Risk Factors For Autism Spectrum Disorder Research Articles

Relationship of Nonsteroidal Anti-Inflammatory Drug Use During Pregnancy with Autism Spectrum Disorder and Intellectual Disability Among Offspring.

Objective: This study aimed to examine the association of nonsteroidal anti-inflammatory drug (NSAID) use by pregnant women during pregnancy with autism spectrum disorder (ASD) and intellectual disability (ID) in their children among Medicaid-insured mother-child dyads. Materials and Methods: We conducted a retrospective cohort study linking multiple datasets of South Carolina for the years between 2010 and 2017, in which the main exposure variable was NSAID use during pregnancy and outcome variables were ASD only, ID only, and ASD with ID. We conducted a multinomial logistic regression analysis, controlling for identified risk factors for ASD (mother's age, race, body-mass index, preeclampsia, and gestational diabetes). Results: NSAID use during pregnancy was found to be associated with ID only in both unadjusted and adjusted analyses. Children with mothers who had NSAID prescriptions were 26% more likely to have ID in comparison with children whose mothers did not have NSAID prescriptions (odds ratio: 1.26 [1.10-1.46]). The other risk factors identified for ASD were maternal age, race, preeclampsia, smoking, low birth weight, and obesity. For ID, the risk factors were maternal age, race, smoking, birth weight, overweight, and obesity, all of which were also associated with ASD with ID, except for overweight. Conclusions: NSAID usage during pregnancy was found to be associated with ID only and not with ASD. However, more research is needed to validate the effect of NSAIDs during pregnancy on ASD and ID among children.

Epidemiology of autism spectrum disorders: Global burden of disease 2019 and bibliometric analysis of risk factors.

To explore the geographical pattern and temporal trend of autism spectrum disorders (ASD) epidemiology from 1990 to 2019, and perform a bibliometric analysis of risk factors for ASD. In this study, ASD epidemiology was estimated with prevalence, incidence, and disability-adjusted life-years (DALYs) of 204 countries and territories by sex, location, and sociodemographic index (SDI). Age-standardized rate (ASR) and estimated annual percentage change (EAPC) were used to quantify ASD temporal trends. Besides, the study performed a bibliometric analysis of ASD risk factors since 1990. Publications published were downloaded from the Web of Science Core Collection database, and were analyzed using CiteSpace. Globally, there were estimated 28.3 million ASD prevalent cases (ASR, 369.4 per 100,000 populations), 603,790 incident cases (ASR, 9.3 per 100,000 populations) and 4.3 million DALYs (ASR, 56.3 per 100,000 populations) in 2019. Increases of autism spectrum disorders were noted in prevalent cases (39.3%), incidence (0.1%), and DALYs (38.7%) from 1990 to 2019. Age-standardized rates and EAPC showed stable trend worldwide over time. A total of 3,991 articles were retrieved from Web of Science, of which 3,590 were obtained for analysis after removing duplicate literatures. "Rehabilitation", "Genetics & Heredity", "Nanoscience & Nanotechnology", "Biochemistry & Molecular biology", "Psychology", "Neurosciences", and "Environmental Sciences" were the hotspots and frontier disciplines of ASD risk factors. Disease burden and risk factors of autism spectrum disorders remain global public health challenge since 1990 according to the GBD epidemiological estimates and bibliometric analysis. The findings help policy makers formulate public health policies concerning prevention targeted for risk factors, early diagnosis and life-long healthcare service of ASD. Increasing knowledge concerning the public awareness of risk factors is also warranted to address global ASD problem.

Inductively coupled plasma mass spectrometry based urine metallome to construct clinical decision models for autism spectrum disorder.

