Editing Maternal effect (section)

==Maternal diet and environment epigenetically influences susceptibility for adult diseases==

===Hyperglycemia during gestation correlated with obesity and heart disease in adulthood===

[[Hyperglycemia]] during pregnancy is thought to cause epigenetic changes in the leptin gene of newborns leading to a potential increased risk for obesity and heart disease. [[Leptin]] is sometimes known as the “satiety hormone” because it is released by fat cells to inhibit hunger. By studying both animal models and human observational studies, it has been suggested that a leptin surge in the perinatal period plays a critical role in contributing to long-term risk of obesity. The perinatal period begins at 22 weeks gestation and ends a week after birth.[34]  DNA methylation near the leptin locus has been examined to determine if there was a correlation between maternal glycemia and neonatal leptin levels. Results showed that glycemia was inversely associated with the methylation states of LEP gene, which controls the production of the leptin hormone.  Therefore, higher glycemic levels in mothers corresponded to lower methylation states in LEP gene in their children. With this lower methylation state, the LEP gene is transcribed more often, thereby inducing higher blood leptin levels.<ref>{{cite journal |vauthors=Allard C, Desgagné V, Patenaude J, Lacroix M, Guillemette L, Battista MC, Doyon M, Ménard J, Ardilouze JL, Perron P, Bouchard L, Hivert MF |title=Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns |journal=Epigenetics |volume=10 |issue=4 |pages=342–51 |year=2015 |pmid=25800063 |doi=10.1080/15592294.2015.1029700 |pmc=4622547 }}</ref>  These higher blood leptin levels during the perinatal period were linked to obesity in adulthood, perhaps due to the fact that a higher “normal” level of leptin was set during gestation.  Because obesity is a large contributor to heart disease, this leptin surge is not only correlated with obesity but also heart disease.

===High fat diets during gestation correlated with metabolic syndrome===
High fat diets in utero are believed to cause metabolic syndrome. [[Metabolic syndrome]] is a set of symptoms including obesity and insulin resistance that appear to be related.  This syndrome is often associated with type II diabetes as well as hypertension and atherosclerosis.  Using mice models, researchers have shown that high fat diets in utero cause modifications to the [[adiponectin]] and leptin genes that alter gene expression; these changes contribute to metabolic syndrome.  The adiponectin genes regulate glucose metabolism as well as fatty acid breakdown; however, the exact mechanisms are not entirely understood.  In both human and mice models, adiponectin has been shown to add insulin-sensitizing and anti-inflammatory properties to different types of tissue, specifically muscle and liver tissue.  Adiponectin has also been shown to increase the rate of fatty acid transport and oxidation in mice, which causes an increase in fatty acid metabolism.<ref name="care.diabetesjournals.org">{{cite journal |vauthors=Chandran M, Phillips SA, Ciaraldi T, Henry RR |title=Adiponectin: more than just another fat cell hormone? |journal=Diabetes Care |volume=26 |issue=8 |pages=2442–50 |year=2003 |pmid=12882876 |doi=10.2337/diacare.26.8.2442 |doi-access=free }}</ref>  With a high fat diet during gestation, there was an increase in methylation in the promoter of the adiponectin gene accompanied by a decrease in acetylation. These changes likely inhibit the transcription of the adiponectin genes because increases in methylation and decreases in acetylation usually repress transcription.  Additionally, there was an increase in methylation of the leptin promoter, which turns down the production of the leptin gene.  Therefore, there was less adiponectin to help cells take up glucose and break down fat, as well as less leptin to cause a feeling of satiety.  The decrease in these hormones caused fat mass gain, glucose intolerance, hypertriglyceridemia, abnormal adiponectin and leptin levels, and hypertension throughout the animal's lifetime.  However, the effect was abolished after three subsequent generations with normal diets. This study highlights the fact that these epigenetic marks can be altered in as many as one generation and can even be completely eliminated over time.<ref>{{cite journal |vauthors=Masuyama H, Mitsui T, Nobumoto E, Hiramatsu Y |title=The Effects of High-Fat Diet Exposure In Utero on the Obesogenic and Diabetogenic Traits Through Epigenetic Changes in Adiponectin and Leptin Gene Expression for Multiple Generations in Female Mice |journal=Endocrinology |volume=156 |issue=7 |pages=2482–91 |year=2015 |pmid=25853666 |doi=10.1210/en.2014-2020 |doi-access=free }}</ref>  This study highlighted the connection between high fat diets to the adiponectin and leptin in mice.  In contrast, few studies have been done in humans to show the specific effects of high fat diets in utero on humans.  However, it has been shown that decreased adiponectin levels are associated with obesity, insulin resistance, type II diabetes, and coronary artery disease in humans.  It is postulated that a similar mechanism as the one described in mice may also contribute to metabolic syndrome in humans.<ref name="care.diabetesjournals.org"/>

