Human Behavior and the Social Environment II Part III Chapter 14 Childhood Experiences & Epigenetics

Chapter 14 Childhood Experiences Explain how may impact child development and generational cycles of poverty and abuse . Discuss how stress programming can impact a childs development and potentially influence the development of mental health diagnoses and substance use disorders . Discuss the ACE and how to offset abuse and trauma experienced in childhood . Early childhood experience The development of an individual is an active process of adaptation that occurs within a social and economic context . For example , the closeness or degree of positive attachment of the Chapter 14 Childhood Experiences 491

parent ( typically the mother ) bond and parental investment ( including nutrient supply provided by the parent ) that define early childhood experience also program the development of individual differences in stress responses in the brain , which then affect memory , attention , and emotion . In terms of evolution , this process provides the offspring with the ability to physiologically adjust gene expression profiles contributing to the organization and function of neural circuits and molecular pathways that support ( biological defensive systems for survival ( stress resilience ) reproductive success to promote establishment and persistence in the present environment , and ( adequate parenting in the next generation ( 1965 ) Parental investment and programming of stress responses in the offspring The most comprehensive study to date of variations in parental investment and epigenetic inheritance in mammals is that of the maternally transmitted responses to stress in rats . In rat pups , maternal nurturing ( licking and grooming ) during the first week of life is associated with programming of individual differences in stress responsiveness , emotionality , cognitive performance , and reproductive behavior ( et , 1998 Francis , Liu , 1999 Liu et , 1997 Myers , Squire , 1989 Stern , 1997 ) In adulthood , the offspring of mothers that exhibit increased levels of pup licking and grooming over the first week of life show increased expression of the receptor in the hippocampus ( a brain structure associated with stress responsivity as well as learning and memory ) and a lower hormonal response to stress compared with adult 492 I Chapter 14 Childhood Experiences

animals reared by low licking and grooming mothers ( Francis et , 1999 Liu et , 1997 ) Moreover , rat pups that received low levels of maternal licking and grooming during the first week of life showed decreased histone acetylation and increased DNA methylation of a promoter of the receptor gene ( Weaver et , 2004 ) The expression of this gene is then reduced , the number of receptors in the brain is decreased , and the animals show a higher hormonal response to stress throughout their life . The effects of maternal care on stress hormone responses and behavior in the offspring can be eliminated in adulthood by pharmacological treatment ( inhibitor A , TSA ) or dietary amino acid supplementation ( methyl donor ) treatments that influence histone acetylation , DNA methylation , and expression of the receptor gene ( Weaver et , 2004 Weaver et , 2005 ) This series of experiments shows that histone acetylation and DNA methylation of the receptor gene promoter is a necessary link in the process leading to the physiological and behavioral sequelae of poor maternal care . This points to a possible molecular target for treatments that may reverse or ameliorate the traces of childhood maltreatment . Several studies have attempted to determine to what extent the findings from model animals are transferable to humans . Examination of brain tissue from healthy human subjects found that the human equivalent of the receptor gene promoter ( exon promoter ) is also unique to the individual ( Turner , amp Muller , 2008 ) A similar study examining newborns showed that methylation of the receptor gene promoter may be an early epigenetic marker of maternal mood and risk of increased hormonal responses to stress in infants months of age ( et , 2008 ) Although further studies are required to examine the functional consequence of this DNA methylation , these findings are consistent with our studies in the neonate and adult offspring of low licking Chapter 14 Childhood Experiences 493

and grooming mothers that show increased DNA methylation of the promoter of the receptor gene , decreased receptor gene expression , and increased hormonal responses to stress ( Weaver et , 2004 ) Examinations of brain tissue from suicide victims found that the human receptor gene promoter is also more methylated in the brains of individuals who had experienced maltreatment during childhood ( et , 2009 ) This finding suggests that DNA methylation the effects of early environment in both rodents and humans and points to the possibility of new therapeutic approaches stemming from translational epigenetic research . Indeed , similar processes at comparable epigenetic labile regions could explain why the adult offspring of high and low mothers exhibit widespread differences in hippocampal gene expression and cognitive function ( Weaver , amp , 2006 ) However , this type of research is limited by the inaccessibility of human brain samples . The translational potential of this finding would be greatly enhanced if the relevant epigenetic modification can be measured in an accessible tissue . Examination of blood samples from adult patients with bipolar disorder , who also retrospectively reported on their experiences of childhood abuse and neglect , found that the degree of DNA methylation of the human receptor gene promoter was strongly positively related to the reported experience of childhood maltreatment decades earlier . For a relationship between a molecular measure and reported historical exposure , the size of the effect is extraordinarily large . This opens a range of new possibilities given the large effect size and consistency of this association , measurement of the promoter methylation may effectively become a blood test measuring the physiological traces left on the genome by early experiences . Although this blood test can not replace current methods of diagnosis , this unique and additional information adds to our knowledge of how the disease may arise and be manifested throughout life . research 494 Chapter 14 Childhood Experiences

