A Mitochondrial Etiology of Neuropsychiatric Disorders

This Viewpoint explores the hypothesis that mitochondrial dysfunction is associated with neuropsychiatric disorders

Abstract

Enormous resources have been invested in the analysis of neuropsychiatric disorders using powerful genomics techniques, including genome-wide association studies (GWAS), whole-exome sequencing (WES), and whole-genome sequencing, to search for nuclear DNA (nDNA) gene variants associated with these disorders.

Yet, no coherent pathophysiological etiology for psychiatric disorders has emerged. For example, after analysis of thousands of autism cases by GWAS and WES, numerous copy number variants and loss-of-function mutations have been identified, but no single variant accounts for a significant proportion of cases.

Moreover, the genes that have been found to harbor loss-of-function mutations in patients with autism overlap with those associated with congenital heart disease and metabolic disorders.

What do “brain” diseases have to do with congenital heart disease and metabolic disorders?

Time Bomb: a Journey into Old Exposures, Gametic Glitches, and the Autism Explosion

Slides from Society for Neuroscience Wonder, February 2017

This presentation to a student-run chapter of SFN explained the history and science behind the “Time Bomb” hypothesis of autism.

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Environmental factors, epigenetics, and developmental origin of reproductive disorders

US National Library of Medicine National Institutes of Health, Reproductive toxicology, 2016

Highlights

  • Epidemiological and model system studies support an early origin of reproductive dysfunction.
  • Estrogenic/anti-androgenic chemicals as endocrine disrupting chemicals (EDCs) have vast developmental influences on adult reproductive outcomes.
  • Gestational, perinatal, neonatal, and pubertal periods are “windows of susceptibility” for epigenetic programming.
  • EDCs induce exposure-specific epigenetic modifications in regulatory genes in organs of the reproductive system.
  • Germline epigenetic disruption is a mechanism underlying transgenerational inheritance of reproductive disorders.

2017 Study Abstract

Environmental factors, epigenetics, and developmental origin of reproductive disorders, US National Library of Medicine National Institutes of Health, Reproductive toxicology (Elmsford, N.Y.), NCBI PubMed PMID: 27421580, 2016 Jul.

Image credit Daniel Friedman.

Sex-specific differentiation, development, and function of the reproductive system are largely dependent on steroid hormones.

For this reason, developmental exposure to estrogenic and anti-androgenic endocrine disrupting chemicals (EDCs) is associated with reproductive dysfunction in adulthood.

Human data in support of “Developmental Origins of Health and Disease” (DOHaD) comes from multigenerational studies on offspring of diethylstilbestrol-exposed mothers/grandmothers.

Animal data indicate that ovarian reserve, female cycling, adult uterine abnormalities, sperm quality, prostate disease, and mating behavior are susceptible to DOHaD effects induced by EDCs such as bisphenol A, genistein, diethylstilbestrol, p,p’-dichlorodiphenyl-dichloroethylene, phthalates, and polyaromatic hydrocarbons.

Mechanisms underlying these EDC effects include direct mimicry of sex steroids or morphogens and interference with epigenomic sculpting during cell and tissue differentiation.

Exposure to EDCs is associated with abnormal DNA methylation and other epigenetic modifications, as well as altered expression of genes important for development and function of reproductive tissues.

Here we review the literature exploring the connections between developmental exposure to EDCs and adult reproductive dysfunction, and the mechanisms underlying these effects.

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High doses of pesticides can potentially impact DNA, triggering cancers later in life

Researchers find pesticide spills, accidents may alter farmworkers’ DNA

Farmworkers who have a high pesticide exposure event—such as a spill—are more likely to experience molecular changes on DNA that may lead to certain cancers, according to a large U.S. study of pesticide applicators in Iowa and North Carolina.

The research, part of the ongoing Agricultural Health Study that is monitoring the health of more than 57,000 private and commercial pesticide applicators in Iowa and North Carolina, adds to growing evidence that high exposure to certain pesticides may spur prostate and other cancers in people handling the chemicals.

2017 Study Abstract

High pesticide exposure events and DNA methylation among pesticide applicators in the agricultural health study, Environmental and molecular mutagenesis, NCBI PubMed PMID: 27996157, 2017 Jan.

