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It is important to note that in disadvantaged families, the rate of boys with chronic aggressive behaviour represents about 4% of the population. This greatly restricts the selection of potential participants. "Once they are adults, they are difficult to find because they have disorganized lifestyles," Tremblay said.






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Chronic aggressive behavior in boys: Epigenetic sources?

Genes related to self-control could be 'disabled' by the prenatal environment.

Chronic aggressive behaviour exhibited by some boys from disadvantaged families may be due to epigenetic changes during pregnancy and early childhood. This is highlighted by two studies conducted by a team led by Richard E. Tremblay, professor emeritus at the University of Montreal and Moshe Szyf, professor at McGill University. Both articles are published in the PLOS ONE journal.

"Childhood Chronic Physical Aggression Associates with Adult Cytokine Levels in Plasma" here: PLOS ONE.

"Differential DNA Methylation Regions in Cytokine and Transcription Factor Genomic Loci Associate with Childhood Physical Aggression"  linked here: PlOS ONE

The first author of the two papers, Nadine Provençal, was jointly supervised by professors Szyf and Tremblay.

Epigenetic changes possibly related to the prenatal environment
In the first study, published in July, the team found that among men who had chronic aggressive behaviour during childhood and adolescence, blood levels of four biomarkers of inflammation were lower than in men who exhibited average levels of aggressive behaviour in their youth, from 6 to 15 years of age.


"This means that using four specific biomarkers of inflammation, called cytokines, we were able to distinguish men with chronic physical aggression histories from those without."

Richard Tremblay, researcher specializing in developmental psychology


In the second study, it was observed in the same men with aggressive pasts, that the DNA encoding the cytokines showed methylation patterns different from those of the comparison group.

"Methylation is an epigenetic modification—hence reversible—of DNA, in relation to parental imprinting. It plays a role in regulating gene expression," says Szyf, who specializes in epigenetics.

"The pre- and postnatal environment could cause these differences in biomarkers associated with chronic aggression," Szyf added. Various studies conducted with animals show that hostile environments during pregnancy and early childhood have an impact on gene methylation and gene programming leading to problems with brain development, particularly in regard to the control of aggressive behaviour.

Previous work by Tremblay's team suggest that men with aggressive pasts have one thing in common: the characteristics of their mothers. "They are usually young mothers at the birth of their first child, with low education, often suffering from mental health problems, and with substance use problems," Tremblay explained.


The significant difficulties these mothers experienced during pregnancy and the early childhood of their child may have an impact on the expression of genes related to brain development, the immune system, and many other biological systems critical for the development of their child.



A nearly 30-year follow-up
The blood samples used in the studies published this summer in PLOS ONE were collected from 32 participants who took part in either of two longitudinal studies that begun nearly 30 years ago by Tremblay's team. The first study followed young Quebecers from disadvantaged backgrounds, while the second involved a representative sample of children who were in kindergarten in Quebec in 1986-87.

It is important to note that in disadvantaged families, the rate of boys with chronic aggressive behaviour represents about 4% of the population. This greatly restricts the selection of potential participants. "Once they are adults, they are difficult to find because they have disorganized lifestyles," Tremblay said.

A prevention perspective
This difficulty has not stopped him from pursuing his research further. "We are studying the impact of the socioeconomic environment on the third generation, now that these children are grown up and have children," Tremblay noted. No study has yet been published on the subject, he anticipates "significant intergenerational ties, since we observed an association between parental criminality of the first generation and the behaviour of their children."

Nevertheless, the researcher, who has conducted his work for decades with a prevention perspective, is optimistic. "If our results show that behavioural problems originate from as far back as pregnancy, it means that we can reduce violence through preventive intervention from as early as pregnancy," says Tremblay. We have already shown that support given to families of aggressive boys in kindergarten prevents school dropout and crime in adulthood.

°First article in PLOS ONE: Childhood Chronic Physical Aggression Associates with Adult Cytokine Levels in Plasma
Abstract
Background
Animal and human studies suggest that inflammation is associated with behavioral disorders including aggression. We have recently shown that physical aggression of boys during childhood is strongly associated with reduced plasma levels of cytokines IL-1α, IL-4, IL-6, IL-8 and IL-10, later in early adulthood. This study tests the hypothesis that there is an association between differential DNA methylation regions in cytokine genes in T cells and monocytes DNA in adult subjects and a trajectory of physical aggression from childhood to adolescence.