===High fat diets during gestation correlated with chronic inflammation===

In addition, high fat diets cause chronic low-grade inflammation in the placenta, adipose, liver, brain, and vascular system. [[Inflammation]] is an important aspect of the bodies’ natural defense system after injury, trauma, or disease.  During an inflammatory response, a series of physiological reactions, such as increased blood flow, increased cellular metabolism, and vasodilation, occur in order to help treat the wounded or infected area.  However, chronic low-grade inflammation has been linked to long-term consequences such as cardiovascular disease, renal failure, aging, diabetes, etc.  This chronic low-grade inflammation is commonly seen in obese individuals on high fat diets.  In a mice model, excessive [[cytokine]]s were detected in mice fed on a high fat diet.  Cytokines aid in cell signaling during immune responses, specifically sending cells towards sites of inflammation, infection, or trauma.  The mRNA of proinflammatory cytokines was induced in the placenta of mothers on high fat diets.  The high fat diets also caused changes in microbiotic composition, which led to hyperinflammatory colonic responses in offspring.  This hyperinflammatory response can lead to [[inflammatory bowel disease]]s such as [[Crohn's disease]] or [[ulcerative colitis]].[35]  As previously mentioned, high fat diets in utero contribute to obesity; however, some proinflammatory factors, like IL-6 and MCP-1, are also linked to body fat deposition.  It has been suggested that histone acetylation is closely associated with inflammation because the addition of [[histone deacetylase inhibitor]]s has been shown to reduce the expression of proinflammatory mediators in [[Neuroglia|glial cells]].  This reduction in inflammation resulted in improved neural cell function and survival.  This inflammation is also often associated with obesity, cardiovascular disease, [[fatty liver]], brain damage, as well as preeclampsia and preterm birth.  Although it has been shown that high fat diets induce inflammation, which contribute to all these chronic diseases; it is unclear as to how this inflammation acts as a mediator between diet and chronic disease.<ref>{{cite journal |vauthors=Zhou D, Pan YX |title=Pathophysiological basis for compromised health beyond generations: role of maternal high-fat diet and low-grade chronic inflammation |journal=The Journal of Nutritional Biochemistry |volume=26 |issue=1 |pages=1–8 |year=2015 |pmid=25440222 |doi=10.1016/j.jnutbio.2014.06.011 |doi-access=free }}</ref>

