Search

Exposure to environmental pollutants, such as metals, pesticides, and air pollutants during early life, is a risk factor for neurodevelopmental disorders (NDDs), including Autism Spectrum Disorder (ASD). Our systematic review aimed to select and summarize more recent case-control studies that examined the association between prenatal and early postnatal exposure to environmental pollutants and NDDs. We searched five databases (Web of Science, PubMed, Embase, Scopus, Ovid), screened 2261 records, and included 24 eligible case-control studies. Meta-analyses were conducted on subgroups of at least three studies that shared both the outcome and the exposure. A noteworthy discovery from this literature review is the existence of non-linear or non-monotonic dose-response relationships between the exposure to certain metals and the risk of ASD. The meta-analysis revealed a significant association between exposure to particular matter (PM) 10 during the first year of life and the risk of ASD. Overall, studies included in our systematic review indicate that exposure to several pollutants within the first three years of life was significantly associated with the risk of NDDs., Competing Interests: Declaration of Competing Interest None, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Autism and autistic traits onset in childhood but persist into adulthood. Little is known about how genetic and environmental factors influence autism and autistic traits into adulthood. We aimed to determine age effects on the heritability of clinically diagnosed autism and the etiological stability of autistic traits from childhood to adulthood using twin methods., Methods: From 23,849 twin pairs in the Swedish Twin Register born between 1959 and 2010, we identified 485 individuals (1.01%, 31.5% female) with a clinical autism diagnosis. We estimated and compared the relative contribution of genetic, shared, and nonshared environmental influences to autism in childhood and adulthood. We further used multivariate twin analysis with four measurement points among 1,348 twin pairs in the longitudinal Twin Study of Child and Adolescent Development to assess the phenotypic and etiological stability of autistic traits - measured with three scales from the Child Behavior Checklist - from childhood to adulthood., Results: Autism heritability was comparable from childhood, (96% [95% CI, 76-99%]) to adulthood (87% [67-96%]). Autistic traits were moderately stable (phenotypic correlation = 0.35-0.61) from childhood to adulthood, and their heritability varied between 52 and 71%. We observed stable as well as newly emerging genetic influences on autistic traits from ages 8-9 to 19-20, and unique nonshared environmental influences at each age., Conclusions: Genetic factors are important for autism and autistic traits in adulthood and separate genetic studies in adults are warranted., (© 2024 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Autism spectrum disorders (ASD) can be caused by environmental factors. These factors act early in the development of the nervous system and induce stereotyped repetitive behaviors and diminished social interactions, among other outcomes. Little is known about how these behaviors are produced. In pregnant women, delivery of valproic acid (VPA) (to control seizure activity or stabilize mood) or immune activation by a virus increases the incidence of ASD in offspring. We found that either VPA or Poly Inosine:Cytosine (which mimics a viral infection), administered at mouse embryonic day 12.5, induced a neurotransmitter switch from GABA to glutamate in PV- and CCK-expressing interneurons in the medial prefrontal cortex by postnatal day 10. The switch was present for only a brief period during early postnatal development, observed in male and female mice at postnatal day 21 and reversed in both males and females by postnatal day 30. At postnatal day 90, male mice exhibited stereotyped repetitive behaviors and diminished social interaction while female mice exhibited only stereotyped repetitive behavior. Transfecting GAD1 in PV- and CCK-expressing interneurons at postnatal day 10, to reintroduce GABA expression, overrode the switch and prevented expression of autistic-like behavior. These findings point to an important role of neurotransmitter switching in mediating the environmental causes of autism., Competing Interests: Competing interests statement:The authors declare no competing interest.

Fetal brain development is an important determinant of neuropsychological performance in children. Any alterations in the intrauterine environment at different stages of pregnancy, such as maternal metabolic disorders, can lead to the development of chronic conditions in the offspring. Therefore, maternal diabetes, especially gestational diabetes mellitus, is an important factor in the development of pathological changes, such as miscarriage, fetal macrosomia, or neurodevelopmental disorders. During pregnancy, the hyperglycemic intrauterine environment adversely affects fetal brain development. A growing body of scientific research indicates that prenatal environmental factors, by affecting fetal brain development, can contribute to the appearance of autism spectrum disorders. According to the latest estimates from the International Diabetes Federation (2021), approximately 21.1 million live births worldwide (16.7%) have been affected by some form of hyperglycemia during pregnancy. The condition is more prevalent in low- and middle-income countries, where access to obstetric care is limited. The following factors have been identified as potential risk factors for gestational diabetes: advanced maternal age, overweight and obesity, family history of diabetes, and any form of diabetes. The purpose of this review is to summarize recent studies evaluating the effect of prenatal and maternal risk factors such as maternal pre-pregnancy diabetes, gestational diabetes, and obesity on the risk of developing autism spectrum disorder in offspring.

Increasing evidence suggests an association between atopic dermatitis, the most chronic inflammatory disease of the skin, and autism spectrum disorders, which are a group of neurodevelopmental diseases. Inflammation and immune dysregulation associated with genetic and environmental factors seem to characterize the pathophysiological mechanisms of both conditions. We conducted a literature review of the PubMed database aimed at identifying the clinical features and alleged risk factors that could be used in clinical practice to predict the onset of ASD and/or AD or worsen their prognosis in the context of comorbidities.

Background: Recent studies have reported the burden of attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and depressive disorder. Also, there is mounting evidence on the effects of environmental factors, such as ambient air pollution, on these disorders among children and adolescents. However, few studies have evaluated the burden of mental disorders attributable to air pollution exposure in children and adolescents., Methods: We estimated the risk ratios of major mental disorders (ADHD, ASD, and depressive disorder) associated with air pollutants among children and adolescents using time-series data (2011-2019) obtained from a nationwide air pollution monitoring network and healthcare utilization claims data in the Republic of Korea. Based on the estimated risk ratios, we determined the population attributable fraction (PAF) and calculated the medical costs of major mental disorders attributable to air pollution., Results: A total of 33,598 patients were diagnosed with major mental disorders during 9 years. The PAFs for all the major mental disorders were estimated at 6.9% (particulate matter < 10 μm [PM 10 ]), 3.7% (PM 2.5 ), and 2.2% (sulfur dioxide [SO 2 ]). The PAF of PM 10 was highest for depressive disorder (9.2%), followed by ASD (8.4%) and ADHD (5.2%). The direct medical costs of all major mental disorders attributable to PM 10 and SO 2 decreased during the study period., Conclusion: This study assessed the burden of major mental disorders attributable to air pollution exposure in children and adolescents. We found that PM 10, PM 2.5 , and SO 2 attributed 7%, 4%, and 2% respectively, to the risk of major mental disorders among children and adolescents., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Animal studies have shown that exposure to cigarette smoke during pregnancy can induce neurobehavioral anomalies in multiple subsequent generations. However, little work has examined such effects in humans. We examined the risk of grandchild autism spectrum disorder (ASD) in association with grandmother's smoking during pregnancy, using data from 53 562 mothers and grandmothers and 120 267 grandchildren in Nurses' Health Study II. In 1999, Nurses' Health Study II participants with children reported on their mothers' smoking. Grandchildren's ASD diagnoses were reported by the mothers in 2005 and 2009. Among grandmothers, 13 383 (25.0%) smoked during pregnancy, and 509 (0.4%) grandchildren were diagnosed with ASD. The adjusted odds ratio for ASD for grandmother smoking during pregnancy was 1.52 (95% CI, 1.06-2.20). Results were similar with direct grandmother reporting in 2001 of her smoking during pregnancy from the Nurses' Mothers Cohort Study subgroup (n = 22 167 grandmothers, n = 49 917 grandchildren) and were stronger among grandmothers who smoked ≥15 cigarettes per day during pregnancy (adjusted odds ratio = 1.93 [95% CI, 1.10-3.40]; n = 1895 grandmothers, n = 4212 grandchildren). Results were similar when we adjusted for mother's smoking during pregnancy. There was no association with grandfather's smoking as reported by the grandmother. Our results suggest a potential persistent impact of gestational exposure to environmental insults across 3 generations., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The burden of autism spectrum disorder (ASD) is increasing worldwide with genetic, epigenetic, and environmental factors being possibly responsible for the observed epidemiological figures. In the setting of environmental exposure, the city of Taranto, in Southern Italy, represents an interesting case study as it hosts well inside the city one of the biggest steel plants in Europe. This is a cross-sectional ecological study carried out in the year 2020 in the province of Taranto designed to estimate the burden of ASD in the municipalities of Taranto and Statte, classified as high environmental risk areas (Contaminated Site of National Interest-SIN), compared to the other 27 municipalities of the same province. Differences have been evaluated using the Chi Square Test. Children aged 6-11 years identified in SIN municipalities had a statistically significant higher prevalence of ASD than children of other municipalities (9.58 vs. 6.66/1000 respectively, p = 0.002). No statistically significant difference was observed for the 12-18 years group (3.41 vs. 2.54/1000, p = 0.12). The findings observed in this study are suggestive of the association between urban residential proximity to industrial facilities emitting air pollutants and higher ASD prevalence., (© 2024. The Author(s).)