The global prevalence of autism spectrum disorder (ASD) is on the rise, and high levels of exposure to toxic heavy metals may be associated with this increase. Urine analysis is a noninvasive method for investigating the accumulation and excretion of heavy metals. The aim of this study was to identify ASD-associated urinary metal markers. Overall, 70 children with ASD and 71 children with typical development (TD) were enrolled in this retrospective case-control study. In this metallomics investigation, inductively coupled plasma mass spectrometry was performed to obtain the urine profile of 27 metals. Children with ASD could be distinguished from children with TD based on the urine metal profile, with ASD children showing an increased urine metal Shannon diversity. A metallome-wide association analysis was used to identify seven ASD-related metals in urine, with cobalt, aluminum, selenium, and lithium significantly higher, and manganese, mercury, and titanium significantly lower in the urine of children with ASD than in children with TD. The least absolute shrinkage and selection operator (LASSO) machine learning method was used to rank the seven urine metals in terms of their effect on ASD. On the basis of these seven urine metals, we constructed a LASSO regression model for ASD classification and found an area under the receiver operating characteristic curve of 0.913. We also constructed a clinical prediction model for ASD based on the seven metals that were different in the urine of children with ASD and found that the model would be useful for the clinical prediction of ASD risk. The study findings suggest that altered urine metal concentrations may be an important risk factor for ASD, and we recommend further exploration of the mechanisms and clinical treatment measures for such alterations.

Folate in maternal rheumatoid arthritis-filial autism spectrum disorder continuum

Rheumatoid Arthritis (RA) is an inflammatory autoimmune disease that affects women three times more than men. Epidemiological studies found that the incidence of Autism Spectrum Disorder (ASD), a neurological and developmental disorder, in children born to mothers suffering from RA is higher compared with the control population. Considering that the pathogenesis of ASD could be traced back to pregnancy and in uterine conditions, and the evidence of reduced folate levels in the brain of ASD-affected children, we aimed to study the role of folate, as an important nutritional factor during pregnancy, in associating maternal RA to ASD development in the offspring. Folate balance during RA could be influenced twice, initially during the immune activation associated with disease onset, and later during the treatment with anti-folate drugs, with a potential consequence of folate deficiency. Maternal folate deficiency during pregnancy could increase homocysteine levels, oxidative stress, and global DNA hypomethylation, all known risk factors in ASD pathogenesis. These effects could be intensified by genetic polymorphisms in the folate system, which were also found as genetic risk factors for both RA and ASD. The available evidence suggests that folate level as an important factor during RA, pregnancy and ASD could have pathological and therapeutical significance and should be carefully monitored and investigated in the RA-pregnancy-ASD axis.

Autism Spectrum Disorder Comorbid with Gilles De La Tourette Syndrome in a Child of in Vitro Fertilization: About A Case and A Review of the Literature

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder characterized by persistent impairment in reciprocal communication and social interactions and a restricted repetitive pattern of behaviors, interests, or activities. Tourette syndrome (TS) is a neurological disorder with a genetic component characterized by involuntary, sudden, brief and intermittent tics, resulting in movements (motor tics) or vocalizations (sound tics). Although a differential diagnosis of the two conditions can often be made, there are also cases of comorbidity in the same patient. Recently, a number of studies have attempted to explore modifiable environmental risk factors for ASD and TS. Among these risk factors is in vitro fertilization, an assisted reproduction technique, which has become increasingly common. The aim of our work is to highlight via a clinical case and a review of the literature on the association between the use of in vitro fertilization, the risk of autism spectrum disorder and Tourette syndrome. Compared to spontaneous conception, in vitro fertilization treatment as a whole was associated with a small but statistically significantly increased risk of autism spectrum disorder and Tourette syndrome.

Association between history of miscarriage and autism spectrum disorder.

This case-control study was designed to examine the association between different types of miscarriage history and autism spectrum disorder (ASD), and determine whether the number of miscarriage history affects the risk of ASD. All of 2274 children with ASD and 1086 healthy controls were recruited. Sociodemographic and prenatal, perinatal, and neonatal characteristics were compared between the two groups. Multivariable logistic regression analyses were applied to investigate association between miscarriage history and ASD. Stratified analyses based on sex and types of miscarriages were similarly performed. History of miscarriage was potential risk factors for ASD ([aOR] = 2.919; 95% [CI] = 2.327-3.517). Stratified analyses revealed that induced ([aOR] = 2.763, 95% [CI] = 2.259-3.379) and spontaneous miscarriage history ([aOR] = 3.341, 95% [CI] = 1.939-4.820) were associated with high risk of ASD, respectively. A sex-biased ratio in the risk of ASD was observed between females ([aOR] = 3.049, 95% [CI] = 2.153-4.137) and males ([aOR] = 2.538, 95% [CI] = 1.978-3.251). Stratified analysis of induced miscarriage history revealed that only iatrogenic miscarriage history was associated with an increased risk ASD ([aOR] = 2.843, 95% [CI] = 1.534-4.268). Also, multiple spontaneous miscarriage histories ([aOR] = 1.836, 95% [CI] = 1.252-2.693) were associated with higher autism risk than one spontaneous miscarriages history ([aOR] = 3.016, 95% [CI] = 1.894-4.174). In conclusion, miscarriage history is related to an increased risk for ASD in offspring, which is affected by the types of miscarriage and sex of the fetus.