===Undernutrition during gestation correlated with cardiovascular disease===

A study done after the Dutch Hunger Winter of 1944-1945 showed that undernutrition during the early stages of pregnancy are associated with hypomethylation of the [[Insulin-like growth factor 2|insulin-like growth factor II (IGF2)]] gene even after six decades.  These individuals had significantly lower methylation rates as compared to their same sex sibling who had not been conceived during the famine.  A comparison was done with children conceived prior to the famine so that their mothers were nutrient deprived during the later stages of gestation; these children had normal methylation patterns. The IGF2 stands for insulin-like growth factor II; this gene is a key contributor in human growth and development.  IGF2 gene is also maternally [[Genomic imprinting|imprinted]] meaning that the mother's gene is silenced.  The mother's gene is typically methylated at the differentially methylated region (DMR); however, when hypomethylated, the gene is bi-allelically expressed.  Thus, individuals with lower methylation states likely lost some of the imprinting effect.  Similar results have been demonstrated in the Nr3c1 and Ppara genes of the offspring of rats fed on an isocaloric protein-deficient diet before starting pregnancy.  This further implies that the undernutrition was the cause of the epigenetic changes.  Surprisingly, there was not a correlation between methylation states and birth weight.  This displayed that birth weight may not be an adequate way to determine nutritional status during gestation.  This study stressed that epigenetic effects vary depending on the timing of exposure and that early stages of mammalian development are crucial periods for establishing epigenetic marks.  Those exposed earlier in gestation had decreased methylation while those who were exposed at the end of gestation had relatively normal methylation levels.<ref name="pnas.org">{{cite journal |vauthors=Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES, Slagboom PE, Lumey LH |title=Persistent epigenetic differences associated with prenatal exposure to famine in humans |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=105 |issue=44 |pages=17046–9 |year=2008 |pmid=18955703 |pmc=2579375 |doi=10.1073/pnas.0806560105 |bibcode=2008PNAS..10517046H |doi-access=free }}</ref>  The offspring and descendants of mothers with hypomethylation were more likely to develop cardiovascular disease.  Epigenetic alterations that occur during embryogenesis and early fetal development have greater physiologic and metabolic effects because they are transmitted over more mitotic divisions.  In other words, the epigenetic changes that occur earlier are more likely to persist in more cells.<ref name="pnas.org"/>

===Nutrient restriction during gestation correlated with diabetes mellitus type 2===

In another study, researchers discovered that perinatal nutrient restriction resulting in [[intrauterine growth restriction]] (IUGR) contributes to [[diabetes mellitus type 2]] (DM2).  IUGR refers to the poor growth of the baby in utero.  In the pancreas, IUGR caused a reduction in the expression of the promoter of the gene encoding a critical transcription factor for beta cell function and development.  Pancreatic beta cells are responsible for making insulin; decreased beta cell activity is associated with DM2 in adulthood.  In skeletal muscle, IUGR caused a decrease in expression of the Glut-4 gene.  The Glut-4 gene controls the production of the Glut-4 transporter; this transporter is specifically sensitive to insulin.  Thus, when insulin levels rise, more glut-4 transporters are brought to the cell membrane to increase the uptake of glucose into the cell.  This change is caused by histone modifications in the cells of skeletal muscle that decrease the effectiveness of the glucose transport system into the muscle. Because the main glucose transporters are not operating at optimal capacity, these individuals are more likely to develop [[insulin resistance]] with energy rich diets later in life, contributing to DM2.<ref>{{cite journal |vauthors=Lopez-Jaramillo P, Gomez-Arbelaez D, Sotomayor-Rubio A, Mantilla-Garcia D, Lopez-Lopez J |title=Maternal undernutrition and cardiometabolic disease: a Latin American perspective |journal=BMC Medicine |volume=13 |pages=41 |year=2015 |pmid=25858591 |pmc=4346113 |doi=10.1186/s12916-015-0293-8 |doi-access=free }} {{open access}}</ref>

