The developing brain: What is the role of antenatal stress-mediated epigenetics

The human brain develops following a complex, highly orchestrated series of histogenic events that depend upon exquisite regulation of gene expression. As knowledge of human development increases, it is becoming evident that the foundations for much of our life are established prior to birth. Early life experiences long have been believed to be associated with long-lasting consequences including neuropsychiatric disease in the adult. From a combination of epidemiologic studies in humans and investigation in laboratory animals, has emerged the concept of in utero programming or the fetal origins of adult disease. This phenomenon is believed to occur by complex interactions between genetic heritage and the intrauterine environment. These stressinduced epigenetic changes that occur in the embryo or fetus can eventuate in a number of chronic clinical conditions in the adult offspring. These include: hypertension, coronary artery disease, metabolic syndrome, type 2 diabetes, and some malignancies. Associated neuropsychiatric disorders include schizophrenia, bipolar disorder, and a host of other syndromes. Of vital importance, antenatal stress such as maternal nutritional deprivation, hypoxia, environmental toxins, and other invidious factors can play a crucial role in mediating the epigenetic regulation/dysregulation of gene transcription, as well as influencing post-transcriptional mechanisms. These epidemiological associations raise the question of the mechanism(s) by which adverse early life experiences become integrated at the cellular-subcellular level into the architecture of the developing brain and other organs. Mechanistically, rather than genomic mutations in the DNA nucleotide sequence per se, environmental stress has been shown to alter epigenetic regulation of transcription by a mosaic of multifactorial mechanisms. These include: methylation of DNA nucleotide cytosine residues, methylation, acetylation, or other changes of the nucleosome core histone proteins, altered short RNA/transcription factor complexes (such as microRNAs), transcriptional splice variation, mitochondrial nuclear disorders, and/or other mechanisms. In short, these epigenetic-mediated molecular changes can play a major role not only in the genesis of many clinical disorders, but they even may have transgenerational effects. Beyond descriptive phenomenology, this Chapter will explore both population based epidemiologic and laboratory animal studies that support (and a few that argue against) the role of developmental epigenetics in adult disease. Importantly, we attempt to elucidate their fundamental cellular and molecular mechanisms, an understanding of which may allow for the implementation of antenatal maternal and early life interventions and/or targeted approaches to reprogram expression during development, and possibly later in life. Finally of considerable clinical relevance, we consider the relation of epigenetic changes in the developing organism to national and global health issues, and what we as basic scientists, obstetrician-gynecologists, pediatricians or other clinicians may do to help mitigate the associated pandemic of disease.