Common genetic risk factors in ASD and ADHD co-occurring families.

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are two major neurodevelopmental disorders that frequently co-occur. However, the genetic mechanism of the co-occurrence remains unclear. The New Jersey Language and Autism Genetics Study (NJLAGS) collected more than 100 families with at least one member affected by ASD. NJLAGS families show a high prevalence of ADHD and provide a good opportunity to study shared genetic risk factors for ASD and ADHD. The linkage study of the NJLAGS families revealed regions on chromosomes 12 and 17 that are significantly associated with ADHD. Using whole-genome sequencing data on 272 samples from 73 NJLAGS families, we identified potential risk genes for ASD and ADHD. Within the linkage regions, we identified 36 genes that are associated with ADHD using a pedigree-based gene prioritization approach. KDM6B (Lysine Demethylase 6B) is the highest-ranking gene, which is a known risk gene for neurodevelopmental disorders, including ASD and ADHD. At the whole-genome level, we identified 207 candidate genes from the analysis of both small variants and structure variants, including both known and novel genes. Using enrichment and protein-protein interaction network analyses, we identified gene ontology terms and pathways enriched for ASD and ADHD candidate genes, such as cilia function and cation channel activity. Candidate genes and pathways identified in our study improve the understanding of the genetic etiology of ASD and ADHD and will lead to new diagnostic or therapeutic interventions for ASD and ADHD in the future.

Maternal immune activation induces autism-like changes in behavior, neuroinflammatory profile and gut microbiota in mouse offspring of both sexes

Autism Spectrum Disorder (ASD) is a sex-biased neurodevelopmental disorder with a male to female prevalence of 4:1, characterized by persistent deficits in social communication and interaction and restricted-repetitive patterns of behavior, interests or activities. Microbiota alterations as well as signs of neuroinflammation have been also reported in ASD. The involvement of immune dysregulation in ASD is further supported by evidence suggesting that maternal immune activation (MIA), especially during early pregnancy, may be a risk factor for ASD. The present study was aimed at characterizing the effects of MIA on behavior, gut microbiota and neuroinflammation in the mouse offspring also considering the impact of MIA in the two sexes. MIA offspring exhibited significant ASD-like behavioral alterations (i.e., deficits in sociability and sensorimotor gating, perseverative behaviors). The analysis of microbiota revealed changes in specific microbial taxa that recapitulated those seen in ASD children. In addition, molecular analyses indicated sex-related differences in the neuroinflammatory responses triggered by MIA, with a more prominent effect in the cerebellum. Our data suggest that both sexes should be included in the experimental designs of preclinical studies in order to identify those mechanisms that confer different vulnerability to ASD to males and females.

The association between prenatal greenspace exposure and Autism spectrum disorder, and the potentially mediating role of air pollution reduction: A population-based birth cohort study.

