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Cited by 240Stress Responses and CortisolChild Abuse and TraumaEpigenetics and DNA Methylation

Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function

Open access
Anacker, Christoph, O'Donnell, Kieran J., Meaney, Michael J.·2014·Dialogues in Clinical Neuroscience
DOI 10.31887/dcns.2014.16.3/canackerPMC PMC4214175
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Abstract

We review studies with human and nonhuman species that examine the hypothesis that epigenetic mechanisms, particularly those affecting the expression of genes implicated in stress responses, mediate the association between early childhood adversity and later risk of depression. The resulting studies provide evidence consistent with the idea that social adversity, particularly that involving parent-offspring interactions, alters the epigenetic state and expression of a wide range of genes, the products of which regulate hypothalamic-pituitary-adrenal function. We also address the challenges for future studies, including that of the translation of epigenetic studies towards improvements in treatments.

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Written from the paper’s full text.

TL;DR

This review synthesizes rodent and human evidence that early-life adversity, especially parent-offspring interactions, alters epigenetic regulation of HPA-axis genes and stress reactivity, potentially linking childhood adversity to depression risk. It also highlights caveats and challenges for translating epigenetic findings into treatment.

Key findings

  • In rats, offspring of High licking/grooming (LG) mothers show increased hippocampal glucocorticoid receptor (GR) expression, enhanced glucocorticoid negative feedback, decreased hypothalamic CRF mRNA, and more modest plasma ACTH/corticosterone responses to acute stress than offspring of Low LG mothers; cross-fostering reverses these effects.
  • Maternal care regulates the hippocampal GR exon 17 promoter: Low LG offspring show hypermethylation at the 5′ CpG of the NGFI-A site, reduced NGFI-A binding, and lower H3K9ac/H3K4me3; 5-hydroxymethylcytosine at this promoter was three times higher in Low vs High LG offspring, and trichostatin A infusion reversed maternal effects on GR expression and HPA responses.
  • Human postmortem hippocampal samples from suicide completers with childhood maltreatment show decreased GR expression and altered exon 1 variant methylation; exon 1F (homolog of rat exon 17) shows increased methylation and decreased NGFI-A binding. Peripheral studies associate childhood maltreatment or parental loss with increased exon 1F NR3C1 methylation, and FKBP5 allele-specific demethylation interacts with childhood trauma to predict PTSD risk.
  • Early-life stress in mice alters methylation of AVP and Pomc genes, increasing hypothalamic AVP synthesis and ACTH; maternal care also reduces hypothalamic CRF expression via NRSF and glutamatergic input. Approximately a third of individuals who die by suicide have histories of childhood adversity.

Methods

  • Narrative review of human and nonhuman studies; no new primary data.
  • Rodent models include Long-Evans rats varying in pup LG, cross-fostering, tactile stimulation, and HDAC inhibitor infusion; mouse maternal separation. Human samples include Quebec Suicide Brain Bank postmortem hippocampus and peripheral blood/leukocytes/saliva.
  • Main analysis is qualitative synthesis of molecular, endocrine, behavioral, and clinical findings; no meta-analysis or systematic search reported.

Limitations

  • Stated: altered HPA activity is apparent only in a subset of MDD patients, and it is unclear whether this subset is defined by developmental history; genotype moderates the impact of adverse childhood experience and epigenetic modifications; few preclinical models of gene × environment interactions exist.
  • Stated: preclinical studies have not widely capitalized on the finding that adverse childhood experience alters antidepressant response, and integrating childhood experience into treatment models remains a challenge.
  • Evident: as a narrative review, it lacks systematic search/quality appraisal or meta-analysis; human epigenetic findings often rely on peripheral tissues (blood, saliva) or postmortem samples, and the paper notes DNA methylation can be tissue- and cell-type-specific.

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Integrity signals

Registry

Crossref · 10.31887/dcns.2014.16.3/canacker

Cites

144 of 144 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 172 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    Lactating female Long-Evans rats exhibit considerable variation in the frequency of pup licking/grooming.

    “Lactating female Long-Evans rats (an outbred strain of rattus norvegicus) exhibit considerable variation in the frequency of pup licking/grooming (LG).”
    Quote in the paperSubstantial claim
  • Findingcitation

    Variations in pup LG over the first week of postnatal life affect the development of behavioral and HPA responses to stress in adulthood.