===High protein diet during gestation correlated with higher blood pressure and adiposity===
Further studies have examined the epigenetic changes resulting from a high protein/low carbohydrate diet during pregnancy.  This diet caused epigenetic changes that were associated with higher blood pressure, higher [[cortisol]] levels, and a heightened [[Hypothalamic–pituitary–adrenal axis|Hypothalamic-pituitary-adrenal (HPA) axis]] response to stress.  Increased methylation in the 11β-hydroxysteroid dehydrogenase type 2 (HSD2), [[Glucocorticoid receptor|glucocorticoid receptor (GR)]], and [[H19 (gene)|H19]] ICR were positively correlated with adiposity and blood pressure in adulthood.  Glucocorticoids play a vital role in tissue development and maturation as well as having effects on metabolism.  Glucocorticoids’ access to GR is regulated by HSD1 and HSD2.  H19 is an imprinted gene for a [[Long non-coding RNA|long coding RNA (lncRNA)]], which has limiting effects on body weight and cell proliferation.  Therefore, higher methylation rates in H19 ICR repress transcription and prevent the lncRNA from regulating body weight.  Mothers who reported higher meat/fish and vegetable intake and lower bread/potato intake in late pregnancy had a higher average methylation in GR and HSD2.  However, one common challenge of these types of studies is that many epigenetic modifications have tissue and cell-type specificity DNA methylation patterns.  Thus, epigenetic modification patterns of accessible tissues, like peripheral blood, may not represent the epigenetic patterns of the tissue involved in a particular disease.<ref>{{cite journal |vauthors=Drake AJ, McPherson RC, Godfrey KM, Cooper C, [[Karen A. Lillycrop|Lillycrop KA]], Hanson MA, Meehan RR, Seckl JR, Reynolds RM |title=An unbalanced maternal diet in pregnancy associates with offspring epigenetic changes in genes controlling glucocorticoid action and foetal growth |journal=Clinical Endocrinology |volume=77 |issue=6 |pages=808–15 |year=2012 |pmid=22642564 |doi=10.1111/j.1365-2265.2012.04453.x |s2cid=28199749 |doi-access=free }}</ref>

===Neonatal estrogen exposure correlated with prostate cancer===

Strong evidence in rats supports the conclusion that neonatal [[estrogen]] exposure plays a role in the development of [[prostate cancer]]. Using a human fetal prostate xenograft model, researchers studied the effects of early exposure to estrogen with and without secondary estrogen and testosterone treatment.  A [[Xenotransplantation|xenograft model]] is a graft of tissue transplanted between organisms of different species.  In this case, human tissue was transplanted into rats; therefore, there was no need to extrapolate from rodents to humans.  Histopathological lesions, proliferation, and serum hormone levels were measured at various time-points after xenografting. At day 200, the xenograft that had been exposed to two treatments of estrogen showed the most severe changes. Additionally, researchers looked at key genes involved in prostatic glandular and stromal growth, cell-cycle progression, apoptosis, hormone receptors, and tumor suppressors using a custom PCR array. Analysis of DNA methylation showed methylation differences in CpG sites of the stromal compartment after estrogen treatment. These variations in methylation are likely a contributing cause to the changes in the cellular events in the KEGG prostate cancer pathway that inhibit apoptosis and increase cell cycle progression that contribute to the development of cancer.<ref>{{cite journal |vauthors=Saffarini CM, McDonnell-Clark EV, Amin A, Huse SM, Boekelheide K |title=Developmental exposure to estrogen alters differentiation and epigenetic programming in a human fetal prostate xenograft model |journal=PLOS ONE |volume=10 |issue=3 |pages=e0122290 |year=2015 |pmid=25799167 |pmc=4370592 |doi=10.1371/journal.pone.0122290 |bibcode=2015PLoSO..1022290S |doi-access=free }} {{open access}}</ref>

=== Supplementation may reverse epigenetic changes ===

In utero or neonatal exposure to [[Bisphenol A|bisphenol A (BPA)]], a chemical used in manufacturing polycarbonate plastic, is correlated with higher body weight, breast cancer, prostate cancer, and an altered reproductive function. In a mice model, the mice fed on a BPA diet were more likely to have a yellow coat corresponding to their lower methylation state in the promoter regions of the retrotransposon upstream of the Agouti gene.  The Agouti gene is responsible for determining whether an animal's coat will be banded (agouti) or solid (non-agouti).  However, supplementation with methyl donors like folic acid or phytoestrogen abolished the hypomethylating effect.  This demonstrates that the epigenetic changes can be reversed through diet and supplementation.<ref>{{cite journal |vauthors=Dolinoy DC, Huang D, Jirtle RL |title=Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=104 |issue=32 |pages=13056–61 |year=2007 |pmid=17670942 |pmc=1941790 |doi=10.1073/pnas.0703739104 |bibcode=2007PNAS..10413056D |doi-access=free }}</ref>