Autism spectrum disorder (ASD) incidence has increased in past decades. ASD etiology remains inconclusive, but research suggests genetic, epigenetic, and environmental contributing factors and likely prenatal origins. Few studies have examined modifiable environmental risk factors for ASD, and far fewer have examined protective exposures. Greenspace has been associated with positive child development, but very limited greenspace research has examined ASD risk or prenatal exposures. Only one ecological study in 2017 has evaluated the association between greenspace and ASD, observing protective benefits. Greenspace may have direct effects on ASD risk and indirect effects by reducing air pollution exposure, a growing suspected ASD risk factor. To measure the association between prenatal greenspace exposure and ASD risk and examine if reduced air pollution levels in areas of higher greenspace mediate this association. We linked a population-based birth cohort of all deliveries in Metro Vancouver, Canada, from 2004 to 2009, with follow-up to 2014. Diagnoses were based on Autism Diagnostic Observation Schedule and Autism Diagnostic Interview-Revised instruments. Greenspace was quantified as the average of the annual mean Normalized Difference Vegetation Index (NDVI) within a 250m buffer of a residential postal code. Air pollutant exposures-particulate matter with a diameter less than 2.5µm (PM2.5), nitric oxide (NO), and nitrogen dioxide (NO2)-were derived from previously developed and temporally adjusted land use regression models. We estimated air pollutant exposures as the mean concentration per month during pregnancy. We calculated odds ratios (ORs) using logistic regression per NDVI interquartile range (IQR) increase, adjusting for child sex, birth month and year, maternal age and birthplace, and neighborhood-level urbanicity and income. To estimate the health impact of greenspace on ASD at the population level, we used the logistic regression model and marginal standardization to derive risk differences (RDs). Lastly, to quantify the mediating effect of greenspace on ASD risk through air pollution reduction, we used marginal structural models and a potential outcomes framework to calculate marginal risk differences (RDs) to decompose the total effect of greenspace on ASD into natural direct and indirect effects. Of 129,222 births, 1,921 (1.5%) children were diagnosed with ASD. The adjusted OR for ASD per NDVI IQR (0.12) increase was 0.96 (95% CI: 0.90, 1.02) in 250m buffer zones and 0.94 (95% CI: 0.89, 1.00) in 100m buffer zones. On the additive scale, the adjusted RDs were null. Natural direct, natural indirect, and total effect RDs were null for PM2.5, NO, and NO2 mediation models. Prenatal greenspace exposure was associated with reduced odds of ASD, but in the additive scale, this effect was null at the population level. No mediating effect was observed through reduced air pollution, suggesting that air pollution may act as a confounder rather than as a mediator.

GARBHOPAGHATAKARA BHAVA, PRECONCEPTIONAL RISK FACTORS FOR AUTISM: A CROSS-SECTIONAL SURVEY

Background: Garbhopaghatakara bhava, inclusive of altered maternal habits, diet, behaviours, and exposures in the perinatal period disrupt normal growth and development of the foetus. Autism spectrum disorders (ASD) are characterized by impaired social behaviour and communication skills. Many risk factors for ASD are identified but with no generalization of definite aetiology. Psychosocial anomalies in Ayurveda have been explained under the spectrum of unmada. Such diseases are said to present early in life and persist throughout the lifespan when associated with garbhopaghatakara bhava. This study explores the association of garbhopaghatakara bhava with the etiopathogenesis of ASD. Materials and Methods: Parents of 50 children who have ASD enquired about garbhopaghatakara bhava using a structured survey format. Results: Male preponderance (80%) with middle socio-economic strata (62%) predominated the study population. 48% had delayed speech and communication with poor eye contact, and 24% with delay in gross motor milestones. Garbhopaghatakara bhava leading to ashaya dushti (structural and functional variation in uterine milieu) were secondary to abortions (22%), hypothyroidism (10%), advanced parental age (64%), diabetes mellitus (8%). Amongst diet and activities in the mother, madhura- katu rasa (22%), eating less (28%), frequent meals (28%), day sleep (42%), night wakening (54%), excess travel (18%) and withhold of urges (16%) were seen. The genetic risk was sporadic (14%). Discussion: Garbhopaghatakara bhava can act by changing the epigenetics or disturbing the nutrition, psyche, and intellectual faculties in the child. Conclusion: Baseline information about the association of garbhopaghatakara bhava with ASD was identified. However, further analytical studies can provide substantial information and evidence.

Not breastfeeding and risk of autism spectrum disorders among children: a meta-analysis.

To our knowledge, this is the first meta-analysis of the association of not breastfeeding and the risk of autism spectrum disorder (ASD) based on observational studies. This meta-analysis aimed to evaluate of the association of not breastfeeding and the risk of ASD. Three databases (PubMed, Web of Science, and Scopus) were systematically searched until December 2021. Heterogeneity was determined using the chi-square test and its quantity was measured using the I2 statistic. The Begg line regression test was used to assess publication bias. A random-effects model was used to analyze the data. Seven studies were included in this meta-analysis. The total study population included 3,270 individuals. According to the random-effects model, the estimated odds ratio of the risk of ASD associated with not breastfeeding was 1.81 (95% confidence interval, 1.35-2.27; I2=0%). The results of the included studies were homogeneous. Our findings showed that not breastfeeding is a risk factor for ASD. These results suggest the importance of breastfeeding in decreasing the risk of ASD in children.