Evidence shows that Autism Spectrum Disorder (ASD) stems from an interplay of genetic and environmental factors, which may include propionic acid (PPA), a microbial byproduct and food preservative. We previously reported that in vitro treatment of neural stem cells with PPA leads to gliosis and neuroinflammation. In this study, mice were exposed ad libitum to a PPA-rich diet for four weeks before mating. The same diet was maintained through pregnancy and administered to the offspring after weaning. The brains of the offspring were studied at 1 and 5 months postpartum. Glial fibrillary acidic protein (astrocytic marker) was significantly increased (1.53 ± 0.56-fold at 1 M and 1.63 ± 0.49-fold at 5 M) in the PPA group brains. Tubulin IIIβ (neuronal marker) was significantly decreased in the 5 M group. IL-6 and TNF-α expression were increased in the brain of the PPA group (IL-6: 2.48 ± 1.25-fold at 5 M; TNF-α: 2.84 ± 1.16-fold at 1 M and 2.64 ± 1.42-fold, at 5 M), while IL-10 was decreased. GPR41 and p-Akt were increased, while PTEN (p-Akt inhibitor) was decreased in the PPA group. The data support the role of a PPA-rich diet in glia over-proliferation and neuro-inflammation mediated by the GPR41 receptor and PTEN/Akt pathway. These findings strongly support our earlier study on the role of PPA in ASD.

Background: The nutritional status and growth of children with Autism spectrum disorders (ASD) is influenced significantly by two factors; food selectivity behaviors due to their consumption of a limited variety of food and the high incidence of gastrointestinal (GIT) disorders., Aim: This study aimed to assess the nutritional adequacy and growth pattern of ASD children aged three to twelve years compared to their healthy developing peers., Methods: A national comparative, facility-based cross-sectional study was conducted in eight Egyptian governorates on 285 Egyptian children diagnosed with ASD and 224 children who are their relatives as healthy developing peers. Anthropometric measurements were obtained, including weight, height, head circumference, and mid-upper arm circumference. Body Mass Index (BMI) was calculated and all numbers were plotted on WHO growth charts. Assessment of food preferences, and nutrient intake adequacy of children was done using the Food preference questionnaire, and the Dietary Reference Intakes (DRIs) of Egyptian children., Results: Calorie-dense food and sugar intake were higher among ASD children than their healthy developing peers. ASD children omit some important protein sources such as dairy (COR = 5.2, 95% CI:2.7-9.9), meat, and poultry (COR = 2.7, 95% CI: 1.6-4.7), and a lower intake of fruits and vegetables than their healthy developing peers. For children with ASD in all age groups, a deficiency in the range of 50-60% was detected for vitamins (C, D, B6, thiamine, riboflavin, niacin) and minerals (iron). A deficiency in the range of 60-70% was detected for folate and calcium. A deficiency of vitamin C calcium and iron was also detected for both children with ASD and their healthy developing relatives aged 6 to 12 years. GIT disorders were common among ASD children compared to healthy developing peers (COR = 2.8 to 10.3). Children with ASD had four-fold higher odds of stunting (COR = 4.1, CI: 1.7-10.1), threefold higher odds of being overweight (COR = 3.3, CI: 1.48-7.32), and nearly eleven-fold higher odds of obesity (COR = 11.4, CI: 4.05-32.17) compared to their healthy developing peers., Conclusion: ASD children are prone to overweight and protein malnutrition. Their intake of fruits and vegetables is inadequate and hence their intake of vitamins and minerals is insufficient, contributing to stunting., (© 2024. The Author(s).)

Objective: The relationship between diabetes mellitus (DM) and autism spectrum disorder (ASD) remains controversial. This study aimed to analyze the causal relationship between different types of DM and ASD by bidirectional Mendelian randomization (MR)., Methods: Single nucleotide polymorphisms for type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM), and ASD were obtained from genome-wide association studies. Subsequently, inverse variance weighted, MR-Egger, and weighted median were used to test the exposure-outcome causality. Finally, MR-Egger's intercept, Cochran's Q, and leave-one-out method were used to assess horizontal pleiotropy, heterogeneity, and sensitivity of the results, respectively., Results: The positive analysis showed that T2DM was associated with an increased risk of ASD, whereas neither T1DM nor GDM was associated with the risk of ASD. The reverse analysis showed that ASD was associated with an increased risk of T2DM, while it was not associated with the risk of either T1DM or GDM. MR-Egger intercept showed no horizontal pleiotropy ( p > 0.05) for these results. Cochran's Q showed no heterogeneity expect for the results of T1DM on the risk of ASD, and leave-one-out sensitivity analysis showed these results were robust., Conclusion: This MR analysis suggests that T2DM and ASD are reciprocal risk factors and that they may create an intergenerational risk cycling in female patients. Aggressive prevention and treatment of T2DM and ASD help to break the trap of this risk cycling. Additionally, this study does not support a causal relationship between T1DM and ASD, as well as GDM and ASD. And more studies are needed in the future to continue to explore the interactions and underlying mechanisms between different types of DM and ASD., 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 Yu, Yang, Hu, Tong, Wu and Yu.)

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interaction and communication, anxiety, hyperactivity, and interest restricted to specific subjects. In addition to the genetic factors, multiple environmental factors have been related to the development of ASD. Animal models can serve as crucial tools for understanding the complexity of ASD. In this study, a chemical model of ASD has been developed in zebrafish by exposing embryos to valproic acid (VPA) from 4 to 48 h post-fertilization, rearing them to the adult stage in fish water. For the first time, an integrative approach combining behavioral analysis and neurotransmitters profile has been used for determining the effects of early-life exposure to VPA both in the larval and adult stages. Larvae from VPA-treated embryos showed hyperactivity and decreased visual and vibrational escape responses, as well as an altered neurotransmitters profile, with increased glutamate and decreased acetylcholine and norepinephrine levels. Adults from VPA-treated embryos exhibited impaired social behavior characterized by larger shoal sizes and a decreased interest for their conspecifics. A neurotransmitter analysis revealed a significant decrease in dopamine and GABA levels in the brain. These results support the potential predictive validity of this model for ASD research.