Researchers find pesticide spills, accidents may alter farmworkers’ DNA, Environmental Health News , February 16, 2017.

Image credit Brad Covington.

Pesticide exposure has been associated with acute and chronic adverse health effects. DNA methylation (DNAm) may mediate these effects.

We evaluated the association between experiencing unusually high pesticide exposure events (HPEEs) and DNAm among pesticide applicators in the Agricultural Health Study (AHS), a prospective study of applicators from Iowa and North Carolina.

DNA was extracted from whole blood from male AHS pesticide applicators (n = 695). Questionnaire data were used to ascertain the occurrence of HPEEs over the participant’s lifetime. Pyrosequencing was used to quantify DNAm in CDH1, GSTp1, and MGMT promoters, and in the repetitive element, LINE-1. Linear and robust regression analyses evaluated adjusted associations between HPEE and DNAm. Ever having an HPEE (n = 142; 24%) was associated with elevated DNAm in the GSTp1 promoter at CpG7 (chr11:67,351,134; P < 0.01) and for the mean across the CpGs measured in the GSTp1 promoter (P < 0.01). In stratified analyses, elevated GSTP1 promoter DNAm associated with HPEE was more pronounced among applicators >59 years and those with plasma folate levels ≤16.56 ng/mL (p-interaction <0.01); HPEE was associated with reduced MGMT promoter DNAm at CpG2 (chr10:131,265,803; P = 0.03), CpG3 (chr10:131,265,810; P = 0.05), and the mean across CpGs measured in the MGMT promoter (P = 0.03) among applicators >59 years and reduced LINE-1 DNAm (P = 0.05) among applicators with ≤16.56 ng/mL plasma folate. Non-specific HPEEs may contribute to increased DNAm in GSTp1, and in some groups, reduced DNAm in MGMT and LINE-1.

The impacts of these alterations on disease development are unclear, but elevated GSTp1 promoter DNAm and subsequent gene inactivation has been consistently associated with prostate cancer.

Can prenatal alcohol exposure cause a distinct DNA methylation pattern?

DNA methylation signature of human fetal alcohol spectrum disorder

Abstract

Background
Prenatal alcohol exposure is the leading preventable cause of behavioral and cognitive deficits, which may affect between 2 and 5 % of children in North America. While the underlying mechanisms of alcohol’s effects on development remain relatively unknown, emerging evidence implicates epigenetic mechanisms in mediating the range of symptoms observed in children with fetal alcohol spectrum disorder (FASD). Thus, we investigated the effects of prenatal alcohol exposure on genome-wide DNA methylation in the NeuroDevNet FASD cohort, the largest cohort of human FASD samples to date.

DNA methylation signature of human fetal alcohol spectrum disorder, BioMed Central, epigeneticsandchromatin, 17 June 2016.

Methods
Genome-wide DNA methylation patterns of buccal epithelial cells (BECs) were analyzed using the Illumina HumanMethylation450 array in a Canadian cohort of 206 children (110 FASD and 96 controls). Genotyping was performed in parallel using the Infinium HumanOmni2.5-Quad v1.0 BeadChip.

Results
After correcting for the effects of genetic background, we found 658 significantly differentially methylated sites between FASD cases and controls, with 41 displaying differences in percent methylation change >5 %. Furthermore, 101 differentially methylated regions containing two or more CpGs were also identified, overlapping with 95 different genes. The majority of differentially methylated genes were highly expressed at the level of mRNA in brain samples from the Allen Brain Atlas, and independent DNA methylation data from cortical brain samples showed high correlations with BEC DNA methylation patterns. Finally, overrepresentation analysis of genes with up-methylated CpGs revealed a significant enrichment for neurodevelopmental processes and diseases, such as anxiety, epilepsy, and autism spectrum disorders.

Conclusions
These findings suggested that prenatal alcohol exposure is associated with distinct DNA methylation patterns in children and adolescents, raising the possibility of an epigenetic biomarker of FASD.

Epigenetic disturbances caused by bisphenol-A associated with psychiatric disorders

BDNF DNA methylation in the blood may represent a novel clinical epigenetic biomarker for the early detection of psychopathology

psychiatric-disorders
This study provides evidence in support of the role of epigenetic mechanisms in the neurodevelopmental toxicity of BPA and reveals BDNF as a target gene of this environmental toxicant. Image @Robin_Mesnage.