The Role of Genetics, Epigenetics, and the Environment in ASD: A Mini Review.

According to recent findings, variances in autism spectrum disorder (ASD) risk factors might be determined by several factors, including molecular genetic variants. Accumulated evidence has also revealed the important role of biological and chemical pathways in ASD aetiology. In this paper, we assess several reviews with regard to their quality of evidence and provide a brief outline of the presumed mechanisms of the genetic, epigenetic, and environmental risk factors of ASD. We also review some of the critical literature, which supports the basis of each factor in the underlying and specific risk patterns of ASD. Finally, we consider some of the implications of recent research regarding potential molecular targets for future investigations.

Maternal and neonatal risk factors for autism spectrum disorder: A case-control study from Egypt.

BackgroundThe prevalence of autism spectrum disorder (ASD) has been increasing steadily in Egypt and worldwide. Detecting risk factors for ASD could help initiate screening and risk prevention approaches. Herein, this study aimed to detect several maternal and neonatal risk factors for ASD in Egypt.MethodsIn this case-control study, mothers of children with ASD who were visiting Beni-Suef University Hospital in Egypt (n = 268) were compared to mothers of children without ASD attending one primary school with a kindergarten (n = 504) regarding their preconception, conception, and postconception characteristics. Data were collected using a self-administered questionnaire. The odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to investigate the possible associations between the collected data and the odds of ASD.ResultsIn the multivariable-adjusted models, urban residence: OR (95% CI) = 2.33 (1.60–3.38), relative father: 2.63 (1.74–3.96), history of diabetes: 5.98 (1.99–17.97), previous abortion: 2.47 (1.20–13.38), assisted fertility: 4.01 (1.20–13.38), family history of ASD: 7.24 (2.00–26.24), multiple pregnancy: 11.60 (2.54–53.07), exposure to passive smoking during pregnancy: 2.95 (1.86–4.68), vaginal bleeding during pregnancy: 3.10 (1.44–6.67), hypertension with pregnancy: 3.64 (1.06–12.51), preterm labor: 2.64 (1.26–5.57), neonatal convulsions: 14.88 (5.01–44.20), and admission to neonatal intensive care unit 2.13: (1.21–3.74) were associated with the increased odds of ASD. On the other hand, the intake of vitamins during pregnancy: 0.09 (0.06–0.16) and C-section: 0.44 (0.27–0.70) were associated with the decreased odds of ASD.ConclusionThis study detected several maternal and neonatal risk factors for ASD in Egyptian children.

Migration modulates the prevalence of ASD and ADHD: a systematic review and meta-analysis

BackgroundMigration has been implicated as a risk factor for autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), but evidence is still limited and inconsistent. We aim to investigate the relationship between migration status and risk of ASD and ADHD.MethodsElectronic databases including PubMed, EMBASE, Web of Science, and PsychINFO were searched to identify observational studies on this topic, from inception to February 2021. Random-effects meta-analysis models were used to pool the summary odds ratio (OR) and 95% confidence interval (95% CI), and subgroup analyses were conducted to detect possible discrepancies in associations. Certainty of evidence was assessed as per the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) guidelines.ResultsA total of 13 studies (6,532,546 participants) for ASD, five studies (2,875,070 participants) for ADHD, and six studies (31,158 participants) for hyperactivity were included. Overall, the pooled results indicated that migration was associated with increased risk of ASD (pooled OR: 1.32; 95% CI: 1.07–1.63; P for Z test = 0.010), but no association was found between migration and ADHD (pooled OR: 0.84; 95% CI: 0.53–1.32; P for Z test = 0.452) or hyperactivity (pooled standardized mean difference: -0.073; 95% CIs: − 0.383–0.236; P for Z test = 0.642). Subgroup analyses further demonstrated that maternal migration was ASD risk factor (pooled OR: 1.49; 95% CI: 1.19–1.87), and migrant children were more likely to develop ASD with comorbid intellectual disability (ID) (pooled OR: 1.21, P for interaction = 0.006) than ASD without ID. After standardized the origin of migrants, European migrant children from Americas were at higher risk of ASD and ADHD (pooled OR were 4.13 and 1.26), and increased ASD risk was also observed in African children (pooled OR: 2.72). The GRADE of evidence was very low.ConclusionsMaternal migration is a risk factor for ASD, and migrant ASD children are more likely comorbid ID. The role of migration on ADHD remains controversial, more studies are needed to assess the association between migration status and ADHD. Health care practitioners should consider screening and providing extra resources for migrant children.