Methodology/Principal Findings
We compared the methylation profiles of the entire genomic loci encompassing the IL-1α, IL-6, IL-4, IL-10 and IL-8 and three of their regulatory transcription factors (TF) NFkB1, NFAT5 and STAT6 genes in adult males on a chronic physical aggression trajectory (CPA) and males with the same background who followed a normal physical aggression trajectory (control group) from childhood to adolescence. We used the method of methylated DNA immunoprecipitation with comprehensive cytokine gene loci and TF loci microarray hybridization, statistical analysis and false discovery rate correction. We found differentially methylated regions to associate with CPA in both the cytokine loci as well as in their transcription factors loci analyzed. Some of these differentially methylated regions were located in known regulatory regions whereas others, to our knowledge, were previously unknown as regulatory areas. However, using the ENCODE database, we were able to identify key regulatory elements in many of these regions that indicate that they might be involved in the regulation of cytokine expression.

Conclusions
We provide here the first evidence for an association between differential DNA methylation in cytokines and their regulators in T cells and monocytes and male physical aggression.

Citation: Provençal N, Suderman MJ, Caramaschi D, Wang D, Hallett M, et al. (2013) Differential DNA Methylation Regions in Cytokine and Transcription Factor Genomic Loci Associate with Childhood Physical Aggression. PLoS ONE 8(8): e71691. doi:10.1371/journal.pone.0071691

Received: January 16, 2013; Accepted: July 2, 2013; Published: August 19, 2013


Second article also in Plos One : Differential DNA Methylation Regions in Cytokine and Transcription Factor Genomic Loci Associate with Childhood Physical Aggression

Animal and human studies suggest that inflammation is associated with behavioral disorders including aggression. We have recently shown that physical aggression of boys during childhood is strongly associated with reduced plasma levels of cytokines IL-1α, IL-4, IL-6, IL-8 and IL-10, later in early adulthood. This study tests the hypothesis that there is an association between differential DNA methylation regions in cytokine genes in T cells and monocytes DNA in adult subjects and a trajectory of physical aggression from childhood to adolescence.

Methodology/Principal Findings
We compared the methylation profiles of the entire genomic loci encompassing the IL-1α, IL-6, IL-4, IL-10 and IL-8 and three of their regulatory transcription factors (TF) NFkB1, NFAT5 and STAT6 genes in adult males on a chronic physical aggression trajectory (CPA) and males with the same background who followed a normal physical aggression trajectory (control group) from childhood to adolescence. We used the method of methylated DNA immunoprecipitation with comprehensive cytokine gene loci and TF loci microarray hybridization, statistical analysis and false discovery rate correction. We found differentially methylated regions to associate with CPA in both the cytokine loci as well as in their transcription factors loci analyzed. Some of these differentially methylated regions were located in known regulatory regions whereas others, to our knowledge, were previously unknown as regulatory areas. However, using the ENCODE database, we were able to identify key regulatory elements in many of these regions that indicate that they might be involved in the regulation of cytokine expression.

Conclusions
We provide here the first evidence for an association between differential DNA methylation in cytokines and their regulators in T cells and monocytes and male physical aggression.

Citation: Provençal N, Suderman MJ, Caramaschi D, Wang D, Hallett M, et al. (2013) Differential DNA Methylation Regions in Cytokine and Transcription Factor Genomic Loci Associate with Childhood Physical Aggression. PLoS ONE 8(8): e71691. doi:10.1371/journal.pone.0071691

Received: January 16, 2013; Accepted: July 2, 2013; Published: August 19, 2013

The University of Montreal is officially known as Université de Montréal. This document is a translation of a text originally written in French by Martin LaSalle, Université de Montréal. This work was supported by a fellowship from the Genes, Environment and Health Training Program from Canadian Institutes of Health Research (CIHR), grants from the Canadian Institutes of Health Research, the Social Sciences Humanities Research Council of Canada, Fonds de recherche du Québec – Santé (FRQ-S) and Fonds de recherche du Québec – Société et culture (FRQ-SC), the Sackler Program in Psychobiology and Epigenetics at McGill University and from the Canadian Institute for Advanced Research.

Original press releas: http://www.eurekalert.org/pub_releases/2013-09/ru-msa091013.php