Michael Meaney (2004) has commented on similar research [i.e., epigenetic/environmental modulation of gene expression] in insects and reptiles: the helmet size of water fleas and the capacity for flight in grasshoppers are only a few examples of this natural phenomena (see Michael Meaney’s “The nature of nurture: maternal effects and chromatin remodeling” in “Essays in Social Neuroscience” edited in 2004 by John Cacioppo and Gary Berntson for The Massachusetts Institute of Technology Press). The fundamental principle here is that of maternal regulation of the development of rudimentary defensive responses to threat. Meaney, of the Douglas Hospital Research Centre, Montreal, Canada, notes:
“These are classic examples of epigenetic, or nongenomic, inheritance, where traits of the parents are transmitted to offspring in a manner not dependent on information encoded in the nuclear genes. Maternal effects in plants and insects alter the form and intensity of defensive responses to threat. The environmental experience of the mother is thus translated through an epigenetic mechanism of inheritance into phenotypic variation in the offspring. Indeed, maternal effects could result in the transmission of adaptive responses across generations” (p. 5).
Meaney and colleagues have demonstrated that similar effects occur in mammals. In the latter, there are highly stable individual differences in maternal licking and grooming (LG) of offspring. These naturally occurring variations in maternal care are associated with individual differences in LHPA (limbic-hypothalamic-pituitary-adrenal axis) responses to stress/challenge. As adults, offspring of mothers who display high LG and arched-back nursing (high-LG-ABN mothers) are behaviorally less fearful and show attenuated LHPA responses to stress/challenge than offspring of mothers that are low in LG-ABN.Cross-fostering research demonstrated that the biological offspring of low-LG-ABN reared by high-LG-ABN dams resemble the normal offspring of high-LG-ABN (and vice versa). This research has also been corroborated by research done by Stephen Suomi and colleagues at the Laboratory of Comparative Ethology, National Institute of Child health and Human development, NIH (see S. Suomi’s “Aggression, serotonin, gene-environment interactions in rhesus monkeys” also in “Essays in Social Neuroscience” edited in 2004 by John Cacioppo and Gary Berntson for The Massachusetts Institute of Technology Press).
Meaney noted that maternal behavior in the rat permanently alters the development of LHPA responses to threat through tissue-specific effects on gene expression. The magnitude of the LHPA response to threat is a function of the neuronal stimulation of hypothalamic corticotropin-releasing factor (CRF) release which then activates the pituitary-adrenal system, as well as modulatory influences, such as glucocorticoid (cortisol in humans) negative feedback that inhibits CRF synthesis and release and therefore attenuates LHPA responsiveness to threat. The adult offspring of high-LG-ABN compared with low-LG-ABN demonstrate increased hippocampal glucocorticoid receptor expression and enhanced glucocorticoid feedback sensitivity. The offspring of high-LG also demonstrate decreased hypothalmic CRF expression and attenuated LHPA responses to stress.
Transcription factors such as nerve growth factor-inducible factor A (NGFI-A) regulate gene expression, and thus provide a cellular bridge between genes and environmental factors. However, the relation is constrained because DNA operates within a chromatin context. The DNA sequences which form our ‘genetic code’ are wrapped around histone proteins and are only variably accessible to transcription factors. The positive charge of the histones and negatively charged DNA form bonds which preclude transcription factors from binding to DNA regulatory sites (promoter/enhancer). However, the histone acetyl transferases (HAT’s) that acetylate histone tails, thereby neutralizing the charge, relaxes the tightly-coupled histone-DNA packaging system to a state in which transcription factors can enter the fray and bind to DNA sites. There are structural changes to DNA that result in silencing of DNA transcription. DNA methylation (which I believe is really where the ‘genetic action’ lies in many of the disorders we label the schizophrenias, ie, gene-environment interaction, and as underscored by psychoanalyst Peter Fonagy in his “The interpersonal interpretive mechanism: the confluence of genetics and attachment theory in development” in “Emotional Development in Psychoanalysis, Attachment Theory and Neuroscience: Creating Connections” edited in 2003 by Viviane Green for Brunner-Routledge, in humans it is the environment as actually experienced, interpreted and reacted to which matters) is a stable, epigenomic mark that occurs at cytosine nucleotides and it attracts a group of enzymes called “histone deacetylases” which prevent histone acetylation and thereby preserve the tightly-coupled histone-DNA relation. DNA methylation is therefore associated with a stable suppression in gene transcription and is the pathway in which genes are silenced. Importantly for those researchers attempting to challenge the neurogenetic and neurobiological reductionism endemic in much of scientific research and therefore in the popular press/media as well, this may be the process by which maternal care during postnatal life can program the expression of specific genes in the brain and body.
