POINT-OF-VIEW Epigenetics 6:7, 838-842; July 2011; © 2011 Landes Bioscience Environmental epigenetic transgenerational inheritance and somatic epigenetic mitotic stability Michael K. Skinner Center for Reproductive Biology; School of Biological Sciences; Washington State University; Pullman, WA USA he majority of environmental fac- is responsive to environmental factors and Ttors can not modify DNA sequence, can directly impact the genetic cascade of but can influence the epigenome. The events. Just as there is a cascade of genetic mitotic stability of the epigenome and steps during development, a cascade of ability of environmental epigenetics to epigenetic steps also exists and impacts influence phenotypic variation and dis- the transcriptional stages of cellular dif- ease, suggests environmental epigenetics ferentiation and development (Fig. 1). will have a critical role in disease etiology Environmental epigenetics provides a and biological areas such as evolutionary direct molecular mechanism for environ- biology. The current review presents the mental factors or toxicants to influence molecular basis of how environment can the genetic cascade of events involved in promote stable epigenomes and modified development, such that the environment phenotypes, and distinguishes the dif- can directly impact biology. An interest- ference between epigenetic transgenera- ing element of these integrated molecular tional inheritance through the germ line events for developmental biology1 is the versus somatic cell mitotic stability. fact that critical windows of susceptibil- ity exist2 where the environmental factors Role of Environmental have a more dramatic ability to modify and Epigenetics in Development impact important stages of development and Biology (Fig. 1). These critical windows generally are very early in development, such as the A highly differentiated adult cell type or fetal or early postnatal periods, when the biological phenotype has been generated organ systems are rapidly developing and through a complex cascade of developmen- sensitive to subtle shifts in the epigenome.3 tal processes. The stem cell populations of These critical exposure windows allow an the embryo or selected tissues undergo a environmental factor or toxicant to per- cascade of genetic steps through cell fate manently modify an epigenome that then determinations, development of differen- continues throughout development to tiated cell types, organogenesis, specified impact genetic programming and result in physiological states and phenotypes. This a modified adult epigenome and genome genetic process includes classic transitions activity (transcriptome). This promotes in transcriptional control to lead to a cas- a susceptibility to develop disease or cre- Key words: epigenetic, transgenerational, cade of specific transcriptomes at each ates an increased biological variation in inheritance, mitotic, environmental, stage of development. This programmed phenotype that will facilitate an adapta- toxicants, evolution, disease etiology developmental process is hardwired and tion event and influence natural selection Submitted: 05/18/11 follows classic genetic processing. The (Fig. 1). genetic control of developmental biology is The stages or cascade of steps in both Revised: 05/19/11 stable and integrated into the overall phys- the genetics and epigenetics are highly DOI: 10.4161/epi.6.7.16537 iology and phenotype of the organism. In integrated and influence each other dur- Correspondence to: Michael K. Skinner; contrast to the genetic control of cellular ing the developmental process. Therefore, Email: [email protected] activity, the epigenetic cascade of events environmental epigenetics and genetics 838 Epigenetics Volume 6 Issue 7 POINT-OF-VIEW POINT-OF-VIEW Figure 1. Integration epigenetics and genetics in development. should not be considered mutually exclu- germ cell is being reprogrammed at the disease states or phenotype be transmit- sive, but instead highly integrated and DNA methylation level.10 The environ- ted through the germ line in the absence dependent on each other. The genome mental toxicant alters the DNA methyla- of direct exposure.11 If direct exposure of DNA sequence provides the stable nature tion to generate new imprinted-like sites the environmental factor is involved then of an organism that is hardwired and that then are transmitted to subsequent this would simply be direct exposure toxi- programmed. The epigenome provides a generations through the germ line (sperm) cology. An example is exposure of a ges- more plastic molecular process4-6 that is (Fig. 2). All the somatic cells derived from tating female that has the F0 female, F1 responsive to the environment to impact this germ line will have a baseline shift