    “We and other labs find that variations in pup LG over the first week of postnatal life rat affect the development of behavioral and hypothalamic-pituitary-adrenal (HPA) responses to stress in adulthood.66-75”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [66] Liu D., 1997, Science. source

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    • cites [67] Caldji C., 1998, Proc Nat Acad Sci U S A. source

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    • cites [68] Francis D., 1999, Science. source

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    • cites [69] Menard J., 2004, Neuroscience. source

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    • cites [70] Weaver IC., 2004, Nat Neurosci. source

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    • cites [71] Weaver IC., 2005, J Neurosci. source

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    • cites [72] Zhang TY., 2006, Biol Psychiatry. source

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    • cites [73] Bagot RC., 2012, Biol Psychiatry. source

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    • cites [74] Toki S., 2007, Eur J Neurosci. source

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    • cites [75] Kurata A., 2009, Horm Behav source

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  • Findingcitation

    The level of 5-hydroxymethylcytosine of the exon 17 GR promoter was three times higher in hippocampal samples from offspring of Low compared with High-LG mothers.

    “We analyzed levels of 5-hydroxymethylcytosine and 5-methylcytosine across the hippocampal GR exon 17 promoter in rats using antibody capture of hippocampal DNA and found the level of 5-hydroxymethylcytosine of the exon 17 GR promoter was three times higher in hippocampal samples from the offspring of Low compared with High-LG mothers.92”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Zhang TY., 2013, Neuropsychopharmacology. source

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  • Findingown data

    Decreased hippocampal GR expression was found in samples from suicide completers with histories of childhood maltreatment compared with controls.

    “We65,120 showed decreased hippocampal GR expression in samples from suicide completers with histories of childhood maltreatment compared with controls (sudden, involuntary fatalities).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [65] McGowan PO., 2009, Nat Neurosci. source

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    • cites [120] Labonté B., 2013, Am J Psychiatry. source

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  • Findingown data

    5-methylcytosine-dependent immunoprecipitation revealed no differences across the exon 17 GR promoter.

    “In contrast, 5-methylcytosine-dependent immunoprecipitation revealed no differences across the exon 17 GR promoter.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Zhang TY., 2013, Neuropsychopharmacology. source

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    Findingreasoning

    Offspring of High LG mothers show significantly increased hippocampal GR mRNA and protein expression, enhanced glucocorticoid negative feedback sensitivity, and decreased hypothalamic CRF mRNA levels.

    “The offspring of High LG mothers show significantly increased hippocampal GR mRNA and protein expression, enhanced glucocorticoid negative feedback sensitivity and decreased hypothalamic CRF mRNA levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Individual differences in the frequency of pup LG among adult female rats are reliable across multiple litters and thus a stable feature of the maternal phenotype.

    “Individual differences in the frequency of pup LG among adult female rats are reliable across multiple litters, and thus a stable feature of the maternal phenotype.”
    Quote in the paperNot a substantial claim

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    Findingcitation

    Chronic central infusion of adult offspring of Low LG mothers with trichostatin A significantly increased H3K9ac, NGFI-A binding to the GR-17 promoter, and GR expression to levels comparable to offspring of High LG mothers.

    “Chronic, central infusion of adult offspring of Low LG mothers with the broad spectrum HDAC inhibitor, trichostatin A (TSA),109 significantly increased H3K9ac, NGFI-A binding to the GR-17 promoter, and GR expression to levels comparable to those observed in the offspring of High LG mothers.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] Weaver IC., 2006, Proc Natl Acad Sci U S A. source

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    Findingown data

    There are significant differences in methylation at the 5' CpG dinucleotide of the NGFI-A consensus sequence: this site is hypermethylated in offspring of Low LG mothers and hypomethylated in offspring of High LG dams.

    “The results reveal significant differences in methylation at the 5' CpG dinucleotide of the NGFI-A consensus sequence. This site is hypermethylated in the offspring Low LG mothers, and hypomethylated in those of High LG dams.”
    Quote in the paperSubstantial claim

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    Findingcitation

    There is increased H3K9ac and H3K4me3 at both regions of the exon 17 GR promoter, and the levels of these marks are very highly correlated.

    “Thus we find increased H3K9ac and H3K4me3 at both regions of the exon 17 GR promoter, and the levels of these individual marks are very highly correlated.92”
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    • cites [92] Zhang TY., 2013, Neuropsychopharmacology. source

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    Findingcitation

    Cross-fostering reverses the differences in methylation of the 5' CpG site and suggests a direct relation between maternal care and DNA methylation of the exon 17 GR promoter.

