Abstract
Early experiences can modify regulatory factors affecting gene expression in such a way that, although the DNA sequence itself is not changed, the individual’s physiology and behavior is substantially influenced. In some instances these epigenetic effects are exerted upon exposure, while in other instances they are transmitted across generations via incorporation into the germline. Examples of both types of epigenetic effects are presented. First, experience with siblings (littermates) organizes behaviors and their underlying neural substrates in such a way that, as adults, rats and knockout mice behave differently. Second, exposure to the fungicide vinclozolin early in pregnancy imprints the male lineage in such a manner that rats exhibit distinct behavioral profiles as well as unique patterns of gene expression in relevant brain regions. Taken together, this work demonstrates that present and past environments alike modify both social and affiliative related behaviors and their related metabolic activity in specific brain nuclei as well as influencing the abundance of specific genes altering the epigenome in the target brain areas.
Article PDF
Similar content being viewed by others
References
Kaminsky Z, Wang SC, Petronis A, 2006 Complex disease, gender and epigenetics. Ann Med 38: 530–544.
Ptak C, Petronis A, 2008 Epigenetics and complex disease: From etiology to new therapeutics. Ann Rev Pharmacol Toxicol 48: 257–276.
Yaeger D, Smith HG, Altshuler LL, 2006 atypical antipsychotics in the treatment of schizophrenia during pregnancy and the postpartum. Am J Psychiatry 163: 2064–2070.
Hines M, Brook C, Conway GS, 2004 Androgen and psychosexual development: core gender identity, sexual orientation and recalled childhood gender role behavior in women and men with congenital adrenal hyperplasia CAH. J Sex Res 41: 75–81.
Mill J, Petronis A, 2008 Pre- and peri-natal environmental risks for attention-deficit hyperactivity disorder ADHD: The potential role of epigenetic processes in mediating susceptibility. J Child Psychol Psychiatry 49: 1020–1030.
Resnick SM, Gottesman II, McGue M, 1993 Sensation seeking in opposite-sex twins: an effect of prenatal hormones? Behav Genet 23: 323–329.
Cohen-Bendahan CC, Buitelaar JK, van Goozen SH, Cohen-Kettenis PT, 2004 Prenatal exposure to testosterone and functional cerebral lateralization: A study in same-sex and opposite-sex twin girls. Psychoneuroendocrinol 29: 911–916.
Cohen-Bendahan CC, Buitelaar JK, van Goozen SH, Orlebeke JF, Cohen-Kettenis PT, 2005 Is there an effect of prenatal testosterone on aggression and other behavioral traits? A study comparing same-sex and opposite-sex twin girls. Horm Behav 47: 230–237.
Fried-Cassoria M, Scholl TO, Borow LD, Strassman HD, Bowers EJ 1987 Depression and diethylstilbestrol exposure in women. J Reprod Med 32: 847–850.
Pillard RC, Rosen LR, Meyer-Bahlburg H, et al, 1993 Psychopathology and social functioning in men prenatally exposed to diethylstilbestrol DES. Psychosom Med 55: 485–491.
Vessey MP, Fairweather DV, Norman-Smith B, Buckley J, 1983 A randomized double-blind controlled trial of the value of stilboestrol therapy in pregnancy: Long-term follow-up of mothers and their offspring. Br J Obstet Gynaecol 90: 1007–1017.
Landrigan PJ, Kimmel CA, Correa A, Eskanzai B, 2004 Children’s health and the environment: Public health issues and challenges for risk assessment. Environ Health Perspect 112: 257–265.
Bateson P, Barker D, Clutton-Brock T, et al, 2004 Developmental plasticity and human health. Nature 430: 419–421.
Barker DJ, 2003 The developmental origins of adult disease. Eur J Epidemiol 18: 733–736.
Gluckman PD, Hanson MA, 2005 The Fetal Matrix: Evolution Development and Disease. Cambridge University Press, Cambridge.
Perisco AM, Bourgeron T, 2006 Searching for ways out of the autism maze: genetic epigenetic and environmental clues. Trends Neurosci 29: 349–358.
Tsankova N, Renthal W, Kumar A, Nestler EJ, 2007 Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 8: 355–367.
Crews D, 2008 Epigenetics and its implications for behavioral neuroendocrinology. Front Neuroendocrinol 29: 344–357.
Jirtle RL, Skinner MK, 2007 Environmental epigenomics and disease susceptibility. Nature Rev Genetics 8: 253–262.
Waterland RA, Lin JR, Smith CA, Jirtle JG, 2006 Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (lg2) locus. Hum Mol Genet 15: 705–716.
Dolinoy DC, Weidman JR, Jirtle RL, 2007 Epigenetic gene regulation: Linking early developmental environment to adult disease. Reprod Toxicol 23: 297–307.
