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Research Letter
November 2015

Link Between Increased Prevalence of Autism Spectrum Disorder Syndromes and Oxidative Stress, DNA Methylation, and ImprintingThe Impact of the Environment

Author Affiliations
  • 1London Fertility Associates, London, England
  • 2Bourn Hall Clinic, Cambridge, England
  • 3Centre for Assisted Fertilization, Naples, Italy
JAMA Pediatr. 2015;169(11):1066-1067. doi:10.1001/jamapediatrics.2015.2125

Autism is a complex neurodevelopment disorder, with a male to female prevalence of 4.3:1. The number of children diagnosed with autism or related disorders has increased at an alarming rate: the Centers for Disease Control and Prevention estimates that 1 in 68 children in the United States (or 14.7 per 1000 eight-year-olds) was identified with autism spectrum disorder during 2014. The figure reaches 1 in 45 children in the state of Alabama, and this represents an estimated 30% increase over previous estimates reported in 2012. The prevalence of these disorders has more than doubled since 2000. Here we discuss the biochemical link between the process of DNA methylation in gametes and autism.

Methods

This short commentary is the result of the authors’ work on methylation, imprinting, and metabolism in gametes and embryos integrated with the current literature on brain disease and gamete quality.

Results

Disturbances in DNA methylation can originate in the spermatozoon, linked to the age of the male progenitor,1 and this is expressed as deficiencies in epigenetic mechanisms. Sperm of older men have a higher level of DNA damage, due to a lower resistance to oxidative stress: offspring conceived by older men carrying a high level of sperm DNA fragmentation may escape miscarriage but may instead carry disorders originating from DNA damage that may lead to neuropsychiatric disturbance.

The oocyte expresses folic acid transporters to a high level, whereas cystathionine β-synthase is not expressed, while betaine homocysteine methyltransferase is only weakly expressed.2 In the absence of an adequate endogenous pool of folic acid in the oocyte, the early embryo’s ability to recycle homocysteine is handicapped (Figure). Intrafollicular homocysteine levels increase in assisted reproductive technologies; therefore, any deficiency in maternal folic acid supplies will affect methylation during very early preimplantation stages of embryo development. Prenatal folic acid supplements have been shown to partially protect against neurodevelopmental disorders in the offspring,3 as well as have a positive effect on the risk of neural tube defects. A wide range of disorders, including neuropsychiatric disorders, autism, and cognitive impairment, are associated with increased homocysteine levels in biological fluids.4

Figure.
Interrelations Between Oxidative Stress and Methylation Processes
Interrelations Between Oxidative Stress and Methylation Processes

1, Correct recycling of homocysteine allows generation of cysteine and methionine, which allow correct processes of methylation through the formation of S-adenosyl methionine (SAM) (1bis). 2, Correct generation of cysteine allows the synthesis of hypotaurine and glutathione, 2 potent inhibitors of reactive oxygen species (ROS). Hypotaurine is the most important anti-ROS naturally present in vivo in the natural environment of the preimplantation embryo. 3, Generation of ROS induces DNA fragmentation. Advanced age decreases the ability to control ROS-linked decays. 4, High levels of homocysteine perturb DNA methylation processes in sperm, oocytes, and embryos. 5, DNA methylation defects, whether or not linked to imprinting, may result in negative transgenerational health problems. Unrepaired 8 oxoG (oxidized form of guanine) leads to aberrant methylation at CpG sites, which impairs transcription and may affect telomere length (TTAGGG repeats). 6, Plastic derived endocrine disruptors (bisphenol A [BPA], di-[2-ethylhexyl]phthalate [DEHP], and dibutyl phthalate [DBP]) have a negative effect on all of the steps in the pathway.

Bisphenol A and other plastic-derived endocrine disruptors have the capacity to inhibit methylation and affect imprinting, inducing epigenetic transgenerational inheritance of metabolic and reproductive disorders, including sperm epimutations.5 Bisphenol A is a well-known inducer of oxidative stress, as is a high level of circulating glucose. It has been shown that maternal diabetes significantly increases the prevalence of autism in offspring.6

Comment

There is therefore a link between methylation and oxidative stress in gametes and the first stages of embryonic development, which potentially effects epigenetic transgenerational transmission. The increase in autism spectrum diseases may also be linked to an increase in environmental endocrine disruptors, which increase oxidative stress and perturb methylation. This effect may manifest in the first 3 days postfertilization up to the blastocyst stage, the period when maintenance of methylation has a significant effect on the imprinting processes, or in the fetus, when imprinting is reset in the germ cells. The sex ratios observed in some disorders may be explained by the higher resistance of female embryos, linked to the XIAP gene expression. However, DNA methylation by definition differs between male and female genomes, whether or not it is linked to imprinting; a difference in the sex ratio with respect to autism might therefore be expected. These observations advocate treatment with nutritional supplements that support the 1-carbon cycle for older male and female patients, as well as for female diabetic patients who seek to achieve a pregnancy. The supplementation should include all of the cofactors that contribute to the 1-carbon cycle because, for example, vitamin B12 deficiency can induce adverse neurological problems.

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Article Information

Corresponding Author: Brian Dale, PhD, DSc, Centre for Assisted Fertilization, Via Tasso 480, Naples 80123, Italy (brian.dale@virgilio.it).

Published Online: September 28, 2015. doi:10.1001/jamapediatrics.2015.2125.

Author Contributions: Dr Menezo had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: Menezo.

Drafting of the manuscript: Menezo and Elder.

Critical revision of the manuscript for important intellectual content: Menezo and Dale.

Administrative, technical, or material support: Menezo

Study supervision: Menezo and Dale.

Conflict of Interest Disclosures: None reported.

References
1.
Feinberg  JI, Bakulski  KM, Jaffe  AE,  et al.  Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort [published online April 14, 2015]. Int J Epidemiol. doi:10.1093/ije/dyv028.
2.
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Surén  P, Roth  C, Bresnahan  M,  et al.  Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA. 2013;309(6):570-577.
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