This study aimed to investigate the association between pre-pregnancy, prenatal and perinatal exposures to cannabis use disorder (CUD) and the risk of autism spectrum disoder (ASD) in offspring. Data were drawn from the New South Wales (NSW) Perinatal Data Collection (PDC), population-based, linked administrative health data encompassing all-live birth cohort from January 2003 to December 2005. This study involved 222 534 mother-offspring pairs. . The exposure variable (CUD) and the outcome of interest (ASD) were identified using the 10th international disease classification criteria, Australian Modified (ICD-10-AM). We found a three-fold increased risk of ASD in the offspring of mothers with maternal CUD compared to non-exposed offspring. In our sensitivity analyses, male offspring have a higher risk of ASD associated with maternal CUD than their female counterparts. In conclusion, exposure to maternal CUD is linked to a higher risk of ASD in offspring, with a stronger risk in male offspring. Further research is needed to understand these gender-specific effects and the relationship between maternal CUD and ASD risk in children., Competing Interests: Declaration of competing interest All authors have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Autism spectrum disorders (ASD) encompass a collection of neurodevelopmental disorders that exhibit impaired social interactions and repetitive stereotypic behaviors. Although the exact cause of these disorders remains unknown, it is widely accepted that both genetic and environmental factors contribute to their onset and progression. Recent studies have highlighted the potential negative impact of maternal diabetes on embryonic neurodevelopment, suggesting that intrauterine hyperglycemia could pose an additional risk to early brain development and contribute to the development of ASD. This paper presents a comprehensive analysis of the current research on the relationship between various forms of maternal diabetes, such as type 1 diabetes mellitus, type 2 diabetes mellitus, and gestational diabetes mellitus, and the likelihood of ASD in offspring. The study elucidates the potential mechanisms through which maternal hyperglycemia affects fetal development, involving metabolic hormones, immune dysregulation, heightened oxidative stress, and epigenetic alterations. The findings of this review offer valuable insights for potential preventive measures and evidence-based interventions targeting ASD., Competing Interests: Declaration of competing interest These authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Food and nutrition-related factors have the potential to impact development of autism spectrum disorder (ASD) and quality of life for people with ASD, but gaps in evidence exist. On 10 November 2022, Tufts University's Friedman School of Nutrition Science and Policy and Food and Nutrition Innovation Institute hosted a 1-d meeting to explore the evidence and evidence gaps regarding the relationships of food and nutrition with ASD. This meeting report summarizes the presentations and deliberations from the meeting. Topics addressed included prenatal and child dietary intake, the microbiome, obesity, food-related environmental exposures, mechanisms and biological processes linking these factors and ASD, food-related social factors, and data sources for future research. Presentations highlighted evidence for protective associations with prenatal folic acid supplementation and ASD development, increases in risk of ASD with maternal gestational obesity, and the potential for exposure to environmental contaminants in foods and food packaging to influence ASD development. The importance of the maternal and child microbiome in ASD development or ASD-related behaviors in the child was reviewed, as was the role of discrimination in leading to disparities in environmental exposures and psychosocial factors that may influence ASD. The role of child diet and high prevalence of food selectivity in children with ASD and its association with adverse outcomes were also discussed. Priority evidence gaps identified by participants include further clarifying ASD development, including biomarkers and key mechanisms; interactions among psychosocial, social, and biological determinants; interventions addressing diet, supplementation, and the microbiome to prevent and improve quality of life for people with ASD; and mechanisms of action of diet-related factors associated with ASD. Participants developed research proposals to address the priority evidence gaps. The workshop findings serve as a foundation for future prioritization of scientific research to address evidence gaps related to food, nutrition, and ASD., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

ADHD and ASD are highly heritable and show a high co-occurrence and persistence into adulthood. This study aimed to identify pre and perinatal risk factors, and early psychosocial exposures related to later diagnosis of ADHD, ASD, and their co-occurrence. 16,365 children born 1997-1999 and their families, involved in the prospective population-based ABIS study (All Babies in Southeast Sweden), were included in this sub-study. Pre and perinatal factors and early environmental psychosocial exposures were collected from parental-questionnaires at birth and 1-year follow-up. Diagnoses from birth up to 23 years of age were obtained from the Swedish National Diagnosis Register in 2020. The cumulative incidence of ADHD, ASD, and their co-occurrence in the ABIS-cohort Study were 4.6%, 1.7%, and 1.1%, respectively. Being male was associated with an increased risk for ADHD, ASD, and their co-occurrence (aOR 1.30, 1.56, and 1.91, respectively), while higher household income reduced it (aOR 0.82, 0.73, and 0.64). Serious life events during pregnancy (aOR 1.40) and maternal smoking (aOR 1.51) increased the risk of ADHD, while older maternal age (aOR 0.96), higher parental education (aOR 0.72 maternal and aOR 0.74 paternal) and longer exclusive breastfeeding (aOR 0.72) reduced it. Non-Swedish paternal nationality (aOR 0.40) and higher maternal education (aOR 0.74) were associated with a lower risk of ASD, while a family history of autoimmune diseases increased the risk of the co-occurrence of both disorders (aOR 1.62). Obtained results suggest that the etiology of ADHD, ASD, and their co-occurrence is independently associated with environmental psychosocial predictors. The co-occurrence seems to overlap the etiology of ADHD, in which psychosocial determinants have a larger role, however, it is also independently influenced by a family history of autoimmune diseases., (© 2024. The Author(s).)

Zika virus (ZIKV) infection was first associated with Central Nervous System (CNS) infections in Brazil in 2015, correlated with an increased number of newborns with microcephaly, which ended up characterizing the Congenital Zika Syndrome (CZS). Here, we investigated the impact of ZIKV infection on the functionality of iPSC-derived astrocytes. Besides, we extrapolated our findings to a Brazilian cohort of 136 CZS children and validated our results using a mouse model. Interestingly, ZIKV infection in neuroprogenitor cells compromises cell migration and causes apoptosis but does not interfere in astrocyte generation. Moreover, infected astrocytes lost their ability to uptake glutamate while expressing more glutamate transporters and secreted higher levels of IL-6. Besides, infected astrocytes secreted factors that impaired neuronal synaptogenesis. Since these biological endophenotypes were already related to Autism Spectrum Disorder (ASD), we extrapolated these results to a cohort of children, now 6-7 years old, and found seven children with ASD diagnosis (5.14 %). Additionally, mice infected by ZIKV revealed autistic-like behaviors, with a significant increase of IL-6 mRNA levels in the brain. Considering these evidence, we inferred that ZIKV infection during pregnancy might lead to synaptogenesis impairment and neuroinflammation, which could increase the risk for ASD., 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. Published by Elsevier B.V.)

Background: Synthetic oxytocin (sOT) is frequently administered during parturition. Studies have raised concerns that fetal exposure to sOT may be associated with altered brain development and risk of neurodevelopmental disorders. In a large and diverse sample of children with data about intrapartum sOT exposure and subsequent diagnoses of two prevalent neurodevelopmental disorders, i.e., attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), we tested the following hypotheses: (1) Intrapartum sOT exposure is associated with increased odds of child ADHD or ASD; (2) associations differ across sex; (3) associations between intrapartum sOT exposure and ADHD or ASD are accentuated in offspring of mothers with pre-pregnancy obesity., Methods: The study sample comprised 12,503 participants from 44 cohort sites included in the Environmental Influences on Child Health Outcomes (ECHO) consortium. Mixed-effects logistic regression analyses were used to estimate the association between intrapartum sOT exposure and offspring ADHD or ASD (in separate models). Maternal obesity (pre-pregnancy BMI ≥ 30 kg/m 2 ) and child sex were evaluated for effect modification., Results: Intrapartum sOT exposure was present in 48% of participants. sOT exposure was not associated with increased odds of ASD (adjusted odds ratio [aOR] 0.86; 95% confidence interval [CI], 0.71-1.03) or ADHD (aOR 0.89; 95% CI, 0.76-1.04). Associations did not differ by child sex. Among mothers with pre-pregnancy obesity, sOT exposure was associated with lower odds of offspring ADHD (aOR 0.72; 95% CI, 0.55-0.96). No association was found among mothers without obesity (aOR 0.97; 95% CI, 0.80-1.18)., Conclusions: In a large, diverse sample, we found no evidence of an association between intrapartum exposure to sOT and odds of ADHD or ASD in either male or female offspring. Contrary to our hypothesis, among mothers with pre-pregnancy obesity, sOT exposure was associated with lower odds of child ADHD diagnosis., (© 2024. The Author(s).)

Autism spectrum disorder (ASD) exhibits a gender bias, with boys more frequently affected than girls. Similarly, in mouse models induced by prenatal exposure to valproic acid (VPA), males typically display reduced sociability, while females are less affected. Although both males and females exhibit VPA effects on neuroinflammatory parameters, these effects are sex-specific. Notably, females exposed to VPA show increased microglia and astrocyte density during the juvenile period. We hypothesized that these distinct neuroinflammatory patterns contribute to the resilience of females to VPA. To investigate this hypothesis, we treated juvenile animals with intraperitoneal bacterial lipopolysaccharides (LPS), a treatment known to elicit brain neuroinflammation. We thus evaluated the impact of juvenile LPS-induced inflammation on adult sociability and neuroinflammation in female mice prenatally exposed to VPA. Our results demonstrate that VPA-LPS females exhibit social deficits in adulthood, overriding the resilience observed in VPA-saline littermates. Repetitive behavior and anxiety levels were not affected by either treatment. We also evaluated whether the effect on sociability was accompanied by heightened neuroinflammation in the cerebellum and hippocampus. Surprisingly, we observed reduced astrocyte and microglia density in the cerebellum of VPA-LPS animals. These findings shed light on the complex interactions between prenatal insults, juvenile inflammatory stimuli, and sex-specific vulnerability in ASD-related social deficits, providing insights into potential therapeutic interventions for ASD., (© 2024. The Author(s).)

