Artificial Neural Networks Reveal Sex Differences in Gene Methylation, and Connections Between Maternal Risk Factors and Symptom Severity in Autism Spectrum Disorder

Stoccoro, Andrea; Gallo, Roberta; Calderoni, Sara; Cagiano, Romina; Muratori, Filippo; Migliore, Lucia; Grossi, Enzo; Coppedè, Fabio

doi:10.2217/epi-2022-0179

Cited by 7 publications

(9 citation statements)

References 74 publications

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“…We are aware of the limits of the present study in terms of sample size and monocentric nature of the study. Despite the Auto-CM system that we employed proved to be able to find reliable connections even in small datasets [ 31 , 32 , 33 , 34 , 37 , 68 , 69 , 70 ], replication of the present findings in larger cohorts is required both to confirm the observed associations and to test for the contribution of geographic, ethnic, genetic and region-specific environmental factors.…”

Section: Discussionmentioning

confidence: 78%

“…The added value of this approach in investigating biological systems is represented by its ability in evidencing the organizing principles of a network of variables and therefore to map biological processes using automatic and analytical models to reconstruct the imprecise, nonlinear and simultaneous pathways, underlying a complex set of data. In recent years, Auto-CM has been extensively applied to unravel the complexity of connections among environmental, clinical and biological variables in several medical datasets, leading to the identification of genetic and epigenetic biomarkers for neurodevelopmental disorders, cancer and lifestyle outcomes [ 31 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

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Prenatal Environmental Stressors and DNA Methylation Levels in Placenta and Peripheral Tissues of Mothers and Neonates Evaluated by Applying Artificial Neural Networks

Stoccoro

Nicolì

Coppedè

et al. 2023

Genes

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Exposure to environmental stressors during pregnancy plays an important role in influencing subsequent susceptibility to certain chronic diseases through the modulation of epigenetic mechanisms, including DNA methylation. Our aim was to explore the connections between environmental exposures during gestation with DNA methylation of placental cells, maternal and neonatal buccal cells by applying artificial neural networks (ANNs). A total of 28 mother–infant pairs were enrolled. Data on gestational exposure to adverse environmental factors and on mother health status were collected through the administration of a questionnaire. DNA methylation analyses at both gene-specific and global level were analyzed in placentas, maternal and neonatal buccal cells. In the placenta, the concentrations of various metals and dioxins were also analyzed. Analysis of ANNs revealed that suboptimal birth weight is associated with placental H19 methylation, maternal stress during pregnancy with methylation levels of NR3C1 and BDNF in placentas and mother’s buccal DNA, respectively, and exposure to air pollutants with maternal MGMT methylation. Associations were also observed between placental concentrations of lead, chromium, cadmium and mercury with methylation levels of OXTR in placentas, HSD11B2 in maternal buccal cells and placentas, MECP2 in neonatal buccal cells, and MTHFR in maternal buccal cells. Furthermore, dioxin concentrations were associated with placental RELN, neonatal HSD11B2 and maternal H19 gene methylation levels. Current results suggest that exposure of pregnant women to environmental stressors during pregnancy could induce aberrant methylation levels in genes linked to several pathways important for embryogenesis in both the placenta, potentially affecting foetal development, and in the peripheral tissues of mothers and infants, potentially providing peripheral biomarkers of environmental exposure.

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Prenatal Environmental Stressors and DNA Methylation Levels in Placenta and Peripheral Tissues of Mothers and Neonates Evaluated by Applying Artificial Neural Networks

Stoccoro

Nicolì

Coppedè

et al. 2023

Genes

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“…Sex differences in RELN methylation were observed in the blood DNA of ASD individuals. Indeed, RELN methylation was higher in males than in females [ 48 ]. In ASD females, blood RELN methylation levels were inversely correlated with disease severity, as assessed through the ADOS-2 score [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…In ASD females, blood RELN methylation levels were inversely correlated with disease severity, as assessed through the ADOS-2 score [ 38 ]. In males, blood RELN methylation levels were linked to the methylation levels of EN2 , a gene that protects dopaminergic neurons against mitochondrial insult from pesticides [ 48 ]. Reduced RELN in the mother can directly affect neurodevelopment of her offspring, or alternatively the hypermethylation profile can be “transmitted” to the fetus via maternal germline.…”