Waterland RA, Dolinoy DC, Lin JR, Smith CA, Shi X, Tahiliani KG, 2006 Maternal methyl supplements increase offspring DNA methylation at Axin Fused. Genesis 44: 401–406.
Weaver IC, Champagne FA, Brown SE, et al, 2005 Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: Altering epigenetic marking later in life. J Neurosci 25: 11045–11054.
Weaver IC, Meaney JJ, Szyf M, 2006 Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proc Nat Acad Sci USA 103: 3480–3484.
Meaney MJ, 2001 Maternal care gene expression and the transmission of individual differences instress reactivity across generations. Ann Rev Neurosci 24: 161–192.
Meaney MJ, Syzf M, 2005 Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome. Dialogues Clin Neurosci 7: 103–123.
Caspi A, McClay J, Moffitt TE, et al, 2002 Role of genotype in the cycle of violence in maltreated children. Science 297: 851–854.
Caspi A, Sugden K, Moffitt TE, et al, 2003 Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301: 386–389.
Davies W, Lynn PM, Y Relkovic D, Wilkinson LS, 2008 Imprinted genes and neuroendocrine function. Front Neuroendocrinol 29: 413–427.
Keverne EB, Curley J P, 2008 Epigenetics brain evolution and behaviour. Front Neuroendocrinol 29: 398–412.
Crews D, McLachlan JA, 2006 Epigenetics evolution endocrine disruption health and disease. Endocrinology 147:Suppl: 4–10.
Woolf CM, 1997 Does the genotype for schizophrenia often remain unexpressed because of canalization and stochastic events during development? Psychol Med 27: 659–668.
Grossman AW, Churchill JD, McKinney BC, Kodish IM, Otte SL, Greenough WT, 2003 Experience effects on brain development: Possible contributions to psychopathology. J Child Psych 44: 33–63.
Cohen-Bendahan CC, van de Beek C, Berenbaum SA, 2005 Prenatal sex hormone effects on child and adult sex-typed behavior: Methods and findings. Neurosci Biobehav Rev 29: 353–384.
McEwen BS, 2004 Protection and damage from acute and chronic stress: Allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Ann N Y Acad Sci 1032: 1–7.
McEwen BS, 2005 Glucocorticoids depression and mood disorders: Structural remodeling in the brain. Metab Clin Exper 54: Suppl 3: 20–23.
Sapolsky R, 2005 The influence of social hierarchy on primate health. Science 308: 648–652.
Magarinos AM, Verdugo JM, McEwen BS, 1997 Chronic stress alters synaptic terminal structure in hippocampus. Proc Natl Acad Sci 94: 14002–14008.
Mitra R, Jadhav S, McEwen BS, Vyas A, Chattarji S, 2005 Stress duration modulates the spatiotemporal patterns of spine formation in the basolateral amygdala. Proc Natl Acad Sci 102: 9371–9376.
Vyas A, Mitra R, Shakaranarayana R, McEwen BS, Chattarji S, 2002 Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci 22: 6810–6818.
Wellman CL, 2001 Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. J Neurobiol 49: 245–253.
Liston C, Miller MM, Goldwater DS, et al, 2006 Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neuroscience 26: 7870–7874.
Czéh B, Mtlller-Keuker JI, Rygula R, et al, 2007 Chronic social stress inhibits cell proliferation in the adult medial prefrontal cortex: Hemispheric asymmetry and reversal by fluoxetine treatment. Neuropsychopharmacol 32: 1490–1503.
Pham K, Nacher J, Hoff PR, McEwen BS, 2003 Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus. Eur J Neurosci 17: 879–886.
Sandi C, Merino JJ, Cordero MI, Touyarot K, Venero C, 2001 Effects of chronic stress on contextual fear conditioning and the hippocampal expression of the neural cell adhesion molecule its polysialylation and L1. Neuroscience 102: 329–339.
Wood GE, Young LT, Reagan LP, McEwen BS, 2005 Acute and chronic restraint stress alter the incidence of social conflict in male rats. Horm Behav 43: 205–213.
Luine V, Beck K, Frankfurt M, MacLusky N, 2007 Chronic stress and neural function: Accounting for and age J Neuroendocr 19: 743–751.
Isgor C, Kabbaj M, Akil H, Watson SJ, 2004 Delayed effects of chronic variable stress during peripubertal-juvenile period on hippocampal morphology and on cognitive and stress axis functions in rats. Hippocampus 14: 693–648.
Westenbroek C, Den Boer JA, Veenhuis M, Ter Horst CJ, 2004 Chronic stress and social housing differentially affect neurogenesis in male and female rats. Brain Res Bull 64: 303–308.
Yehuda R, Engel SM, Brand SR, Seckl J, Marcus SM, Berkowitz GS, 2005 Transgenerational effects of posttraumatic stress disorder in babies of mothers exposed to the World Trade Center attacks during pregnancy. J Clin Endocrinol Metab 90: 4115–4118.