Autism Spectrum Disorder (ASD) is a neurodevelopmental behavioral disorder characterized by social, communicative, and motor deficits. There is no single etiological cause for ASD, rather, there are various genetic and environmental factors that increase the risk for ASD. It is thought that some of these factors influence the same underlying neural mechanisms, and that an interplay of both genetic and environmental factors would better explain the pathogenesis of ASD. To better appreciate the influence of genetic-environment interaction on ASD-related behaviours, rats lacking a functional copy of the ASD-linked gene Cntnap2 were exposed to maternal immune activation (MIA) during pregnancy and assessed in adolescence and adulthood. We hypothesized that Cntnap2 deficiency interacts with poly I:C MIA to aggravate ASD-like symptoms in the offspring. In this double-hit model, we assessed attention, a core deficit in ASD due to prefrontal cortical dysfunction. We employed a well-established attentional paradigm known as the 5-choice serial reaction time task (5CSRTT). Cntnap2-/- rats exhibited greater perseverative responses which is indicative of repetitive behaviors. Additionally, rats exposed to poly I:C MIA exhibited premature responses, a marker of impulsivity. The rats exposed to both the genetic and environmental challenge displayed an increase in impulsive activity; however, this response was only elicited in the presence of an auditory distractor. This implies that exacerbated symptomatology in the double-hit model may situation-dependent and not generally expressed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Maroon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder with onset in infancy or early childhood. Mendelian randomization (MR) is a statistical method used to infer causal relationships between exposures and outcomes. This article summarizes MR studies related to ASD. Existing research supports a causal relationship between maternal inflammatory bowel disease in children with ASD, parental education levels, screen time exposure, obesity, insomnia, serum transferrin, decreased blood selenium, abnormal signals in brain functional MRI, interleukin-6, phosphodiesterase 2A, mitogen-activated protein kinase kinase 3, mitochondrial ribosomal protein L33, serotonin, and ASD. However, it does not support a causal relationship between parental rheumatoid arthritis, systemic lupus erythematosus, neonatal jaundice in children with ASD, cytomegalovirus infection, asthma, oral ulcers, vitamin D levels, and ASD. This article reviews the etiological factors related to ASD and MR studies, aiming to explore and deepen the understanding of the pathophysiology of ASD. It provides strong statistical support for the prevention, diagnosis, and treatment of ASD, and offers new methods and strategies for the etiological analysis of complex traits.

Background: Cerebellar mutism syndrome (CMS) is a common and debilitating complication of posterior fossa tumor surgery in children. Affected children exhibit communication and social impairments that overlap phenomenologically with subsets of deficits exhibited by children with Autism spectrum disorder (ASD). Although both CMS and ASD are thought to involve disrupted cerebro-cerebellar circuitry, they are considered independent conditions due to an incomplete understanding of their shared neural substrates., Methods: In this study, we analyzed postoperative cerebellar lesions from 90 children undergoing posterior fossa resection of medulloblastoma, 30 of whom developed CMS. Lesion locations were mapped to a standard atlas, and the networks functionally connected to each lesion were computed in normative adult and pediatric datasets. Generalizability to ASD was assessed using an independent cohort of children with ASD and matched controls (n = 427)., Results: Lesions in children who developed CMS involved the vermis and inferomedial cerebellar lobules. They engaged large-scale cerebellothalamocortical circuits with a preponderance for the prefrontal and parietal cortices in the pediatric and adult connectomes, respectively. Moreover, with increasing connectomic age, CMS-associated lesions demonstrated stronger connectivity to the midbrain/red nuclei, thalami and inferior parietal lobules and weaker connectivity to the prefrontal cortex. Importantly, the CMS-associated lesion network was independently reproduced in ASD and correlated with communication and social deficits, but not repetitive behaviors., Conclusions: Our findings indicate that CMS-associated lesions may result in an ASD-like network disturbance that occurs during sensitive windows of brain development. A common network disturbance between CMS and ASD may inform improved treatment strategies for affected children., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The prevalence of autism spectrum disorder (ASD) has significantly risen in the past three decades, prompting researchers to explore the potential contributions of environmental factors during pregnancy to ASD development. One such factor of interest is gestational hypothyroxinemia (HTX), a frequent condition in pregnancy associated with cognitive impairments in the offspring. While retrospective human studies have linked gestational HTX to autistic traits, the cellular and molecular mechanisms underlying the development of ASD-like phenotypes remain poorly understood. This study used a mouse model of gestational HTX to evaluate ASD-like phenotypes in the offspring., Methods: To induce gestational HTX, pregnant mice were treated with 2-mercapto-1-methylimidazole (MMI), a thyroid hormones synthesis inhibitor, in the tap-drinking water from embryonic days (E) 10 to E14. A separate group received MMI along with a daily subcutaneous injection of T 4 , while the control group received regular tap water during the entire pregnancy. Female and male offspring underwent assessments for repetitive, anxious, and social behaviors from postnatal day (P) 55 to P64. On P65, mice were euthanized for the evaluation of ASD-related inflammatory markers in blood, spleen, and specific brain regions. Additionally, the expression of glutamatergic proteins (NLGN3 and HOMER1) was analyzed in the prefrontal cortex and hippocampus., Results: The HTX-offspring exhibited anxious-like behavior, a subordinate state, and impaired social interactions. Subsequently, both female and male HTX-offspring displayed elevated proinflammatory cytokines in blood, including IL-1β, IL-6, IL-17A, and TNF-α, while only males showed reduced levels of IL-10. The spleen of HTX-offspring of both sexes showed increased Th17/Treg ratio and M1-like macrophages. In the prefrontal cortex and hippocampus of male HTX-offspring, elevated levels of IL-17A and reduced IL-10 were observed, accompanied by increased expression of hippocampal NLGN3 and HOMER1. All these observations were compared to those observed in the Control-offspring. Notably, the supplementation with T 4 during the MMI treatment prevents the development of the observed phenotypes. Correlation analysis revealed an association between maternal T 4 levels and specific ASD-like outcomes., Discussion: This study validates human observations, demonstrating for the first time that gestational HTX induces ASD-like phenotypes in the offspring, highlighting the need of monitoring thyroid function during pregnancy., 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 González-Madrid, Rangel-Ramírez, Opazo, Méndez, Bohmwald, Bueno, González, Kalergis and Riedel.)

Oxytocin plays an important role in brain development and is associated with various neurotransmitter systems in the brain. Abnormalities in the production, secretion, and distribution of oxytocin in the brain, at least during some stages of the development, are critical for the pathogenesis of neuropsychiatric diseases, particularly in the autism spectrum disorder. The etiology of autism includes changes in local sensory and dopaminergic areas of the brain, which are also supplied by the hypothalamic sources of oxytocin. It is very important to understand their mutual relationship. In this review, the relationship of oxytocin with several components of the dopaminergic system, gamma-aminobutyric acid (GABA) inhibitory neurotransmission and their alterations in the autism spectrum disorder is discussed. Special attention has been paid to the results describing a reduced expression of inhibitory GABAergic markers in the brain in the context of dopaminergic areas in various models of autism. It is presumed that the altered GABAergic neurotransmission, due to the absence or dysfunction of oxytocin at certain developmental stages, disinhibits the dopaminergic signaling and contributes to the autism symptoms., (© 2024 Tomas Havranek et al., published by Sciendo.)

Vitamin D deficiency (VDD) during early life emerges as a potential risk factor for autism spectrum disorder (ASD). Individuals with autism commonly exhibit lower vitamin D (VD) levels compared to the general population, and VD deficiency is prevalent during pregnancy and lactation. Moreover, gastrointestinal comorbidity, prevalent in ASD patients, correlates closely with disruptions in the gut microbiota and altered intestinal permeability. Therefore, it is fascinating and significant to explore the effects of maternal VD deficiency during pregnancy and lactation on the maturation of the gut microbiota of the offspring and its relevance to autism spectrum disorders. In this study, we established maternal pregnancy and lactation VD-deficient mouse models, employed shotgun macrogenomic sequencing to unveil alterations in the gut microbiome of offspring mice, and observed autism-related behaviours. Furthermore, fecal microbial transplantation (FMT) reversed repetitive and anxious behaviours and alleviated social deficits in offspring mice by modulating the gut microbiota and increasing short-chain fatty acid levels in the cecum, along with influencing the concentrations of claudin-1 and occludin in the colon. Our findings confirm that VDD during pregnancy and lactation is a risk factor for autism in the offspring, with disturbances in the structure and function of the offspring's gut microbiota contributing at least part of the effect. The study emphasises the importance of nutrition and gut health early in life. Simultaneously, this study further demonstrates the effect of VDD on ASD and provides potential ideas for early prevention and intervention of ASD.