Section: Discussionmentioning

confidence: 99%

Maternal Epigenetic Dysregulation as a Possible Risk Factor for Neurodevelopmental Disorders

Lintas

Cassano

Azzarà

et al. 2023

Genes

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Neurodevelopmental Disorders (NDs) are a heterogeneous group of disorders and are considered multifactorial diseases with both genetic and environmental components. Epigenetic dysregulation driven by adverse environmental factors has recently been documented in neurodevelopmental disorders as the possible etiological agent for their onset. However, most studies have focused on the epigenomes of the probands rather than on a possible epigenetic dysregulation arising in their mothers and influencing neurodevelopment during pregnancy. The aim of this research was to analyze the methylation profile of four well-known genes involved in neurodevelopment (BDNF, RELN, MTHFR and HTR1A) in the mothers of forty-five age-matched AS (Asperger Syndrome), ADHD (Attention Deficit Hyperactivity Disorder) and typically developing children. We found a significant increase of methylation at the promoter of the RELN and HTR1A genes in AS mothers compared to ADHD and healthy control mothers. For the MTHFR gene, promoter methylation was significantly higher in AS mothers compared to healthy control mothers only. The observed dysregulation in AS mothers could potentially contribute to the affected condition in their children deserving further investigation.

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“…Such differences in the OXTR gene expression were also evident in the mRNA levels [ 62 ]. Furthermore, recent analyses on the use of artificial neural networks indicated that changes in methylation levels of the OXTR gene were specific to females with autism spectrum disorder [ 63 ].…”

Section: Oxtr In Mental Disordersmentioning

confidence: 99%

Roles of the Oxytocin Receptor (OXTR) in Human Diseases

Pierzynowska

Gaffke

Żabińska

et al. 2023

IJMS

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The oxytocin receptor (OXTR), encoded by the OXTR gene, is responsible for the signal transduction after binding its ligand, oxytocin. Although this signaling is primarily involved in controlling maternal behavior, it was demonstrated that OXTR also plays a role in the development of the nervous system. Therefore, it is not a surprise that both the ligand and the receptor are involved in the modulation of behaviors, especially those related to sexual, social, and stress-induced activities. As in the case of every regulatory system, any disturbances in the structures or functions of oxytocin and OXTR may lead to the development or modulation of various diseases related to the regulated functions, which in this case include either mental problems (autism, depression, schizophrenia, obsessive-compulsive disorders) or those related to the functioning of reproductive organs (endometriosis, uterine adenomyosis, premature birth). Nevertheless, OXTR abnormalities are also connected to other diseases, including cancer, cardiac disorders, osteoporosis, and obesity. Recent reports indicated that the changes in the levels of OXTR and the formation of its aggregates may influence the course of some inherited metabolic diseases, such as mucopolysaccharidoses. In this review, the involvement of OXTR dysfunctions and OXTR polymorphisms in the development of different diseases is summarized and discussed. The analysis of published results led us to suggest that changes in OXTR expression and OXTR abundance and activity are not specific to individual diseases, but rather they influence processes (mostly related to behavioral changes) that might modulate the course of various disorders. Moreover, a possible explanation of the discrepancies in the published results of effects of the OXTR gene polymorphisms and methylation on different diseases is proposed.

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Artificial Neural Networks Reveal Sex Differences in Gene Methylation, and Connections Between Maternal Risk Factors and Symptom Severity in Autism Spectrum Disorder

Cited by 7 publications

References 74 publications

Prenatal Environmental Stressors and DNA Methylation Levels in Placenta and Peripheral Tissues of Mothers and Neonates Evaluated by Applying Artificial Neural Networks

Prenatal Environmental Stressors and DNA Methylation Levels in Placenta and Peripheral Tissues of Mothers and Neonates Evaluated by Applying Artificial Neural Networks

Maternal Epigenetic Dysregulation as a Possible Risk Factor for Neurodevelopmental Disorders

Roles of the Oxytocin Receptor (OXTR) in Human Diseases

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