Mill J, Tang T, Kaminsky Z, et al, 2008 Epigenomic profiling reveals DNA-methylation changes associated with major psychoses. Am J Hum Genet 82: 696–711.
Cook JD, Davis BJ, Cai S-L, Barrett JC, Conti CJ, Walker CL, 2005 Interaction between genetic susceptibility and early-life environmental exposure determines tumorsuppressor-gene penetrance. Proc Nat Acad Sci USA 102: 8644–8649.
Thomassin H, Flavin M, Espinás M, Grange T, 2001 Glucocorticoid- induced DNA demethylation and gene memory during development. FREE EMBO J 20: 1974–1983.
Lawford BR, Young R, Noble EP, Kann B, Ritchie T, 2006 The D2 dopamine receptor DRD2 gene is associated with co-morbid depression anxiety and social dysfunction in untreated veterans with post-traumatic stress disorder. Eur Psychiatry 21: 180–185.
Popendikyte V, Laurinavicius A, Paterson AD, Macciardi F, Kennedy JL, Petronis A, 1999 DNA methylation at the putative promoter region of the human dopamine D2 receptor gene. NeuroReport 10 1249–1255
Petronis A, Gottesman II, Kan P, et al, 2003 Monozygotic twins exhibit numerous epigenetic differences: Clues to twin discordance? Schizophr Bull 29: 169–178.
Lee E-S, Chena H, Shepherd KR, Lamango NS, Soliman KFA, Charlton CG, 2004 The inhibitory role of methylation on the binding characteristics of dopamine receptors and transporter. Neurosci Res 48: 335–344.
Li J, Guo Y, Schroeder FA, et al, 2004 Dopamine D2-like antagonists induce chromatin remodeling in striatal neurons through cyclic AMP-protein kinase A and NMDA receptor signaling. J Neurochem 90: 1117–1131.
Gross C, Hen R, 2004 The developmental origins of anxiety. Nature Rev Neurosci 5: 545–552.
Fraga MF, Ballestar E, Paz MF, et al, 2005 Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci 102: 10604–10609.
Petronis A, 2006 Epigenetics and twins: Three variat ions on the theme. Trends Genet 22: 347–350.
O’Donovan MC, Williams NM, Owen MJ, 2003 Recent advances in the genetics of schizophrenia. Hum Mol Genet 12: R125–R133.
Mill J, Dempster E, Caspi A, Williams B, Moffitt T, Craig I, 2006 Evidence for monozygotic twin MZ discordance in methylation level at two CpG sites in the promoter region of the catechol-o-methyltransferase COMT gene. Am J Med Genet Part B 141B: 421–425.
Hull EM, Meisel RL, Sachs BD 2002 Malesexual behavior. In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT (eds) Hormones Brain and Behavior Volume One. Academic Press New York; pp, 1–138.
Blaustein JD, Erskine MS 2002 Feminine sexual behavior: Cellular integration of hormonal and afferent information in the rodent brain. In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT (eds) Hormones Brain and Behavior Volume One. Academic Press New York; pp, 139–214.
DeVries GJ, Simerly RB 2002 Anatomy development function of sexually dimorphic neural circuits in the mammalian brain. In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT (eds) Hormones Brain and Behavior Volume Four. Academic Press New York; pp, 137–192.
Fleming AS, O’Day D, Kraemer G, 1999 Neurobiology of mother-infant interactions: Experience and central nervous system plasticity across development. Neurosci Biobehav Rev 23: 673–685.
Febo M, Numan M, Ferris CF, 2005 Functional magnetic resonance imaging shows oxytocin activates brain regions associated with mother-pup bonding during suckling. J Neurosci 25: 11637–11644.
Numan MJ, Insel TR 2003 The Neurobiology of Parental Behavior. Springer, New York.
Gonzalez-Mariscal G, Poindron P 2002 Parental care in mammals: Immediate internal and sensory factors of control In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT (eds) Hormones Brain and Behavior Volume One. Academic Press New York; pp, 215–298.
Simon NG 2002 Hormonal processes in the development and expression of aggressive behavior. In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT (eds) Hormones Brain and Behavior Volume One. Academic Press New York; pp, 339–392.
Newman SW, 1999 The medial extended amygdala in male reproductive behavior: A node in the mammalian social behavior network. Ann N Y Acad Sci 877: 242–257.
Crews D, Lou W, Fleming A, Ogawa S, 2006 From gene networks underlying sex determination and gonadal differentiation to the development of neural networks regulating sociosexual behavior. Brain Res 1126: 109–121.
Fleming AS, Kraemer GW, Gonzalez A, Lovic V, Rees S, Melo A, 2002 Mothering begets mothering: The transmission of behavior and its neurobiology across generations. Physiol Pharm Behav 73: 61–75.