will examine whether this measure adds value over and above simple reporting of early adversities when it comes to predicting important outcomes , such as response to treatment or suicide . Child nutrition and the The old adage you are what you eat might be true on more than just a physical level The food you choose ( and even what your parents and grandparents chose ) is reflected in your own personal development and risk for disease in adult life ( Wells , 2003 ) Nutrients can reverse or change DNA methylation and histone modifications , thereby modifying the expression of critical genes associated with and pathologic processes , including embryonic development , aging , and carcinogenesis . It appears that nutrients can influence the either by directly inhibiting enzymes that catalyze DNA methylation or histone modifications or by altering the availability of necessary for those enzymatic reactions . For example , rat mothers fed a diet low in methyl group donors during pregnancy produce offspring with reduced expression , decreased DNA methylation , and increased histone acetylation at promoter regions of specific genes , including the receptor , and increased gene expression in the liver of juvenile offspring ( Phillips , Jackson , Hanson , amp , 2005 ) and adult offspring ( et , 2007 ) These data suggest that early life nutrition has the potential to influence epigenetic programming in the brain not only during early development but also in adult life , thereby modulating health throughout life . In this regard , nutritional has been viewed as an attractive tool to prevent pediatric developmental diseases and cancer , as well as to delay associated processes . The best evidence relating to the impact of adverse Chapter 14 Childhood Experiences 495

environmental conditions development and health comes from studies of the children of women who were pregnant during two civilian famines of World War II the Siege of ( 2001 ) and the Dutch Hunger Winter ( Stanner et , 1997 ) In the Netherlands famine , women who were previously were subjected to low caloric intake and associated environmental stressors . Women who endured the famine in the late stages of pregnancy gave birth to smaller babies ( Stein , 1997 ) and these children had an increased risk of insulin resistance later in life ( Painter , 2005 ) In addition , offspring who were starved prenatally later experienced impaired glucose tolerance in adulthood , even when food was more abundant ( Stanner et , 1997 ) Famine exposure at various stages of gestation was associated with a wide range of risks such as increased obesity , higher rates of coronary heart disease , and lower birth weight ( Stein , 1997 ) Interestingly , when examined 60 years later , people exposed to famine prenatally showed reduced DNA methylation compared with their unexposed siblings ( et , 2008 ) References , 2001 ) Fetal experience and good adult design . International Journal of Epidemiology , 30 ( AD . 1965 ) Evolutionary significance of phenotypic plasticity in plants . Advances in Genetics , 13 , Sharma , Francis , 1998 ) Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat . Proceedings of the National Academy of Sciences A , 95 ( 496 Chapter 14 Childhood Experiences

Francis , Liu , 1999 ) transmission across generations of maternal behavior and stress responses in the rat . Science , 286 ( 5442 ) Stein , Putter , 2008 ) Persistent epigenetic differences associated with prenatal exposure to famine in humans . Proceedings of the National Academy of Sciences A , 105 ( 44 ) doi 0806560105 , Phillips , Jackson , A . Hanson , 2005 ) Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring . Journal of Nutrition , 135 ( doi , Hanson , Godfrey , Jackson , A . 2007 ) Induction of altered epigenetic regulation of the hepatic receptor in the offspring of rats fed a diet during pregnancy suggests that reduced DNA expression is involved in impaired DNA methylation and changes in histone modifications . British Journal of Nutrition , 97 ( doi Liu , Francis , Freedman , 1997 ) Maternal care , hippocampal receptors , and responses to stress see comments . Science , 277 ( 5332 ) Stein , 1997 ) Offspring birth weights after maternal intrauterine undernutrition a comparison within . American Journal of Epidemiology , 146 ( 10 ) Chapter 14 Childhood Experiences 497

, 2009 ) Epigenetic regulation of the receptor in human brain associates with childhood abuse . Nature Neuroscience , 12 ( doi Myers , Squire , A . 1989 ) Relationships between maternal behavior of and dams and adult blood pressures of pups . Developmental Psychobiology , 22 ( 2008 ) Prenatal exposure to maternal depression , neonatal methylation of human receptor gene ( and infant cortisol stress responses . doi 6034 Painter , 2005 ) Prenatal exposure to the Dutch famine and disease in later life an overview . Reproductive Toxicology , 20 ( doi ( 05 ) Reproductive Stanner , Andres , Poteen , 1997 ) Does malnutrition in utero determine diabetes and coronary heart disease in adulthood ?

Results from the siege study , a study . British Medical Journal , 315 ( 7119 ) Stern , 1997 ) parallels . Developmental , 31 ( Turner , Muller , 2008 ) Highly individual methylation patterns of alternative receptor promoters suggest individualized epigenetic regulatory mechanisms . Nucleic Acids Research , 36 ( 22 ) doi 498 Chapter 14 Childhood Experiences

Weaver , Champagne , Sharma , 2004 ) Epigenetic programming by maternal behavior . Nature Neuroscience , doi Weaver , Champagne , Brown , Sharma , 2005 ) Reversal of maternal programming of stress responses in adult offspring through methyl supplementation altering epigenetic marking later in life . Journal of Neuroscience , 25 ( 47 ) doi Weaver , 2006 ) Maternal care effects on the hippocampal and behaviors in the offspring that are reversible in adulthood . Proceedings of the National Academy of Sciences A , 103 ( doi Wells , 2003 ) The thrifty phenotype hypothesis thrifty offspring or thrifty mother ?

Journal of Theoretical Biology , 221 ( Attribution Adapted from in Psychology by Ian Weaver under the license . Chapter 14 Childhood Experiences 499