Objectives: To investigate the levels of serum folate and vitamin B 12 (VB 12 ) and their association with the level of neurodevelopment in preschool children with autism spectrum disorder (ASD)., Methods: A total of 324 ASD children aged 2-6 years and 318 healthy children aged 2-6 years were recruited. Serum levels of folate and VB 12 were measured using chemiluminescent immunoassay. The Social Responsiveness Scale and the Childhood Autism Rating Scale were used to assess the core symptoms of ASD children, and the Gesell Developmental Schedule was employed to evaluate the level of neurodevelopment., Results: The levels of serum folate and VB 12 in ASD children were significantly lower than those in healthy children ( P <0.05). Serum folate levels in ASD children were positively correlated with gross and fine motor developmental quotients ( P <0.05), and serum VB 12 levels were positively correlated with adaptive behavior, fine motor, and language developmental quotients ( P <0.05). In ASD children aged 2 to <4 years, serum folate levels were positively correlated with developmental quotients in all domains ( P <0.05), and serum VB 12 levels were positively correlated with language developmental quotient ( P <0.05). In male ASD children, serum VB 12 levels were positively correlated with language and personal-social developmental quotients ( P <0.05)., Conclusions: Serum folate and VB 12 levels in preschool ASD children are lower than those in healthy children and are associated with neurodevelopmental levels, especially in ASD children under 4 years of age. Therefore, maintaining normal serum folate and VB 12 levels may be beneficial for the neurodevelopment of ASD children, especially in ASD children under 4 years of age.

Background: Growing evidence has revealed the impacts of exposure to fine particulate matter (PM 2.5 ) and dysbiosis of gut microbiota on neuropsychiatric disorders, but the causal inference remains controversial due to residual confounders in observational studies., Methods: This study aimed to examine the causal effects of exposure to PM 2.5 on 4 major neuropsychiatric disorders (number of cases = 18,381 for autism spectrum disorder [ASD], 38,691 for attention deficit hyperactivity disorder [ADHD], 67,390 for schizophrenia, and 21,982 cases for Alzheimer's disease [AD]), and the mediation pathway through gut microbiota. Two-sample Mendelian randomization (MR) analyses were performed, in which genetic instruments were identified from genome-wide association studies (GWASs). The included GWASs were available from (1) MRC Integrative Epidemiology Unit (MRC-IEU) for PM 2.5 , PM coarse , PM 10 , and NO X ; (2) the Psychiatric Genomics Consortium (PGC) for ASD, ADHD, and schizophrenia; (3) MRC-IEU for AD; and (4) MiBioGen for gut microbiota. Multivariable MR analyses were conducted to adjust for exposure to NO X , PM coarse , and PM 10 . We also examined the mediation effects of gut microbiota in the associations between PM 2.5 exposure levels and neuropsychiatric disorders, using two-step MR analyses., Results: Each 1 standard deviation (1.06 ug/m 3 ) increment in PM 2.5 concentrations was associated with elevated risk of ASD (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.00-2.02), ADHD (1.51, 1.15-1.98), schizophrenia (1.47, 1.15-1.87), and AD (1.57, 1.16-2.12). For all the 4 neurodevelopmental disorders, the results were robust under various sensitivity analyses, while the MR-Egger method yielded non-significant outcomes. The associations remained significant for all the 4 neuropsychiatric disorders after adjusting for PM coarse , while non-significant after adjusting for NO X and PM 10 . The effects of PM 2.5 exposure on ADHD and schizophrenia were partially mediated by Lachnospiraceae and Barnesiella, with the proportions ranging from 8.31% to 15.77%., Conclusions: This study suggested that exposure to PM 2.5 would increase the risk of neuropsychiatric disorders, partially by influencing the profile of gut microbiota. Comprehensive regulations on air pollutants are needed to help prevent neuropsychiatric disorders., 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.)

Autism spectrum disorder (ASD) is clinically and etiologically heterogeneous. A causal genetic variant can be identified in approximately 20% to 25% of affected individuals with current clinical genetic testing, and all patients with an ASD diagnosis should be offered genetic etiologic evaluation. We suggest that exome sequencing with copy number variant coverage should be the first-line etiologic evaluation for ASD. Neuroimaging, neurophysiologic, metabolic, and other biochemical evaluations can provide insight into the pathophysiology of ASD but should be recommended in the appropriate clinical circumstances., Competing Interests: Disclosure None of the authors report any financial conflicts of interests as they pertain to the subject of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a complex environmental etiology involving maternal risk factors, which have been combined with machine learning to predict ASD. However, limited studies have considered the factors throughout preconception, perinatal, and postnatal periods, and even fewer have been conducted in multi-center. In this study, five predictive models were developed using 57 maternal risk factors from a cohort across ten cities (ASD:1232, typically developing[TD]: 1090). The extreme gradient boosting model performed best, achieving an accuracy of 66.2 % on the external cohort from three cities (ASD:266, TD:353). The most important risk factors were identified as unstable emotions and lack of multivitamin supplementation using Shapley values. ASD risk scores were calculated based on predicted probabilities from the optimal model and divided into low, medium, and high-risk groups. The logistic analysis indicated that the high-risk group had a significantly increased risk of ASD compared to the low-risk group. Our study demonstrated the potential of machine learning models in predicting the risk for ASD based on maternal factors. The developed model provided insights into the maternal emotion and nutrition factors associated with ASD and highlighted the potential clinical applicability of the developed model in identifying high-risk populations., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Preeclampsia (PE) is a multisystem disorder characterized by elevated blood pressure in the mother, typically occurring after 20 weeks of gestation and posing risks to both maternal and fetal health. PE causes placental changes that can affect the fetus, particularly neurodevelopment. Its key pathophysiological mechanisms encompass hypoxia, vascular and angiogenic dysregulation, inflammation, neuronal and glial alterations, and disruptions in neuronal signaling. Animal models indicate that PE is correlated with neurodevelopmental alterations and cognitive dysfunctions in offspring and in humans, an association between PE and conditions such as cerebral palsy, autism spectrum disorder, attention deficit hyperactivity disorder, and sexual dimorphism has been observed. Considering the relevance for mothers and children, we conducted a narrative literature review to describe the relationships between the pathophysiological mechanisms behind neurodevelopmental alterations in the offspring of PE mothers, along with their potential consequences. Furthermore, we emphasize aspects pertinent to the prevention/treatment of PE in pregnant mothers and alterations observed in their offspring. The present narrative review offers a current, complete, and exhaustive analysis of (i) the pathophysiological mechanisms that can affect neurodevelopment in the children of PE mothers, (ii) the relationship between PE and neurological alterations in offspring, and (iii) the prevention/treatment of PE.