Moore CL 1995 Maternal contributions to mammalian reproductive development and divergence of males and females. In: Slater PJP, Rosenblatt JS, Snowdon CT, Milinski M (eds) Advances in the Study of Behavior, Academic Press, New York; pp, 47–118.
Crews D, Fuller T, Mirasol EG, Pfaff DW, Ogawa S, 2004 Postnatal environment affects behavior of adult transgenic mice. Exp Biol Med 229: 935–939.
Crews D, Rushworth D, Gonzalez-Lima F, Ogawa S, 2009 Litter environment affects agonistic behavior and brain metabolic activity of adult estrogen receptor a knockout mice. Front Behav Neurosci 3: 12. doi:10.3389/neuro.08.012.200.
deMedeiros CBL, Rees SL, Llianas M, Fleming A, Crews D, 2009 Effects of prenatal and postnatal litter sex composition on adult sexual behavior of male rats. Submitted to Hormones and Behavior.
Sakata JT, Crews D, Gonzalez-Lima F, 2005 Behavioral correlates of differences in neural metabolic activity. Brain Res Rev 48: 1–15.
Anway MD, Cupp AS, Uzumcu M, Skinner MK, 2005 Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308: 1466–1469.
Anway MD, Skinner MK, 2006 Epigenetic transgenerational actions of endocrine disruptors. Endocrinology 147:Suppl: 43–49.
Anway MD, Leathers C, Skinner MK, 2006 Endocrine disruptor vinclozolin induced epigenetic transgenerational adult onset disease. Endocrinology 147: 5515–5523.
Guerrero-Bosagna CM, Skinner MK, 2009 Epigenetic transgenerational effects of endocrine disruptors on male reproduction. Semin Reprod Med 27: 403–408.
Crews D, Gore AC, Hsu TS, et al, 2007 Transgenerational epigenetic imprints and mate preference. Proc Nat Acad Sci USA 104: 5942–5946.
Skinner MK, Anway MD, Savenkova MI, Gore AC, Crews D, 2008 Transgenerational epigenetic programming of the brain transcriptome and anxiety behavior. PLoS One 3 (E3745) 1–11.
Wilson GM, Flibotte S, Chopra V, Melnyk BL, Honer WG, Holt RA, 2006 DNA copy-number analysis in bipolar disorder and schizophrenia reveals aberrations in genes involved in glutamate signaling. Hum Mol Genet 15: 743–749.
Pezet S, Malcangio M, 2004 Brain-derived neurotrophic factor as a drug target for CNS disorders. Expert Opin Ther Targets 8: 391–399.
Tsai SJ, 2004 Down-regulation of the Trk-B signal pathway: the possible pathogenesis of major depression. Med Hypotheses 62: 215–218.
Tsai SJ, 2006 TrkB partial agonists: Potential treatment strategy for epilepsy mania and autism. Med Hypotheses 66): 173–175.
Wang H, Ferguson GD, Pineda VV, Cundiff PE, Storm DR, 2004 Overexpression of type-1 adenylyl cyclase in mouse forebrain enhances recognition memory and LTP. Nature Neurosci 7: 635–642.
Muller MB, Zimmermann S, Sillaber I, et al, 2003 Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nature Neurosci 6: 1100–1107.
International Molecular Genetic Study of Autism Consortium (IMGSAC) 2001 Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q. Human Mol Genetics 10: 973–982.
Muhle R, Trentacoste SV, Rapin I, 2004 The genetics of autism. Pediatrics 113: 472–486.
Cantor RM, Kono N, Duvall JA, et al, 2005 Replication of autism linkage: Fine mapping peak at 17q21. Amer J Hum Genet 76: 1050–1056.
Sultana R, Yu CE, Yu J, et al, 2002 Identification of a novel gene on chromosome 7q11 2 interrupted by a translocation breakpoint in a pair of autistic twins. Genomics 80: 129–134.
Zhang H, Ozbay F, Lappalainen J, et al, 2006 Brain derived neurotrophic factor BDNF gene variants and Alzheimer’s disease affective disorders posttraumatic stress disorder schizophrenia and substance dependence. Am J Med Genet Part B 141B: 387–393.
Costa E, Chen Y, Davis J, et al, 2002 REELIN and schizophrenia: A disease at the interface of the genome and the epigenome. Mol Intervent 2: 47–57.
Dong E, Agis-Balboa RC, Simonini MV, Grayson DR, Costa E, Guidotti A, 2005 Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia. Proc Natl Acad Sci 102: 12578–12583.
Jamain S, Quach H, Betancur C, et al, 2003 Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genet 34: 27–29.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Crews, D. Epigenetics, brain, behavior, and the environment. Hormones 9, 41–50 (2010). https://doi.org/10.14310/horm.2002.1251
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.14310/horm.2002.1251