in fetus and germ line within the fetus that biology, disease etiology and evolutionary their epigenome and, as the cells differ- will generate the F2 generation directly biology. Epigenetics and genetics should entiate, a corresponding shift in genome exposed.17 Therefore, an F3 generation is be considered cooperative and together activity and transcriptomes that in some required to assess a potential transgenera- provide a more complex and integrated tissues will promote disease states or phe- tional phenotype from a gestating female molecular mechanism for the control of notypic variation (Fig. 2).11 The transmis- exposure.17 In the event an adult male or development and biology. sion of any genetic or epigenetic molecular female is exposed, the F0 generation adult information between generations requires and the germ line that will generate the Environmental Epigenetic germ line transmission and permanent F1 generation are directly exposed, such Transgenerational Inheritance alterations in DNA sequence or the epig- that an F2 generation is required to obtain enome.11 Due to the reprogramming of an epigenetic transgenerational pheno- Epigenetic transgenerational inheritance the epigenome (DNA methylation) at fer- type.18 Although previous literature has requires germ line transmission of epigen- tilization,10,11 the modified epigenetic sites suggested transgenerational phenotypes in etic information between generations in will need to be imprinted-like to escape F1 or F2 generations, these studies often the absence of direct environmental expo- the demethylation process.3,8,11,12 The sug- had direct exposures involved so can not sures. During a critical window of germ gestion that an altered epigenome may be considered epigenetic transgenerational cell development, embryonic gonadal sex increase genomic instability and allow inheritance phenotypes, but direct expo- determination in mammals, environmen- genetic mutations to develop in subse- sure toxicology. Epigenetic transgenera- tal factors or toxicants have been shown to quent generations12 remains a possibility tional inheritance phenotypes require the influence epigenetic programming in the that needs to be investigated further.7 lack of direct exposure to be considered male germ line (sperm), which becomes A number of environmental factors and transgenerational. permanently programmed (imprinted),7 toxicants have now been shown to promote Environmentally induced epigenetic and then allows the transgenerational epigenetic transgenerational inheritance transgenerational inheritance has signifi- transmission of adult onset disease pheno- of disease states or phenotypic variation cant impacts in the areas of disease etiol- types.8,9 The general mechanism for this including the fungicide vinclozolin,8 ogy, inheritance of phenotypic variation epigenetic transgenerational inheritance plastic compound bisphenol A (BPA),13 and evolutionary biology. This phenom- in mammals involves exposure of a gestat- toxicant dioxin,14 stress responses15 and enon provides an alternate to genetic ing female during the period of gonadal nutrition.16 A critical factor in epigenetic Mendelian inheritance that can provide sex determination when the primordial transgenerational inheritance is that the a molecular mechanism for how the www.landesbioscience.com Epigenetics 839 Figure 2. Scheme for epigenetic transgenerational inheritance. environment can influence disease etiol- The definition of “inheritance” is trans- population or associated physiology. The ogy and general biological phenotypes. mission of information between genera- ability to maintain a specific epigenome In regards to disease etiology, the familial tions of an organism, and is accepted by after mitosis is in part how different cell transmission or non-Mendelian charac- the public and general scientific commu- types maintain distinct differentiated teristics of a variety of disease states can nity as such. The ability of the epigenome states and facilitate a normal developmen- be explained. In regards to evolutionary to be replicated and transmitted upon tal process. biology, the ability to acquire an increased cellular proliferation through the mitotic The mechanisms involved in the rep- biological variation in phenotype follow- process is distinct and should be consid- lication of the epigenome during mitosis ing an ancestral environmental exposure ered “mitotic stability” not “inheritance”. are understood for DNA methylation will facilitate a potential adaptation event The use of the term epigenetic inheritance and small RNAs, but limited informa- to allow the natural selection process. has confused the scientific community tion exists for histone modifications and Environmental epigenetic transgenera- and public