Abstract

Researchers previous study showed that environmentally relevant doses of BPA given to female mice during pregnancy induce lasting epigenetic disruption in the prefrontal cortex and hypothalamus of the offspring and that these changes are sex-specific.

Early-life adversity increases the risk for psychopathology in later life. The underlying mechanism(s) is unknown, but epigenetic variation represents a plausible candidate. Early-life exposures can disrupt epigenetic programming in the brain, with lasting consequences for gene expression and behavior. This evidence is primarily derived from animal studies, with limited study in humans due to inaccessibility of the target brain tissue. In humans, although there is evidence for DNA methylation changes in the peripheral blood of psychiatric patients, a fundamental question remains as to whether epigenetic markers in the blood can predict epigenetic changes occurring in the brain.

DNA methylation of BDNF as a biomarker of early-life adversity, PNAS doi: 10.1073/pnas.1408355111, August 25, 2014.

We used in utero bisphenol A (BPA) exposure as a model environmental exposure shown to disrupt neurodevelopment and exert long-term effects on behavior in animals and humans. We show that prenatal BPA induces lasting DNA methylation changes in the transcriptionally relevant region of the Bdnf gene in the hippocampus and blood of BALB/c mice and that these changes are consistent with BDNF changes in the cord blood of humans exposed to high maternal BPA levels in utero. Our data suggest that BDNF DNA methylation in the blood may be used as a predictor of brain BDNF DNA methylation and gene expression as well as behavioral vulnerability induced by early-life environmental exposure. Because BDNF expression and DNA methylation are altered in several psychiatric disorders that are associated with early-life adversity, including depression, schizophrenia, bipolar disorder, and autism, BDNF DNA methylation in the blood may represent a novel biomarker for the early detection of psychopathology.

Epigenetics: a Historical Overview

In the first half of the twentieth century, developmental biology and genetics were separate disciplines

image of epigenetics
The nature of the continual interactions between proteins and DNA will further advance the field of epigenetics, and illuminate current problems, such as the re-programming of the genome which initiates the normal processes of development.

ABSTRACT

Epigenetics attempts to provide new insights into the mechanisms for unfolding the genetic program for development.

The word epigenetics was coined by Waddington to link developmental biology and genetics. Epigenetics could be broadly defined as the sum of all those mechanisms necessary for the unfolding of the genetic programme for development. Several decades later specific mechanisms were proposed in which information was superimposed on DNA sequences. In particular, it was suggested that 5-methyl cytosine had a role in controlling gene expression, and also that the pattern of methylation was heritable. These predictions are now supported by a large body of evidence which shows that methylation is strongly associated with gene silencing in a variety of biological contexts. There are now also many examples of epigenetic inheritance through the germ line There are several other important epigenetic mechanisms involving chromatin and histone modifications, and also the expanding field of regulatory RNAs. The human epigenome project will unravel the pattern of DNA methylation in different tissues, and will this determine whether the regulation of gene expression is at the level of DNA or chromatin, or both.

Effects of Low-Dose Diethylstilbestrol Exposure on DNA Methylation in Mouse Spermatocytes

Epigenetic modification might be a potential mechanism of low-dose DES-induced male reproductive toxicity

mouse image
These 2015 study results showed that low-dose DES was toxic to spermatocytes and that DNMT expression and DNA methylation were altered in DES-exposed cells. Taken together, these data demonstrate that DNA methylation likely plays an important role in mediating DES-induced spermatocyte toxicity in vitro. Flickr.

2015 Study Abstract

Evidence from previous studies suggests that the male reproductive system can be disrupted by fetal or neonatal exposure to diethylstilbestrol (DES). However, the molecular basis for this effect remains unclear. To evaluate the effects of DES on mouse spermatocytes and to explore its potential mechanism of action, the levels of DNA methyltransferases (DNMTs) and DNA methylation induced by DES were detected.