MiR-92a-2-5p Regulates the Proliferation and Differentiation of ASD-Derived Neural Progenitor Cells

Autism spectrum disorder (ASD) is a group of complex neurodevelopmental disorders with abnormal behavior. However, the pathogenesis of ASD remains to be clarified. It has been demonstrated that miRNAs are essential regulators of ASD. However, it is still unclear how miR-92a-2-5p acts on the developing brain and the cell types directly. In this study, we used neural progenitor cells (NPCs) derived from ASD-hiPSCs as well as from neurotypical controls to examine the effects of miR-92a-2-5p on ASD-NPCs proliferation and neuronal differentiation, and whether miR-92a-2-5p could interact with genetic risk factor, DLG3 for ASD. We observed that miR-92a-2-5p upregulated in ASD-NPCs results in decreased proliferation and neuronal differentiation. Inhibition of miR-92a-2-5p could promote proliferation and neuronal differentiation of ASD-NPCs. DLG3 was negatively regulated by miR-92a-2-5p in NPCs. Our results suggest that miR-92a-2-5p is a strong risk factor for ASD and potentially contributes to neuropsychiatric disorders.

Risk factors for ASD : Risk Factors for Autism Spectrum Disorder in Shanghai, China: A Population-based Case-control Study.

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder that brings heavy burdens to families and the society. This case-control study explored risk factors for ASD based on 74,252 children aged 3-12 years who were recruited from general education kindergartens, primary schools, and special education schools in Shanghai, China. One hundred ninety-two children were identified with ASD according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition. Male sex, the presence of anoxia or asphyxia at birth, artificial feeding, adverse maternal psychological status, complications during pregnancy and higher paternal education were associated with ASD even after controlling for age, residential district, family history of mental disorders, parental personality, and amount of daily TV viewing.

Mutations in trpγ, the homologue of TRPC6 autism candidate gene, causes autism-like behavioral deficits in Drosophila

Autism Spectrum Disorder (ASD) is characterized by impaired social communication, restricted interests, and repetitive and stereotyped behaviors. The TRPC6 (transient receptor potential channel 6) represents an ASD candidate gene under an oligogenic/multifactorial model based on the initial description and cellular characterization of an individual with ASD bearing a de novo heterozygous mutation disrupting TRPC6, together with the enrichment of disruptive TRPC6 variants in ASD cases as compared to controls. Here, we perform a clinical re-evaluation of the initial non-verbal patient, and also present eight newly reported individuals ascertained for ASD and bearing predicted loss-of-function mutations in TRPC6. In order to understand the consequences of mutations in TRPC6 on nervous system function, we used the fruit fly, Drosophila melanogaster, to show that null mutations in transient receptor gamma (trpγ; the fly gene most similar to TRPC6), cause a number of behavioral defects that mirror features seen in ASD patients, including deficits in social interactions (based on courtship behavior), impaired sleep homeostasis (without affecting the circadian control of sleep), hyperactivity in both young and old flies, and defects in learning and memory. Some defects, most notably in sleep, differed in severity between males and females and became normal with age. Interestingly, hyperforin, a TRPC6 agonist and the primary active component of the St. John’s wort antidepressant, attenuated many of the deficits expressed by trpγ mutant flies. In summary, our results provide further evidence that the TRPC6 gene is a risk factor for ASD. In addition, they show that the behavioral defects caused by mutations in TRPC6 can be modeled in Drosophila, thereby establishing a paradigm to examine the impact of mutations in other candidate genes.