Background: Maternal use of valproate during pregnancy has been associated with an increased risk of neurodevelopmental disorders in children. Although most studies of other antiseizure medications have not shown increased risks of these disorders, there are limited and conflicting data regarding the risk of autism spectrum disorder associated with maternal topiramate use., Methods: We identified a population-based cohort of pregnant women and their children within two health care utilization databases in the United States, with data from 2000 through 2020. Exposure to specific antiseizure medications was defined on the basis of prescription fills from gestational week 19 until delivery. Children who had been exposed to topiramate during the second half of pregnancy were compared with those unexposed to any antiseizure medication during pregnancy with respect to the risk of autism spectrum disorder. Valproate was used as a positive control, and lamotrigine was used as a negative control., Results: The estimated cumulative incidence of autism spectrum disorder at 8 years of age was 1.9% for the full population of children who had not been exposed to antiseizure medication (4,199,796 children). With restriction to children born to mothers with epilepsy, the incidence was 4.2% with no exposure to antiseizure medication (8815 children), 6.2% with exposure to topiramate (1030 children), 10.5% with exposure to valproate (800 children), and 4.1% with exposure to lamotrigine (4205 children). Propensity score-adjusted hazard ratios in a comparison with no exposure to antiseizure medication were 0.96 (95% confidence interval [CI], 0.56 to 1.65) for exposure to topiramate, 2.67 (95% CI, 1.69 to 4.20) for exposure to valproate, and 1.00 (95% CI, 0.69 to 1.46) for exposure to lamotrigine., Conclusions: The incidence of autism spectrum disorder was higher among children prenatally exposed to the studied antiseizure medications than in the general population. However, after adjustment for indication and other confounders, the association was substantially attenuated for topiramate and lamotrigine, whereas an increased risk remained for valproate. (Funded by the National Institute of Mental Health.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Autism spectrum disorder (ASD) is heritable neurodevelopmental disorders (NDDs), but environmental risk factors have also been suggested to a play a role in its development. Prenatal, perinatal and parental factors have been associated with an increased risk of ASD in children. The aim of the present study was to explore the prenatal, perinatal, and parenting risk factors in children with autism spectrum disorder (ASD) from Beijing, China by comparing them with typically developing (TD) children., Methods: A sample of 151 ASD children's parents who from rehabilitation institutions in Beijing were enrolled in this study, and an additional 151 children from kindergartens in Beijing were recruited as a control group (child age: mean = 4.4 years). TD children were matched according to age, sex and maternal education. We explored the maternal AQ (Autism Spectrum Quotient) scores (mean:19.40-19.71, no significant difference between two groups) to referring the genetic baseline. This study evaluated 17 factors with unadjusted and adjusted analyses., Results: Birth asphyxia was associated with a more than a thirteen-fold higher risk of ASD (adjusted odds ratio (AOR) = 13.42). Breastfeeding difficulties were associated with a higher risk of ASD(AOR = 3.46). Parenting influenced the risk of ASD, with low responding (LR) and harsh or neglectful parenting associated with a higher risk of ASD in offspring (AOR = 2.37 for LR, AOR = 3.42 for harsh parenting and AOR = 3.01 for neglectful parenting). Maternal fever during pregnancy was associated with a higher risk of ASD in offspring (AOR = 3.81)., Conclusions: Many factors were associated with ASD in offspring. Further assessment is needed to elucidate the role of modifiable environmental factors to inform prevention strategies., (© 2024. The Author(s).)

Background: Air pollution is a global health concern, with fine particulate matter (PM 2.5 ) constituents posing potential risks to human health, including children's neurodevelopment. Here we investigated associations between exposure during pregnancy and infancy to specific traffic-related PM 2.5 components with Autism Spectrum Disorder (ASD) diagnosis., Methods: For exposure assessment, we estimated PM 2.5 components related to traffic exposure (Barium [Ba] as a marker of brake dust and Zinc [Zn] as a tire wear marker, Black Carbon [BC]) and oxidative stress potential (OSP) markers (Hydroxyl Radical [OP OH ] formation, Dithiothreitol activity [OP DTT ], reactive oxygen species [ROS]) modeled with land use regression with co-kriging based on an intensive air monitoring campaign. We assigned exposures to a cohort of 444,651 children born in Southern California between 2016 and 2019, among whom 11,466 ASD cases were diagnosed between 2018 and 2022, Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained with logistic regression for single pollutant and PM 2.5 mass co-adjusted models, also adjusting for sociodemographic characteristics., Results: Among PM 2.5 components, we found the strongest positive association with ASD for our brake wear marker Ba (OR per IQR  = 1.29, 95 % CI: 1.24, 1.34). This was followed by an increased risk for all PM 2.5 oxidative stress potential markers; the strongest association was with ROS formation (OR per IQR  = 1.22, 95 % CI: 1.18, 1.25). PM 2.5 mass was linked to ASD in Hispanic and Black children, but not White children, while traffic-related PM 2.5 and OSP markers increased ASD risk across all groups. In neighborhoods with the lowest socioeconomic status (SES), associations with ASD were stronger for all examined pollutants compared to higher SES areas., Conclusions: Our findings suggest that brake wear-related PM 2.5 and PM 2.5 OSP are associated with ASD diagnosis in Southern California. These results suggest that strategies aimed at reducing the public health impacts of PM 2.5 need to consider specific sources., 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: 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.)

Although the risk of autism spectrum disorder (ASD) has been reported to be associated with interpregnancy intervals (IPIs), their association remains debatable due to inconsistent findings in existing studies. Therefore, the present study aimed to explore their association. PubMed, Embase, Web of Science, and the Cochrane Library were systematically retrieved up to May 25, 2022. An updated search was performed on May 25, 2023, to encompass recent studies. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS). Our primary outcome measures were expressed as adjusted odds ratios (ORs). Given various control measures for IPI and diverse IPI thresholds in the included studies, a Bayesian network meta-analysis was performed. Eight studies were included, involving 24,865 children with ASD and 2,890,289 children without ASD. Compared to an IPI of 24 to 35 months, various IPIs were significantly associated with a higher risk of ASD (IPIs < 6 months: OR = 1.63, 95% CI 1.53-1.74, n = 5; IPIs of 6-11 months: OR = 1.50, 95% CI 1.42-1.59, n = 4; IPIs of 12-23 months: OR = 1.19, 95% CI 1.12-1.23, n = 10; IPIs of 36-59 months: OR = 0.96, 95% CI 0.94-0.99, n = 2; IPIs of 60-119 months: OR = 1.15, 95% CI 1.10-1.20, n = 4; IPIs > 120 months: OR = 1.57, 95% CI 1.43-1.72, n = 4). After adjusting confounding variables, our analysis delineated a U-shaped restricted cubic spline curve, underscoring that both substantially short (< 24 months) and excessively long IPIs (> 72 months) are significantly correlated with an increased risk of ASD.  Conclusion: Our analysis indicates that both shorter and longer IPIs might predispose children to a higher risk of ASD. Optimal childbearing health and neurodevelopmental outcomes appear to be associated with a moderate IPI, specifically between 36 and 60 months. What is Known: • An association between autism spectrum disorder (ASD) and interpregnancy intervals (IPIs) has been speculated in some reports. • This association remains debatable due to inconsistent findings in available studies. What is New: • Our study delineated a U-shaped restricted cubic spline curve, suggesting that both shorter and longer IPIs predispose children to a higher risk of ASD. • Optimal childbearing health and neurodevelopmental outcomes appear to be associated with a moderate IPI, specifically between 36 and 60 months., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Autism Spectrum Disorder (ASD) belongs to the group of neurodevelopmental disorders, and has a high prevalence, affecting 1 in 100 children according to data from the World Health Organization (WHO). To be diagnosed with ASD, the child must have persistent deficits in communication and social interactions, and restricted and repetitive patterns of behavior, interests, or activities. Despite its prevalence, the etiology of ASD is still uncertain, with multifactorial characteristics, including those associated with the gestational period, where maternal exposure to biological, chemical, or physical hazards occurs, some of which have already been proposed as causes of ASD outcomes. Since pregnancy requires a balance between the maternal-fetal binomial, the breakdown of this balance caused by such environmental hazards can lead to altered fetal neurodevelopment, including ASD. With this firmly in mind, this review aims to compile the most recent data on the gestational causes that may be associated with the development of ASD to help health professionals identify risk factors and act for the prevention and management of ASD.

Autism spectrum disorder (ASD) is a neuropsychiatric condition characterized by impaired social interactions and repetitive stereotyped behaviors. Growing evidence highlights an important role of the gut-brain-microbiome axis in the pathogenesis of ASD. Research indicates an abnormal composition of the gut microbiome and the potential involvement of bacterial molecules in neuroinflammation and brain development disruptions. Concurrently, attention is directed towards the role of short-chain fatty acids (SCFAs) and impaired intestinal tightness. This comprehensive review emphasizes the potential impact of maternal gut microbiota changes on the development of autism in children, especially considering maternal immune activation (MIA). The following paper evaluates the impact of the birth route on the colonization of the child with bacteria in the first weeks of life. Furthermore, it explores the role of pro-inflammatory cytokines, such as IL-6 and IL-17a and mother's obesity as potentially environmental factors of ASD. The purpose of this review is to advance our understanding of ASD pathogenesis, while also searching for the positive implications of the latest therapies, such as probiotics, prebiotics or fecal microbiota transplantation, targeting the gut microbiota and reducing inflammation. This review aims to provide valuable insights that could instruct future studies and treatments for individuals affected by ASD.