    “Cross-fostering reverses the differences in the methylation of the 5' CpG site and suggests a direct relation between maternal care and DNA methylation of the exon 17 GR promoter.70”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Weaver IC., 2004, Nat Neurosci. source

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    Findingown data

    Decreased expression levels of GR exon 1B, 1C and 1H transcripts were associated with alterations in methylation of the respective sequences, with particular sites significantly correlated with expression levels.

    “Decreased expression levels of GR exon 1B, 1C and 1H transcripts were also associated with alterations in methylation of the respective sequences, with particular sites significantly correlated with expression levels.”
    Quote in the paperSubstantial claim

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    Findingcitation

    Variation in the methylation of the exon 1F GR promoter associated with PTSD symptoms and predicted treatment outcome.

    “We recently addressed this issue in PTSD patients and provide evidence suggesting that variation in the methylation of the exon 1F GR promoter associated with PTSD symptoms and predicted treatment outcome.135-137”
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    • cites [135] Yehuda R., Biol Psychiatry. In press.

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    • cites [136] Yehuda R., 2014, Am J Psychiatry. source

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    • cites [137] Yehuda R., 2013, Front Psychiatry. source

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  • May combine two claims.

    Findingcitation

    The exon 1F sequence shows increased DNA methylation and decreased NGFI-A binding in samples from suicide victims with a history of maltreatment.

    “Moreover, the exon 1F sequence shows increased DNA methylation and decreased NGFI-A binding in samples from suicide victims with a history of maltreatment.”
    Quote in the paperSubstantial claim

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    Findingown data

    Splice variant analysis revealed decreased expression of noncoding exons 1B, 1C, 1F and 1H in suicides with a history of childhood maltreatment compared with controls and suicides without maltreatment, correlated with differential DNA methylation patterns in the corresponding exon 1 variant promoters.

    “Splice variant analysis revealed decreased expression of noncoding exons 1B, 1C, 1F and 1H in suicides with a history of childhood maltreatment compared with both controls and suicides without a history of maltreatment that correlated with differential DNA methylation patterns between groups in the corresponding exon 1 variant promoters.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Increased basal cortisol levels are particularly marked in melancholic and psychotic depression but not in atypical depression.

    “The increase in basal cortisol levels was particularly marked in melancholic and psychotic depression,43 but not in atypical depression.”
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    • cites [43] Gold PW., 2002, Mol Psychiatry. source

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    Premisecitation

    Antidepressant treatment increases GR expression, GR function, and GR-mediated HPA axis feedback inhibition in rodents and humans, reducing resting and stimulated HPA axis activity.

    “Antidepressant treatment increases GR expression, GR function, and GR-mediated HPA axis feedback inhibition in rodents as well as in humans, thereby reducing resting and stimulated HPA axis activity.40”
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    • cites [40] Pariante CM., 2008, Trends Neurosci. source

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    Premisecitation

    Cushing's disease or prolonged corticosteroid therapy can precipitate Major Depressive Disorder and mania.

    “Interestingly Cushing's disease or prolonged corticosteroid therapy can precipitate Major Depressive Disorder (MDD), but also mania.44”
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    • cites [44] Starkman MN., 1981, Psychosom Med. source

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    Interpretationreasoning

    Because elevated cortisol inhibits subsequent HPA activity, depressed patients show impaired glucocorticoid negative feedback.

    “Since elevated levels of cortisol act to inhibit subsequent HPA activity, this finding suggests impaired glucocorticoid negative feedback in depressed patients.”
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    • cites [44] Starkman MN., 1981, Psychosom Med. source

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    Premisecitation

    Broader familial dysfunction including persistent emotional and physical neglect, family conflict, cold distant parent-child relationships, and harsh inconsistent discipline compromises cognitive and emotional development and increases risk for depression and anxiety disorders to a level comparable to abuse.

    “Broader forms of familial dysfunction including persistent emotional and physical neglect, family conflict, cold, distant parent-child relationships, and conditions of harsh, inconsistent discipline compromise cognitive and emotional development and increase the risk for depression and anxiety disorders to a level comparable to that for abuse.16-23”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [16] Ammerman RT., 1986, Clini Psychol Rev.

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    • cites [17] Trickett PK., 1995, Dev Rev. source

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    • cites [18] Repetti RL., 2002, Psychol Bull. source

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    • cites [19] Lupien SJ., 2009, Nat Rev Neurosci. source

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    • cites [20] Hill J., 2001, Br J Psychiatry. source

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    • cites [21] Holmes SJ., 1987, J Child Psychol Psychiatry. source

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    • cites [22] Canetti L., 1997, Adolescence.

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    • cites [23] Parker G., 1989, Psychiatr Dev.

