Genetics and Epigenetics of One-Carbon Metabolism Pathway in Autism Spectrum Disorder: A Sex-Specific Brain Epigenome?

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition affecting behavior and communication, presenting with extremely different clinical phenotypes and features. ASD etiology is composite and multifaceted with several causes and risk factors responsible for different individual disease pathophysiological processes and clinical phenotypes. From a genetic and epigenetic side, several candidate genes have been reported as potentially linked to ASD, which can be detected in about 10–25% of patients. Folate gene polymorphisms have been previously associated with other psychiatric and neurodegenerative diseases, mainly focused on gene variants in the DHFR gene (5q14.1; rs70991108, 19bp ins/del), MTHFR gene (1p36.22; rs1801133, C677T and rs1801131, A1298C), and CBS gene (21q22.3; rs876657421, 844ins68). Of note, their roles have been scarcely investigated from a sex/gender viewpoint, though ASD is characterized by a strong sex gap in onset-risk and progression. The aim of the present review is to point out the molecular mechanisms related to intracellular folate recycling affecting in turn remethylation and transsulfuration pathways having potential effects on ASD. Brain epigenome during fetal life necessarily reflects the sex-dependent different imprint of the genome-environment interactions which effects are difficult to decrypt. We here will focus on the DHFR, MTHFR and CBS gene-triad by dissecting their roles in a sex-oriented view, primarily to bring new perspectives in ASD epigenetics.

p53/NF-kB Balance in SARS-CoV-2 Infection: From OMICs, Genomics and Pharmacogenomics Insights to Tailored Therapeutic Perspectives (COVIDomics)

“…CYP3A4/5 , CYP2B6 , CYP2C8 , CYP2C9 , CYP2C19 , CYP2D6 ) and are characterized by a wide geographic variability ( Zhou et al, 2017 ; Biswas et al, 2020 ; Sukprasong et al, 2021 ) interacting with large part of those drugs specifically used in COVID-19 ( Sukasem et al, 2013 ; Biswas et al, 2022 ). Interestingly, many clinical complications of COVID-19 belong to the same group of comorbidities responsible for the poor prognosis, and drugs acting as anti-inflammatory, antithrombotic (anti-coagulant and anti-aggregant), anti-hypertensive or with lipid-lowering action, have marked pharmacogenomics features resembling those belonging to the lipoproteins and homocysteine homeostasis genes ( Parmeggiani et al, 2008 ; Gemmati et al, 2009 ; Gemmati et al, 2016 ; Tisato et al, 2019 ; Cappadona et al, 2021 ; Tisato et al, 2021 ; Biswas et al, 2022 ).…”

Folic Acid and Autism: A Systematic Review of the Current State of Knowledge

“…Different forms of folate participate in different important reactions, such as DNA methylation and replication. As a cofactor in a multitude of single-carbon transfer reactions, it has a direct influence in biosynthesis, epigenetic maintenance, amino acid homeostasis, and redox defense [17,18]. FA, as a synthetic compound is metabolized differently to naturally occurring forms of folates with a bioavailability approximately 70% higher [19] (Figure 1).…”

The potential involvement of inhaled iron (Fe) in the neurotoxic effects of ultrafine particulate matter air pollution exposure on brain development in mice

“…The trans-sulfuration pathway is also well known to interact with glutamatergic systems and functions [ 106 – 108 ] and thus it is possible that elevations in frontal cortex glutamate seen in males, and reductions in glutamate seen in females in response to Fe + SO 2 could be due to oxidative stress-related effects of Fe. However, changes in trans-sulfuration systems appear to occur in a sex-dependent capacity and can be influenced by hormones [ 109 – 112 ]. Such sex differences were reflected in the profiles of both trans-sulfuration markers and glutamatergic changes seen in response to Fe + SO 2 in this study (Fig.…”