To determine whether health status during pregnancy is associated with autism spectrum disorder (ASD) and abnormal head circumference (HC) in the offspring. This study included 41 Han children with ASD who visited the Children's Health Clinic of the Second Hospital of Shandong University between March 2018 and February 2019, and 264 Han children with typical development (TD) who visited the clinic during the same period. Physical measurements were performed on the children. The questionnaire obtained information on maternal risk factors that may be related to the increased risk of ASD and folic acid (FA) supplementation. We designed an observational case-control study using propensity score matching and multivariate logistic regression analysis. The incidence of macrocephaly in the ASD group was 22.0%, significantly higher than that in the TD group (1.8%). The incidence of microcephaly in the ASD group was 17.1% (n = 7), significantly higher than that in the TD group (1.8%). The differences between the comparisons were statistically significant. Maternal FA supplementation during pregnancy was significantly associated with ASD (P < .05), with an odds ratio (95% confidence interval of 3.69 (1.76, 7.76)). Also was associated with macrocephaly (P < .05), odds ratio (95% confidence interval) were 8.13 (1.63, 40.61) and 4.16 (1.18, 14.60), respectively. The incidence of abnormal HC was higher in the ASD group than that in the TD group. Maternal FA supplementation during pregnancy may be negatively associated with the occurrence of ASD and abnormal HC in the offspring. Further examination of the role of maternal health status in the etiology of ASD is recommended., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Autism spectrum disorder (ASD) represents an inheritable neurodevelopmental condition characterized by social communication deficits and repetitive behaviors. Numerous studies have underscored the significant roles played by genetic and environmental factors in the etiology of ASD, and these factors are known to perpetuate behavioral impairments across generations., Objectives: The primary objective of this study was to assess the behavioral and cognitive attributes in the second filial (F2) generation of male and female rats, with a particular focus on those whose parents had been exposed to valproic acid (VPA) during embryonic development., Methods: In this study, a cohort of 32 male and 32 female rats from the second filial (F2) generation, referred to as Mother.ASD, Father.ASD, or Both.ASD, was examined. These designations indicate whether the mother, father, or both parents had experienced embryonic exposure to valproic acid (600 mg/kg, i.p.). During adolescence, the F2 pups underwent behavioral and cognitive assessments, including open field testing, marble burying, social interaction evaluations, and Morris water maze tasks., Results: Our data revealed that while both the Mother.ASD and Father.ASD groups, regardless of sex, exhibited elevated anxiety-like behavior in the open field test. Only the Mother.ASD group displayed repetitive behaviors and deficits in social memory. Additionally, spatial memory impairments were observed in both sexes. These findings highlight the transmission of autistic-like behaviors in the offspring of Mother.ASD rats from both sexes. Nevertheless, future research endeavors should be more targeted in identifying the specific genes responsible for this transmission., Conclusion: In summary, our findings underscore the transmission of autistic-like behaviors, including anxiety-like behavior, repetitive actions, impairments in social interactions, and deficits in memory, to the offspring of the Mother.ASD group, irrespective of their sex., (© 2024 Wiley Periodicals LLC.)

Purpose: This study was conducted to investigate the relationship between cesarean section (CS) offspring and autism spectrum disorders (ASD)/attention deficit hyperactivity disorder (ADHD)., Methods: Searching of the databases (PubMed, Web of Science, Embase, and Cochrane Library) for studies on the relationship between mode of delivery and ASD/ADHD until August 2022. The primary outcome was the incidence of ASD/ADHD in the offspring., Results: This meta-analysis included 35 studies (12 cohort studies and 23 case-control studies). Statistical results showed a higher risk of ASD (odds ratio (OR) = 1.25, P < 0.001) and ADHD (OR = 1.11, P < 0.001) in CS offspring compared to the VD group. Partial subgroup analysis showed no difference in ASD risk between CS and VD offspring in sibling-matched groups (OR = 0.98, P = 0.625). The risk of ASD was higher in females (OR = 1.66, P = 0.003) than in males (OR = 1.17, P = 0.004) in the CS offspring compared with the VD group. There was no difference in the risk of ASD between CS under regional anesthesia group and VD group (OR = 1.07, P = 0.173). However, the risk of ASD was higher in the CS offspring under general anesthesia than in the VD offspring (OR = 1.62, P < 0.001). CS offspring developed autism (OR = 1.38, P = 0.011) and pervasive developmental disorder-not otherwise specified (OR = 1.46, P = 0.004) had a higher risk than VD offspring, but there was no difference in Asperger syndrome (OR = 1.19, P = 0.115). Offspring born via CS had a higher incidence of ADHD in different subgroup analyses (sibling-matched, type of CS, and study design)., Conclusions: In this meta-analysis, CS was a risk factor for ASD/ADHD in offspring compared with VD., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The aim of this study was to investigate the association between maternal and paternal licit and illicit drug use, smoking and drinking and autism spectrum disorder (ASD). We conducted a case-control study with children and adolescents diagnosed with ASD and neurotypical individuals. The data were collected using a semi-structured questionnaire administered during interviews with the children's mothers or guardians. The following variables were analyzed: child sex and age; maternal and parental age; use of medicines before and during pregnancy; classes of medicines used during pregnancy; maternal and paternal smoking; maternal and paternal drinking; maternal and paternal illicit drug use. The data were analyzed using logistic regression and crude and adjusted odds ratios (OR). After adjustment, the results showed an association between maternal use of antipyretics/pain killers during pregnancy (OR = 2.26; 95%CI 1.29-3.95; p < 0.040) and ASD. No association was found between maternal and paternal smoking, drinking and illicit drug use before and during pregnancy and ASD. The findings suggest that the development of ASD is influenced by environmental factors.

Purpose of Review: This review examines the most common circadian rhythm disorder in adolescents, delayed sleep phase disorder. It explores the etiology, prevalence, clinical features, diagnostic tools and criteria, and treatment options to identify sleep disorders early in the course. This is important to help improve youths in terms of education and quality of life., Recent Findings: Recent studies indicate that delayed sleep wake phase disorder has a range of prevalence between 1% and 16%. It is often associated with neurodevelopmental disorders (i.e. attention deficit hyperactivity disorder and autism spectrum disorder) as well as psychopathology (i.e. substance use, anxiety, and depression). It can present with a myriad of symptoms, such as insomnia, restless sleep, and poor daytime cognitive function, often seen in pediatric practice. Important diagnostic measures incorporate history-taking, sleep logs, actigraphy (i.e. Apple watches) and measurement of dim light melatonin onset. Treatments include improved sleep hygiene, chronotherapy, exogenous melatonin administration, and bright light therapy., Summary: There are many environmental and genetic factors that can predispose an individual to circadian rhythm disorders. Delayed sleep phase disorder has detrimental effects on overall health, cognition, and behavior. It is important to screen for this disorder in routine pediatric clinic visits. The goal of early intervention is to prevent health and behavioral complications and treat adolescents using a multimodal approach, especially those with affective/neurodevelopmental conditions, who are prone to having delayed sleep wake phase disorder., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition with unknown etiology. Both genetic and environmental factors have been associated with ASD. Environmental exposures during the prenatal period may play an important role in ASD development. This narrative review critically examines the evidence for a relationship between maternal thyroid dysfunction during pregnancy and ASD in the child. Summary: Studies that assessed the associations of hypothyroidism, hyperthyroidism, hypothyroxinemia, thyroid hormone concentrations, or autoimmune thyroid disease with ASD outcomes were included. Most research focused on the relationship between hypothyroidism and ASD. Multiple population-based studies found that maternal hypothyroidism was associated with higher likelihood of an ASD diagnosis in offspring. Associations with other forms of maternal thyroid dysfunction were less consistent. Findings may have been affected by misclassification bias, survival bias, or publication bias. Studies using medical records may have misclassified subclinical thyroid dysfunction as euthyroidism. Two studies that assessed children at early ages may have misclassified those with ASD as typically developing. Most studies adjusted for maternal body mass index (BMI) and/or mental illness, but not interpregnancy interval or pesticide exposure, all factors associated with fetal survival and ASD. Most studies reported a combination of null and statistically significant findings, although publication bias is still possible. Conclusions: Overall, evidence supported a positive association between maternal thyroid dysfunction during pregnancy and ASD outcomes in the child, especially for hypothyroidism. Future studies could reduce misclassification bias by using laboratory measures instead of medical records to ascertain thyroid dysfunction and evaluating children for ASD at an age when it can be reliably detected. Survival bias could be further mitigated by adjusting models for more factors associated with fetal survival and ASD. Additional research is needed to comprehensively understand the roles of maternal levothyroxine treatment, iodine deficiency, or exposure to thyroid-disrupting compounds in the relationship between maternal thyroid dysfunction and child ASD outcomes.