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    Premisecitation

    Childhood maltreatment is associated with increased severity of illness, reduced treatment responsivity, and increased comorbidity.

    “Moreover, childhood maltreatment also associates with an increased severity of illness, reduced treatment responsivity, and increased comorbidity.14,15”
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    • cites [14] Widom CS., 2007, Arch Gen Psychiatry. source

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    • cites [15] Nanni V., 2012, Am J Psychiatry. source

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    Premisecitation

    A meta-analysis confirmed an association of elevated basal ACTH and cortisol with depression, with the greatest cortisol difference in the afternoon.

    “A recent meta-analysis confirmed the association of elevated basal levels of both ACTH and cortisol with depression and showed that the greatest difference in cortisol occurred during the afternoon, a time when cortisol levels are normally falling.42”
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    • cites [42] Stetler C., 2011, Psychosom Med. source

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    Premisecitation

    Warm, nurturing families tend to promote resistance to stress and diminish vulnerability to stress-induced illness.

    “Thus, warm, nurturing families tend to promote resistance to stress and to diminish vulnerability to stress-induced illness.18,25”
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    • cites [18] Repetti RL., 2002, Psychol Bull. source

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    • cites [25] Smith J., 1995, J Am Acad Child Adolesc Psychiatry. source

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    Premisecitation

    Variations in parental care associate with individual differences in neuroendocrine and autonomic responses to stress in humans and with emotional reactivity.

    “Likewise, variations in parental care associate with individual differences in neuroendocrine and autonomic responses to stress in humans as well as emotional reactivity.18,33-36”
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    • cites [18] Repetti RL., 2002, Psychol Bull. source

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    • cites [33] Flinn MV., 1995, Curr Anthropology. source

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    • cites [34] Luecken LJ., 2000, Psychol Health. source

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    • cites [35] Pruessner JC., 2004, J Neurosci. source

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    • cites [36] Taylor SE., 2006, Biol Psychiatry. source

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    Premisecitation

    Administration of the GR antagonist RU486 elevates ACTH and cortisol in humans, implicating GR activation as a mediator of negative feedback inhibition.

    “Administration of the GR antagonist, RU486, results in elevated levels of both ACTH and cortisol in humans, which implicates GR activation as a mediator of negative feedback inhibition.45”
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    • cites [45] Laue L., 1990, J Clin Endocrinol & Metab. source

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    Premisecitation

    Elevated CSF levels of CRF in adults associate with a history of childhood maltreatment, poor quality of parental care, and childhood stressful experience.

    “Elevated CSF levels of CRF in adults associate with a history of childhood maltreatment,58,59 a poor quality of parental care,60 and childhood stressful experience.61”
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    • cites [58] Heim C., 2000, JAMA. source

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    • cites [59] Lee R., 2005, Am J Psychiatry. source

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    • cites [60] Lee RJ., 2006, Neuropsychopharmacology. source

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    • cites [61] Carpenter LL., 2004, Neuropsychopharmacology. source

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    Interpretationcitation

    High CRF may arise from GR downregulation and impaired negative feedback inhibition, as childhood abuse and parental loss are associated with higher cortisol response to the DEX/CRH challenge test in adults with and without depression.

    “High CRF may arise due to GR downregulation and impaired negative feedback inhibition, as evidenced by the finding that childhood abuse58,62 and parental loss63 are associated with higher Cortisol response to the dcxamethasone (DEX)/corticotropin-releasing hormone (CRH) challenge test in adults with and without depression.”
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    • cites [58] Heim C., 2000, JAMA. source

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    • cites [62] Rinne T., 2002, Biol Psychiatry. source

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    • cites [63] Tyrka AR., 2008, Biol Psychiatry. source

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    Premisecitation

    Childhood abuse is the strongest predictor of ACTH responsiveness, followed by number of abuse events, adulthood traumas, and depression.

    “Subsequent statistical analyses revealed that childhood abuse was the strongest predictor of ACTH responsiveness, followed by the number of abuse events, adulthood traumas, and depression.”
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    • cites [58] Heim C., 2000, JAMA. source

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    Interpretationreasoning

    Hippocampal infusion of a GR antagonist into adult offspring of High and Low LG mothers eliminates the maternal effect on HPA responses to stress, suggesting a direct relation between hippocampal GR expression and the magnitude of the HPA response to stress.

    “Hippocampal infusion of a GR antagonist into the adult offspring of High and Low LG mothers completely eliminates the maternal effect on HPA responses to stress, suggesting a direct relation between hippocampal GR expression and the magnitude of the HPA response to stress.”
    Quote in the paperSubstantial claim

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    Premisecitation

    An interaction of childhood and adulthood trauma is the most potent predictor of ACTH responses, suggesting childhood abuse per se relates to increased stress reactivity, further enhanced by additional adulthood trauma.

