Abstract
Epigenetics represents the way by which the environment is able to program the genome; there are three main levels of epigenetic control on genome: DNA methylation, post-translational histone modification and microRNA expression. The term Epigenetics has been widened by NIH to include “both heritable changes in gene activity and expression but also stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable.” These changes might be produced mostly by the early life environment and might affect health influencing the susceptibility to develop diseases, from cancer to mental disorder, during the entire life span. The most studied environmental influences acting on epigenome are diet, infections, wasting, child care, smoking and environmental pollutants, in particular endocrine disrupters (EDs). These are environmental xenobiotics able to interfere with the normal development of the male and female reproductive systems of wildlife, of experimental animals and possibly of humans, disrupting the normal reproductive functions. Data from literature indicate that EDs can act at different levels of epigenetic control, in some cases transgenerationally, in particular when the exposure to these compounds occurs during the prenatal and earliest period of life. Some of the best characterized EDs will be considered in this review. Among the EDs, vinclozolin (VZ), and methoxychlor (MXC) promote epigenetic transgenerational effects. Polychlorinated biphenils (PCBs), the most widespread environmental EDs, affect histone post-translational modifications in a dimorphic way, possibly as the result of an alteration of gene expression of the enzymes involved in histone modification, as the demethylase Jarid1b, an enzyme also involved in regulating the interaction of androgens with their receptor.
Highlights
Polychlorinated biphenils (PCBs), the most widespread environmental endocrine disrupters (EDs), affect histone post-translational modifications in a dimorphic way, possibly as the result of an alteration of gene expression of the enzymes involved in histone modification, as the demethylase Jarid1b, an enzyme involved in regulating the interaction of androgens with their receptor
DNMT1 is involved in maintenance of methylation status during replication (Reik et al, 2001); DNMT2 is related to embryonic stem cells and potential RNA methylation (Clouaire and Stancheva, 2008); and the DNMT3 family consisting of two members, DNMT3a and DNMT3b, which are involved in de novo DNA methylation at CpG sites occurring during early embryogenesis and are essential for the mammalian development (Singh and Li, 2012)
We have hypothesized the involvement of Jarid1b as essential component for the interactions in the arylhydrocarbon receptor (AhR)-androgen receptor (AR) complex, occurring after exposure to PCBs, in particular in presence of DL congeners, since the responsive element XRE, Androgen Responsive Element (ARE) and PLU1 are concomitantly present on promoters of AR target genes
Summary
The genomic distribution of methylated DNA sequences is defined “methylome”; the “methylome” it is able to modify itself in function of the environment or the developmental stage. A number of different proteins able to bind to methyl-CG has been identified and shown to perform critical roles in the regulation of gene expression (Buck-Koehntop and Defossez, 2013). These proteins contains methyl-CpG binding domains (MBDs) which are stretches of about 75 amino acid residues long that are evolutionary conserved. DNA methylation seems to be a starting step for establishing the inactive chromatin state It is followed by an MBD protein association that, in turn, recruits further repressive epigenetic modification enzymes, such as histone deacetylase (Kulis and Esteller, 2010) (see section). DNMT1 is involved in maintenance of methylation status during replication (it can methylate only the CG sequence paired with methylated CG) (Reik et al, 2001); DNMT2 is related to embryonic stem cells and potential RNA methylation (Clouaire and Stancheva, 2008); and the DNMT3 family consisting of two members, DNMT3a and DNMT3b, which are involved in de novo DNA methylation at CpG sites occurring during early embryogenesis and are essential for the mammalian development (Singh and Li, 2012)
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