Epigenetics in Reproduction

James H. Segars, Jr., M.D. Kjersti M. Aagaard-Tillery, M.D., Ph.D.

A fundamental tenet of modern biology is “the environment shapes the organism.” At the species level, the process of evolution involves selection of the fittest DNA specimens over time according to the principles outlined by Charles Darwin. The mechanism involved is the inheritance of genetic traits first described by Gregor Mendel and later understood to be attributable to differences in DNA sequence.

Early modern conception of “genes” as the backbone of inheritance originated with Mendel, a 19th-century Austrian monk who studied heredity in pea plants. Mendel's work, along with that of Wilhelm Johannsen, Thomas Hunt Morgan, Barbara McClintock, and others, led to our understanding of particulate inheritance, or the theory that inherited traits are passed from one generation to the next in discrete units (“genes” on “chromosomes”) that interact in well-defined ways. Since these early days of our understanding that genes and chromosomes function as the backbone of our genetic heredity, our view of heredity has been written in the language of DNA with the assumption that genetic mutations and changes in the nucleotide backbone have driven most descriptions of how phenotypic traits and diseases are handed down from one generation to another.

We now know that this mechanism is only partially correct. The environment shapes the organism through epigenetic mechanisms without effecting changes in DNA sequence. Recent discoveries in the field of epigenetics—the study of heritable changes in gene function that occur without a change in the DNA sequence—have blurred our thinking and are changing the way researchers think about heredity. Epigenetic mechanisms such as DNA methylation, histone acetylation, and RNA interference, and their effects upon gene activation and inactivation, are increasingly understood to have a profound effect in altering an individual's appearance, transmission of a specific congenital abnormality (“birth defect”), and even one's lifetime risk of common diseases such as obesity and cancer. Thus we have arrived at the point in our current understanding of “genetics” that although genomic DNA is the template of our heredity, it is the orchestration and regulation of its expression via epigenetic mechanisms in chromatin remodeling that contributes to the rich complexity and diversity among individuals observed in nature.

One of the most exciting attributes of epigenetic inheritance is the pace of change. The environment during development can lead to immediate changes in the phenotype of the organism that are then passed on to subsequent generations. Epigenetic mechanisms offer great plasticity to the organism's response to environmental challenges. The organism is particularly responsive to environmental challenges during reproduction and development because during gametogenesis, epigenetic imprints are erased and reestablished. The plasticity of change during reproduction and development is dual-sided because the organism is also vulnerable to untoward environmental influences and toxins that may adversely affect development. The effects are not limited to chemical toxins in the environment, but alterations in maternal nutrition may have effects on future generations, now commonly known as the developmental origins of disease hypothesis (or colloquially as Barker's hypothesis).

According to the fetal origins of adult disease hypothesis, perturbations in the in utero environment influence the development of diseases later in life. This was first observed to occur in response to maternal nutritional constraints that resulted in a growth-restricted infant who later developed profound metabolic changes including obesity, insulin resistance, hypertension, heart disease, and lipid disorders. Work in animal models provide multiple and converging lines of evidence to indicate that these lifelong disease risks occur through the static reprogramming of gene expression via epigenetic alterations in chromatin structure (or changes in the “histone code”).

The goal of this monograph is to provide readers with an up-to-date understanding of epigenetics and reproduction. To achieve that goal, the subsequent articles examine the role of epigenetics in parlaying the environmental milieu on the male and female gametes, the effects of the in utero environment on developing offspring, and finally the role of environmental exposures in profoundly shaping an individual's phenotype. Because animal models are the cornerstone for scientific proof of epigenetic effects, current models are described by leaders in the field. The coauthors hope readers will find this issue both an authoritative and interesting review of the subject.