabetes risk in women., Conclusion: Among the pre-defined Chinese famine period of 1959-1962, early-life exposure to famine was associated with increased diabetes risk in men but not in women, and these relations were independent of age., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Selective serotonin reuptake inhibitors (SSRIs) are medications commonly used by pregnant women. While SSRIs have been considered safe during pregnancy, there is limited understanding of the long-term consequences of prenatal SSRI exposure on adult behavioral processes. Recent human studies have demonstrated prenatal exposure to some SSRIs in humans may increase susceptibility to autism spectrum disorder (ASD) and developmental delays. While escitalopram is one of the most effective antidepressants, it is also one of the newer available SSRIs, resulting in less information on its safety profile during pregnancy. The current study administered escitalopram (0 or 10 mg/kg, s.c.) to nulliparous female Long-Evans rats for the first (G1-10) or last half (G11-20) of the gestational period. Young adult male and female offspring were subsequently tested on a battery of behavioral tasks consisting of probabilistic reversal learning task, open field conflict, marble burying and social approach tasks. Results demonstrate that escitalopram exposure during the first half of pregnancy resulted in reduced anxiety-like behavior (disinhibition) on the modified open field and enhanced flexibility on the probabilistic reversal learning task. Exposure to escitalopram later in pregnancy resulted in an increase in marble burying behavior, but no differences were found with the other measures. These results suggest that exposure to escitalopram during the first half of prenatal development can have long lasting changes on adult behavior demonstrating better behavioral flexibility and lower anxiety-like behavior compared to non-exposed controls., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Fetal androgen exposure may be associated with autism spectrum disorder (ASD). We studied 1777 mother-child pairs in the prospective Odense Child Cohort. Prenatal androgen exposure was assessed by maternal 3rd trimester testosterone concentrations, maternal polycystic ovary syndrome (PCOS), and 3 months offspring anogenital distance. ASD traits were assessed at age 3 years with the ASD-symptom scale of the Child Behavior Checklist for ages 1½-5 years. Maternal testosterone was positively associated with traits of ASD in boys (p < 0.05). Maternal PCOS was associated with increased offspring ASD traits (p = 0.046), but became non-significant after excluding parental psychiatric diagnosis. Offspring anogenital distance was not linked to ASD traits. Higher prevalence of ASD in boys could be linked to higher susceptibility to fetal androgen exposure., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)