Epigenomic disruption: The effects of early developmental exposures

Abstract

Through DNA methylation, histone modifications, and small regulatory RNAs the epigenome systematically controls gene expression during development--both in utero and throughout life. The epigenome is also a very reactionary system; its labile nature allows it to sense and respond to environmental perturbations to ensure survival during fetal growth. This pliability can lead to aberrant epigenetic modifications that persist into later life and induce numerous disease states. Endocrine disrupting compounds (EDCs) are ubiquitous chemicals that interfere with growth and development. Several EDCs also interfere with epigenetic programming. The investigation of the epigenotoxic effects of bisphenol A (BPA), an EDC used in the production of plastics and resins, has further raised concern for the impact of EDCs on the epigenome. Using the Agouti viable yellow (A vy ) mouse model, dietary BPA exposure was shown to hypomethylate both the A vy and the Cabp IAP metastable epialleles. This hypomethylating effect was counteracted with dietary supplementation of methyl donors or genistein. These results are consistent with reports of BPA and other EDCs causing epigenetic effects. Epigenotoxicity could lead to numerous developmental, metabolic, and behavioral disorders in exposed populations. The heritable nature of epigenetic changes also increases the risk for transgenerational inheritance of phenotypes. Thus, epigenotoxicity must be considered when assessing these compounds for safety.

Longitudinal epigenetic drift in mice perinatally exposed to lead

“…The metastable epiallele, CDK5-activator binding protein (Cabp IAP ) has been widely used as a biomarker of environmental exposure alteration to the epigenome. [27][28][29][30] Until now, the longitudinal changes in Cabp IAP DNA methylation level had not been described. The Cabp IAP locus has a high baseline level of methylation, explaining the small average increase across exposure groups (1.27%).…”

Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence

“…Although the relative proportions of nonshared (intrauterine) environment versus stochastic influences on the neonatal epigenome remain to be demonstrated, Feinberg and colleagues have proposed a model in which a genetically inherited propensity to stochastic variability in DNA methylation has evolved to increase fitness in a varying environment (Feinberg and Irizarry 2011). Furthermore, a combination of influences have been proposed to explain the phenomenon of metastable epialleles, which are variably expressed due to epigenetic modifications that are established in a stochastic manner during early development, and that are also environmentally labile (for review, see Bernal and Jirtle 2010).…”

Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression

“…8 Many types of environmental challenges imposed on the parent, such as hunger, specific diets, toxins, or trauma have been found to influence the development of the offspring. 3,[9][10][11][12] Whereas some studies examined the phenotype of immediate offspring, others observed changes in several subsequent generations. The transmission of phenotypic changes to grandchildren (F3 generation) and following generations is also termed 'transgenerational inheritance' and assumes that the inducing agent has not been in direct contact with the offspring, whereas an effect on the immediately succeeding generation may be termed 'intergenerational inheritance'.…”