Minireview: transgenerational epigenetic inheritance: focus on endocrine disrupting compounds

Abstract

The idea that what we eat, feel, and experience influences our physical and mental state and can be transmitted to our offspring and even to subsequent generations has been in the popular realm for a long time. In addition to classic gene mutations, we now recognize that some mechanisms for inheritance do not require changes in DNA. The field of epigenetics has provided a new appreciation for the variety of ways biological traits can be transmitted to subsequent generations. Thus, transgenerational epigenetic inheritance has emerged as a new area of research. We have four goals for this minireview. First, we describe the topic and some of the nomenclature used in the literature. Second, we explain the major epigenetic mechanisms implicated in transgenerational inheritance. Next, we examine some of the best examples of transgenerational epigenetic inheritance, with an emphasis on those produced by exposing the parental generation to endocrine-disrupting compounds (EDCs). Finally, we discuss how whole-genome profiling approaches can be used to identify aberrant epigenomic features and gain insight into the mechanism of EDC-mediated transgenerational epigenetic inheritance. Our goal is to educate readers about the range of possible epigenetic mechanisms that exist and encourage researchers to think broadly and apply multiple genomic and epigenomic technologies to their work.

Figure 1.

A cartoon of the multiple generations comprising transgenerational inheritance. A pregnant woman (P0) carries genetic and epigenetic information for up to the F2 generation. Her fetus (F1) and its germ cells (F2) may be affected by environmental exposures such as EDCs. For any changes in the F1 phenotype or epigenetic state to be considered transgenerational, the aberrant epigenetic state has to be sustained until at least the F3 generation. In contrast to females, EDC exposure in males (P0) will potentially change his germ cells, which will be the F1 generation. However, because the F2 germ cells are not exposed, any phenotypic or epigenetic changes noted in F2 can be considered transgenerational.

Figure 2.

Epigenomic features of expressed and silenced chromatin states. Genomic positions and patterns of various histone modifications are based on chromatin immunoprecipitation-sequencing–mediated epigenome mapping. Active genes are marked with H3K4me3 in their promoters and H3K36me3 in the gene body. Active enhancers are marked with H3K4me1 and H3K27 acetylation (ac). On the other hand, silenced genes have repressive H3K9me3 and H3K27me3 marks as well as DNA methylation in their promoter regions.

Figure 3.

A general model depicting epigenetic alterations upon exposure to EDCs. EDCs bind to steroid receptors, and other TFs, thereby changing the local chromatin states and expression of various chromatin modifiers (CM) such as histone and DNA modifiers or ncRNAs. Moreover, EDCs can change the composition or the activity of epigenetic chromatin regulator complexes and thereby act directly on the global epigenome.

Figure 4.

Hypothetical model for potential short-term and long-term effects of EDCs on the genome of germ cells. Direct exposure (in P0) to EDCs induces DRGRs. The chromatin features at some or all of these DRGRs may persist over generations (as pictured here in the F3) and be inherited transgenerationally. We are calling such regions “transgenerational epigenetically regulated regions” (TERRs). In example 1, a DRGR is present in both sexes after exposure to an EDC and retained transgenerationally. Example 2 illustrates a sex difference in establishment of a TERR. Example 3 is a transient DRGR that is not retained as a TERR.