The results showed that low doses of DES inhibited cell proliferation and cell cycle progression and induced apoptosis in GC-2 cells, an immortalized mouse pachytene spermatocyte-derived cell line, which reproduces primary cells responses to E2. Furthermore, global DNA methylation levels were increased and the expression levels of DNMTs were altered in DES-treated GC-2 cells. A total of 141 differentially methylated DNA sites were detected by microarray analysis. Rxra, an important component of the retinoic acid signaling pathway, and mybph, a RhoA pathway-related protein, were found to be hypermethylated, and Prkcd, an apoptosis-related protein, was hypomethylated.

Effects of Low-Dose Diethylstilbestrol Exposure on DNA Methylation in Mouse Spermatocytes, BCBI PubMed PMID: 26588706, PLOS one PMC4654501, Nov 20 2015.

These results showed that low-dose DES was toxic to spermatocytes and that DNMT expression and DNA methylation were altered in DES-exposed cells. Taken together, these data demonstrate that DNA methylation likely plays an important role in mediating DES-induced spermatocyte toxicity in vitro.

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Environmentally induced epigenetic transgenerational inheritance of disease susceptibility

Environmental epigenetics affects disease, evolution

Washington State University researchers say environmental factors are having an underappreciated effect on the course of disease and evolution by prompting genetic mutations through epigenetics, a process by which genes are turned on and off independent of an organism’s DNA sequence.

epigenetics image
Researchers exposed gestating female rats to the fungicide vinclozolin. Third generation, or great-grand offspring, had increased genetic mutations, which the researchers saw in increased DNA structure changes known as copy-number variations. Epigenetic image by Wilfredo Shimura.

2015 Study Abstract

Environmental insults, such as exposure to toxicants or nutritional abnormalities, can lead to epigenetic changes that are in turn related to increased susceptibility to disease. The focus of this review is on the transgenerational inheritance of such epigenetic abnormalities (epimutations), and how it is that these inherited epigenetic abnormalities can lead to increased disease susceptibility, even in the absence of continued environmental insult. Observations of environmental toxicant specificity and exposure-specific disease susceptibility are discussed. How epimutations are transmitted across generations and how epigenetic changes in the germline are translated into an increased disease susceptibility in the adult is reviewed with regard to disease etiology.

Sources and more information
  • Environmentally induced epigenetic transgenerational inheritance of disease susceptibility, NCBI PMCID: 24657180, PMC4148471, Transl Res. 2015 Jan;165(1):12-7. doi: 10.1016/j.trsl.2014.02.003. Epub 2014 Feb 28.
  • Study: Environmental epigenetics affects disease, evolution, Washington State University, August 3, 2015.

Neonatal exposure to DES alters expression of DNA methyltransferases and methylation of genomic DNA

DES alters the expression levels of Dnmts and DNA methylation

mouse
DES alters the expression levels of Dnmts and DNA methylation. Image by Steph Hillier.

 

2009 Study Abstract

Perinatal exposure to diethylstilbestrol (DES) can have numerous adverse effects on the reproductive organs later in life, such as vaginal clear-cell adenocarcinoma. Epigenetic processes including DNA methylation may be involved in the mechanisms.

We subcutaneously injected DES to neonatal C57BL/6 mice. At days 5, 14, and 30, expressions of DNA methyltransferases (Dnmts) Dnmt1, Dnmt3a, and Dnmt3b, and transcription factors Sp1 and Sp3 were examined. We also performed restriction landmark genomic scanning (RLGS) to detect aberrant DNA methylation. Real-time RT-PCR revealed that expressions of Dnmt1, Dnmt3b, and Sp3 were decreased at day 5 in DES-treated mice, and that those of Dnmt1, Dnmt3a, and Sp1 were also decreased at day 14. RLGS analysis revealed that 5 genomic loci were demethylated, and 5 other loci were methylated by DES treatment. Two loci were cloned, and differential DNA methylation was quantified.

Our results indicated that DES altered the expression levels of Dnmts and DNA methylation.

Sources
  • Neonatal exposure to diethylstilbestrol alters expression of DNA methyltransferases and methylation of genomic DNA in the mouse uterus, Sato K1, Fukata H, Kogo Y, Ohgane J, Shiota K, Mori C. Endocr J. 2009;56(1):131-9. Epub 2008 Nov 8. NCBI PMID: 18997445.
  • Full text, The Japan Endocrine Society, PDF.
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