Meaney et al (2003) researched the methylation of the exon I7 glucocorticoid receptor promoter, which revealed significant differences as a function of maternal care. Significant differences in a single cytosine within the NGFI-A consensus sequence (the DNA sequence to which NGFI-A binds) were revealed in the offspring of high and low LG-ABN mothers. Methylation always occurred in the offspring of low-LG mothers and rarely so in the offspring of high-LG mothers. These differences emerged remarkably within the first week of life. In addition, cross-fostering resulted in changes associated with the rearing mother within 12 hours of birth. Meaney concluded:
“Thus DNA methylation does appear to be one mechanism for the enduring maternal effects on the development of defensive responses to threat in mammals...DNA methylation could serve as an intermediate process that imprints dynamic environmental experiences on the fixed genome resulting in stable alterations in phenotype” (p.11).
Weaver et l (2004) used a within-series cross-fostering model and a behavior system in rats in which high licking grooming (LG) arched-back nursing (ABN) mothers were compared with low LG-ABN mothers. The offspring of high LG-ABN are less anxious and fearful as adults and have attenuated limbic-hypothalamic-pituitary-adrenal axis (LHPA) responses to stress/challenge than offspring of mothers with low rates of LG-ABN. However, cross-fostering the offspring of high and low LG-ABN mothers within 12 hours of birth produced adult rats with the stress response patterns associated with their foster-rearing mothers. Evidence that gene expression in the LHPA axis of the offspring was modified is demonstrated by increased glucocorticoid receptor (GR) mRNA in the offspring of high LG-ABN mothers. This is exactly what we see in schizophrenia research as demonstrated by Pekka Tienari and colleagues in Finland, i.e., only those offspring of high risk mothers, i.e.,biological mothers diagnosed with schizophrenia, developed a schizophrenia spectrum disorder who were raised in familial settings blindly rated as dysfunctional on a multiplicity of measures (this was a large double-blind controlled study). Tienari concluded that the research results demonstrate genetic control of sensitivity to the environment or environmental control of gene expression.
Weaver et al (2004) successfully demonstrated that epigenetic alterations in pup offspring were correlated with the physiological and behavioral differences in gene expression. The alterations occurred in chromatin structure at a GR gene promotor in the hippocampus. Stable variations in gene expression are correlated with methylation of DNA. Cross-fostering produced C-methylation changes consistent with the maternal behavior of the rearing mother.Pharmacologic reversibility can be achieved by infusion of a histone deacetylase inhibitor.A potential process operating within the conceptual space between the genome and environment is therefore available to explain the stable alterations in gene expression that result from gene-environment interaction, and at the human level, the gene-environmental interaction as subjectively experienced, perceived, interpreted and acted upon. Weaver et al (2004) concluded: “We propose that effects on chromatin structure [DNA, RNA, protein, etc] such as those described here serve as an intermediate process that imprints dynamic environmental experiences on the fixed genome, resulting in stable alterations in phenotype.”
Waterland & Jirtle (2003) reported in the journal Molecular and Cellular Biology a landmark study demonstrating that an enriched environment can override genetic mutations in mice. Agouti mouse mothers were fed methyl-group-rich supplements (epigenetic modifications)-methylating the DNA and thereby silencing gene activity. Agouti mice pups are yellow and extremely obese, predisposing them to cardiovascular disease, diabetes and cancer. The agouti mothers who were given the methyl-rich supplements, produced lean, brown mice even though they shared the same genes as their mothers. Epigenetics are becoming increasingly important in cancer research, as well as in other medical disorders (cardiovascular, endocrine, etc.).
This research should be used to further support caregivers, mothers and fathers, in the immediate task of raising their offspring. Importantly, it should also be used in guiding societies to support caregivers-as Martti Siirala points out-families, and thus individuals, can become caught in a web of collective splitting processes, impossible economic, social and political situations which make it very difficult for individuals and families to navigate the "slings and arrows of outrageous fortune" (Hamlet-William Shakespeare).
Brian Koehler PhD
New York University
brian_koehler@psychoanalysis.net
