ENVIRONMENTAL EPIGENETICS AND ADULT DISEASE INTRODUCTION Early life environment predicts future health.

This is the core tenet of the Fetal Origin of Adult Disease Hypothesis. The direct impact of rapid changes in our world brought forth by industry, technology, population growth, diet, environmental exposures and all other epochs combined has signifantly affected the population health. Reports exist revealing significant increase in multiple chronic pathologic changes ranging from autism to szhizophrenia, from autoimmune disease to serious infectious disease and from obesity to diabetes. The indirect impact is also significant in terms of health care expenditure. The initial clues that epigenetics may be one of those mechanisms came from patterns observed in th following pioneering studies. VARIOUS STUDIES The studies include Early studies of barker and collaegues and 2 population cohorts The Nurses Health Study and Dutch famine of 1944 to 1945. An important and reasonable assumption for these studies was that poor fetal nurition leads to LBW. Subsequently LBW was used as a phenotypic marker of poor fetal nutrition or an abnormal environment. Of all these cohorts Dutch famine which lasted for 5 months at its extreme height neither lactating nor pregnant women received supplemental rations. The aggregate impact of the insult lead to increased adult incidence of multiple chronic pathologies including schizophrenia spectrum disorders, antisocial personality disorders, affective disorder, obstructive airway disease, CAD, HTN, Dyslipidemia, DM and obesity. Chinese famine is similar to dutch famine and it also affected the offspring of those mothers who endured its impact by reducing the adult height and by affecting population neurodevelopmental outcome. Racial Disparities and environmental epigentics: The observations wich support the role of epigenetics are 1) In women who are normal weight at birth and experiencing neighbourhood poverty, the rate of LBW is less than those who are LBW at birth. So maternal birth weight is a better predictor of pregnancy. This may be due to neuroendocrine reprogramming that seems to occur in LBW mother extremely vulnerable to higher stress reactivity. 2) Sadder is a more recent study that demonstrates perinatal mortality higher in women born in US regardless of race and individual risk factors than their foreign-born counter parts which shows the impact of environment in pregnancy health and further the role of epigenetics.

3) Epigenetics is the study of heritable changes in gene activity which are not caused by changes in the DNA sequence. The term also refers to the changes themselves: functionally relevant changes to the genome that do not involve a change in the nucleotide sequence. Examples of mechanisms that produce such changes are DNA methylation and histone modification, miRNA, lncRNA, etc., each of which alters how genes are expressed without altering the underlying DNA sequence. Glucocorticoid Biology: Although innumerable examples exist of isolated observations on how fetal environment epigenetics leads to later life disease, the impact of poor fetal nutrition upon GR and GC homeostasis provides a useful paradigm. Glucocorticoid receptor: Adaptation and differential expression of GR depends on transcriptional control of the complex 5UTR. Studies in rat model shows that poor fetal nutrition and fetal stress leading to low birth weight affect hippocampal GR DNA methylation and histone modification. Rodent models of LBW utilizing poor fetal nutrition often find altered hippocampal GR mRNA expression. Hippocampus is often studied in these models because it is particularly vulnerable to prenatal insults, and the hippocampus is involved in feedback circuitry with the HPA axis. Glucocorticoid Hoemostasis: The impact of poor fetal nutrition upon GC homeostasis is most widely studied through 2 approaches. The first approach involves studying HPA reactivity and the result is postnatal HPA chronic hyperactivity. The second approach involves the placenta, which is a significant dterminant of in utero fetal nutritional and hormonal milieu. Placental expression of genes involved in GC homeostasis change in response to environmental stress such as altered fetal nutrition. For eg, when 480 placenta were assessed for DNA methylation at GR gne, an association become evident between differential methylation and LGA. Similarly methylation of the GR promoter in placentas of genetically susceptible infants may also predict neurodevelopmental issues. Personalised medicine: So assessing GR epigenetics and expression in lymphocytes presents an oppurtunity not only to predict the disease but also permit bench marking intervention. Environmental epigenetcs are a key component of the future of personalized medicine.