Manipulation of Igf‐1 Expression in the Placenta and Impact on the Fetal Brain

The placenta is an essential organ involved in mammalian development in utero. The main function of the placenta is the control of the transfer of nutrients and waste between mother and fetus, and production and delivery of hormones and growth factors. There is a lack of research that investigates the role of maternal and fetal genetics and molecular biology of the placenta’s impact on fetal neurodevelopment. Igf‐1 is a gene involved in mediating fetal development as well as growth of the brain. It is also involved in regulation of placental growth and transport. The placenta is the main source of fetal Igf‐1. Igf‐1 gene expression is altered in some individuals with autism spectrum disorder (ASD) which may reflect a role of Igf‐1 in ASD etiology. We previously found that prenatal stress, a risk factor for ASD, increased placental Igf‐1 expression and increased proliferation of striatal neural progenitors which express Igfreceptors. Developmental striatal changes are found in ASD. We therefore hypothesized that placental alterations in Igf‐1 lead to ASD‐relevant brain changes.MethodsWe examined this through the use of CRISPR Igf‐1 overexpression or control plasmids directly injected in mouse placenta on embryonic day 12, with subsequent tracking of changes in placenta, fetal body, and fetal brain. Igf‐1 overexpression in placenta had a variable trajectory. While placental weight was unaffected by Igf‐1 overexpression at E18, we found developmental and morphological changes of the embryo, including larger body and larger size and altered morphology of the head (macrocephaly) at E18. Brain volume measures demonstrate a range of effects on the primordial cortex and striatum at E14 and E18. One outcome of this work is advancements in methodology for understanding how placental genetics affect the development of the fetal brain. We also conclude that placental Igf‐1 expression does influence offspring growth and ASD‐relevant brain outcomes which suggests a role for placental genetics in neurodevelopmental disorders.

Prenatal exposure to organophosphate pesticides and autism spectrum disorders in 11-year-old children in the French PELAGIE cohort

BackgroundOrganophosphate (OP) pesticides act by inhibiting acetylcholinesterase activity at synaptic junctions and have already been linked with deleterious effects on neurodevelopment, including autism spectrum disorders (ASD). ObjectivesTo investigate the association of prenatal exposure to OP pesticides with traits related to ASD in 11-year-old children. MethodsThe “Childhood Autism Spectrum Test” (CAST) parent questionnaire was used to screen for autistic traits in 792 children from the French PELAGIE cohort. Prenatal maternal urine samples were collected <19 weeks of gestation in which metabolites of organophosphate insecticides were assessed for 185 of them. Negative binomial regression models were performed to explore the association between the CAST score and 8 groups of urine components, adjusted for potential ASD risk factors. ResultsIn these urine samples, dialkylphosphates (DAP) were detected most often (>80%), terbufos and its metabolites least often (<10%). No association with ASD was found for DAP, terbufos or its metabolites. Incidence rate ratios (IRRs) increased with maternal urinary diazinon concentrations, from 1.11 (95% CI: 0.87–1.42) to 1.17 (95% CI: 0.94–1.46). Higher CAST scores were statistically significantly associated with the maternal urine samples in which chlorpyrifos or two of its metabolites (chlorpyrifos-oxon and 3,5,6-trichloro-2-pyridinol) were detected. The IRR for exposure to chlorpyrifos or chlorpyrifos-oxon was 1.27 (95%CI: 1.05–1.52) among all children, and 1.39 (95%CI: 1.07–1.82) among boys. ConclusionThese findings suggest an increase in autistic traits among 11-year-old children in association with prenatal maternal exposure to chlorpyrifos and possibly diazinon. These associations were previously suspected in the literature, in particular for chlorpyrifos. Further work establishing the causal mechanisms behind these risk association is needed.

P144. Prenatal Cannabis Use and Offspring Autism-Related Behaviors: Examining Maternal Stress as a Moderator in a Black American Cohort

The prevalence of both autism spectrum disorder (ASD) and maternal cannabis use during pregnancy are increasing, yet few empirical studies have examined their potential association. Moreover, it is unclear whether maternal prenatal cannabis use may interact with other ASD risk factors, such as maternal prenatal stress, to impact child neurodevelopment. This question is particularly relevant for Black mothers, who are disproportionately exposed to prenatal stressors including low socioeconomic status (SES) and racial discrimination.