Background: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are neurodevelopmental conditions with early life origins. Alterations in blood lipids have been linked to ADHD and ASD; however, prospective early life data are limited. This study examined (i) associations between the cord blood lipidome and ADHD/ASD symptoms at 2 years of age, (ii) associations between prenatal and perinatal predictors of ADHD/ASD symptoms and cord blood lipidome, and (iii) mediation by the cord blood lipidome., Methods: From the Barwon Infant Study cohort (1074 mother-child pairs, 52.3% male children), child circulating lipid levels at birth were analysed using ultra-high-performance liquid chromatography-tandem mass spectrometry. These were clustered into lipid network modules via Weighted Gene Correlation Network Analysis. Associations between lipid modules and ADHD/ASD symptoms at 2 years, assessed with the Child Behavior Checklist, were explored via linear regression analyses. Mediation analysis identified indirect effects of prenatal and perinatal risk factors on ADHD/ASD symptoms through lipid modules., Findings: The acylcarnitine lipid module is associated with both ADHD and ASD symptoms at 2 years of age. Risk factors of these outcomes such as low income, Apgar score, and maternal inflammation were partly mediated by higher birth acylcarnitine levels. Other cord blood lipid profiles were also associated with ADHD and ASD symptoms., Interpretation: This study highlights that elevated cord blood birth acylcarnitine levels, either directly or as a possible marker of disrupted cell energy metabolism, are on the causal pathway of prenatal and perinatal risk factors for ADHD and ASD symptoms in early life., Funding: The foundational work and infrastructure for the BIS was sponsored by the Murdoch Children's Research Institute, Deakin University, and Barwon Health. Subsequent funding was secured from the Minderoo Foundation, the European Union's Horizon 2020 research and innovation programme (ENDpoiNTs: No 825759), National Health and Medical Research Council of Australia (NHMRC) and Agency for Science, Technology and Research Singapore [APP1149047], The William and Vera Ellen Houston Memorial Trust Fund (via HOMER Hack), The Shepherd Foundation, The Jack Brockhoff Foundation, the Scobie & Claire McKinnon Trust, the Shane O'Brien Memorial Asthma Foundation, the Our Women Our Children's Fund Raising Committee Barwon Health, the Rotary Club of Geelong, the Ilhan Food Allergy Foundation, Geelong Medical and Hospital Benefits Association, Vanguard Investments Australia Ltd, the Percy Baxter Charitable Trust, and Perpetual Trustees., Competing Interests: Declaration of interests 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.)

Objective: To investigate the relationship between maternal folic acid (FA) supplementation during the pre-conceptional and prenatal periods and the subsequent risk of autism spectrum disorder (ASD) in offspring., Methods: A total of 6,049 toddlers aged 16-30 months were recruited from August 2016 to March 2017 for this cross-sectional study conducted in China. The parents of the enrolled toddlers provided information on maternal supplemental FA, socio-demographic information, and related covariates. Standard diagnostic procedures were implemented to identify toddlers with ASD., Results: Among the 6,049 children included in the study, consisting of 3,364 boys with an average age of 22.7 ± 4.1 months, a total of 71 children (1.2%) were diagnosed with ASD. Mothers who did not consume FA supplements during the prenatal period were found to have a significantly increased risk of having offspring with ASD, in comparison to those who were exposed to FA supplements (odds ratio [ OR ] = 2.47). However, we did not find a similar association during the pre-conceptional period. Compared to mothers who consistently used FA supplements from pre-conception to the prenatal period, those who never used FA supplements were statistically significantly associated with a higher risk of ASD in their offspring ( OR  = 2.88)., Conclusion: This study indicated that providing continuous maternal FA supplementation during the pre-conceptional and prenatal periods may decrease the risk of ASD in offspring. The prenatal period is considered to be the most crucial time for intervention., 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 Jiang, Guo, Kuang, Lin, Xu, Pan, Weng, Jing, Shi, Yi and Wang.)

The utilization of assisted reproductive technologies (ART) is on the rise, resulting in a growing population of ART-conceived offspring. The health concerns of this unique population have attracted significant attention. During ART procedures, gametes and early-stage embryos are exposed to various non-physiological conditions, such as manipulation, culture media, and cryopreservation, which may disrupt embryonic development and potentially impact the health of offspring. Notably, the potential impact of ART on neurodevelopment and its association with an increased risk of neurodevelopmental disorders (NDD) later in life remains a subject of debate. This review aims to summarize the current research advancements concerning the effects of ART on neurodevelopment, specifically focusing on the evidence of the relationship between ART, epigenetic modifications, and NDD, including autism spectrum disorder, intellectual disability, attention deficit hyperactivity disorder, and cerebral palsy. Future studies should prioritize large sample sizes, rigorous adjustment for confounding factors, and the use of interdisciplinary approaches to effectively monitor the neurodevelopmental outcomes of ART-conceived children., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Autism spectrum disorders (ASD) are highly heritable, heterogeneous neurodevelopmental disorders characterized by clinical presentation of atypical social, communicative, and repetitive behaviors. Over the past 25 years, hundreds of ASD risk genes have been identified. Many converge on key molecular pathways, from translational control to those regulating synaptic structure and function. Despite these advances, therapeutic approaches remain elusive. Emerging data unearthing the relationship between genetics, microbes, and immunity in ASD suggest an integrative physiology approach could be paramount to delivering therapeutic breakthroughs. Indeed, the advent of large-scale multi-OMIC data acquisition, analysis, and interpretation is yielding an increasingly mechanistic understanding of ASD and underlying risk factors, revealing how genetic susceptibility interacts with microbial genetics, metabolism, epigenetic (re)programming, and immunity to influence neurodevelopment and behavioral outcomes. It is now possible to foresee exciting advancements in the treatment of some forms of ASD that could markedly improve quality of life and productivity for autistic individuals. Here, we highlight recent work revealing how gene X maternal exposome interactions influence risk for ASD, with emphasis on the intrauterine environment and fetal neurodevelopment, host-microbe interactions, and the evolving therapeutic landscape for ASD.

Existing evidence indicates that environmental factors might contribute up to 50% of the variance in autism spectrum disorder (ASD) risk. This structured narrative review offers a comprehensive synthesis of current knowledge on environmental risk factors in ASD, including evaluation of conflicting evidence, exploration of underlying mechanisms, and suggestions for future research directions. Analysis of diverse epidemiological investigations indicates that certain environmental factors, including advanced parental age, preterm birth, delivery complications, and exposure to toxic metals, drugs, air pollutants, and endocrine-disrupting chemicals, are linked to an increased ASD risk through various mechanisms such as oxidative stress, inflammation, hypoxia, and its consequences, changes in neurotransmitters, disruption of signaling pathways and some others. On the other hand, pregnancy-related factors such as maternal diabetes, maternal obesity, and caesarian section show a weaker association with ASD risk. At the same time, other environmental factors, such as vaccination, maternal smoking, or alcohol consumption, are not linked to the risk of ASD. Regarding nutritional elements data are inconclusive. These findings highlight the significance of environmental factors in ASD etiology and emphasize that more focused research is needed to target the risk factors of ASD. Environmental interventions targeting modifiable risk factors might offer promising avenues for ASD prevention and treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Multiple risk factors have been associated with the development of atopic dermatitis (AD). Recent advances in understanding the role of genetics in this disease have been made, with discovery of the filaggrin (FLG) gene as the most notable so far. In addition to FLG gene mutations as a risk factor for AD, a positive family history of atopic or allergic disease in either parent has been shown to confer a greater risk of developing AD. Atopic dermatitis usually presents early in life and is thought to represent the initial step in the "atopic march," which is characterized by the development of other atopic diseases later in life such as asthma, allergic rhinitis, and/or rhinoconjunctivitis, food allergies, and hay fever. Other comorbid diseases that have been associated with AD include increase risk of viral and bacterial skin infections, neuropsychiatric diseases such as attention-deficit hyperactivity disorders (ADHD), and autistic spectrum disorder (ASD). Patients with AD have also been found to have worse sleep quality overall compared to patients without AD. In this chapter, we will discuss the risk factors associated with development of atopic dermatitis as well as the most commonly reported comorbidities in patients with this disease., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)