    “An interaction term of childhood and adulthood trauma proved to be the most potent predictor of ACTH responses, suggesting that a history of childhood abuse per se is related to increased stress reactivity, which is further enhanced when additional trauma occurs in adulthood.58”
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    • cites [58] Heim C., 2000, JAMA. source

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    Premisecitation

    Childhood adversity moderates the relation between stressful life events in adulthood and depression, with increased risk for depression or anxiety in response to moderately stressful circumstances among individuals with a history of childhood adversity.

    “Moreover, childhood adversity moderates the relation between stressful life events in adulthood and depression, with increased risk for depression or anxiety in response to moderately stressful circumstances among individuals with a history of childhood adversity.11,14,37”
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    • cites [11] McLaughlin KA., 2010, Arch Gen Psychiatry. source

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    • cites [14] Widom CS., 2007, Arch Gen Psychiatry. source

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    • cites [37] Wichers M., 2009, Br J Psychiatry. source

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    Premisecitation

    In a novelty-induced suppression of feeding test, adult offspring from High LG mothers show a shorter latency to begin eating and eat for a longer period than offspring of Low LG mothers.

    “For example, in a novelty-induced suppression of feeding test in which food-deprived animals are provided food in a novel context, the adult offspring from High LG mothers show a shorter latency to begin eating and eat for a longer period of time.67”
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    • cites [67] Caldji C., 1998, Proc Nat Acad Sci U S A. source

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    Premisecitation

    In cultured hippocampal neurons, the effect of 5-HT on GR expression is blocked by 5-HT7 antagonists or PKA inhibitors, mimicked by 5-HT7 agonists or cAMP analogs, and eliminated by NGFI-A knockdown.

    “In cultured hippocampal neurons the effect of 5-HT on GR expression is: (i) blocked by 5-HT7 receptor antagonists or inhibitors of protein kinase A; (ii) mimicked by 5-HT7 receptor agonists or treatments with stable cAMP analogs; and (iii) eliminated by antisense or small interfering RNA (siRNA) knockdown of NGFI-A mRNA.82,83”
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    • cites [82] Hellstrom IC., 2012, Philos Trans R Soc Lond B Biol Sci. source

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    • cites [83] Weaver IC., 2007, J Neuroscience. source

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    Interpretationcitation

    The decreased hypothalamic CRF expression occurs earlier in development than the difference in hippocampal GR expression, suggesting that the difference in CRF expression develops independent of GR regulation.

    “However, in these studies the decreased hypothalamic CRF expression occurs earlier in development than does the difference in hippocampal GR expression, suggesting that the difference in CRF expression develops independent of GR regulation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Avishai-Eliner S., 2001, J Neuroendocrinol. source

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    Interpretationreasoning

    Subsequent studies reveal effects of early experience on multiple components of the HPA axis, and in each case there is evidence for stable epigenetic programming.

    “However, subsequent studies reveal effects of early experience on multiple components of the HPA axis, and in each case there is evidence for stable epigenetic programming.”
    Quote in the paperSubstantial claim

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    Premisecitation

    ChIP assays reveal increased binding of NGFI-A to the exon 17 promoter in pups of High compared with Low LG mothers, but only following a nursing bout with pup LG.

    “Thus, chromatin-immunoprecitipation (ChIP) assays reveal increased binding of NGFI-A to the exon 17 promoter in pups of High compared with Low LG mothers, but only in the period following a nursing bout with pup LG: hippocampal tissue samples obtained 20 min following a nursing bout, with no subsequent interaction between the mother and pup, do not reveal the difference in NGFI-A association.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Pup LG increases hippocampal NGFI-A expression and binding to the exon 17 promoter.

    “Pup LG increases hippocampal NGFI-A expression and binding to the exon 17 promoter.70,82,83”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [70] Weaver IC., 2004, Nat Neurosci. source

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    • cites [82] Hellstrom IC., 2012, Philos Trans R Soc Lond B Biol Sci. source

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    • cites [83] Weaver IC., 2007, J Neuroscience. source

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  • May combine two claims.

    Interpretationreasoning

    Variations in maternal care influence the methylation state of the exon 17 GR promoter in hippocampus, regulating NGFI-A binding, GR transcription, and HPA stress responses.

    “These findings suggest that variations in maternal care influence the methylation state of the exon 17 GR promoter in hippocampus, regulating NGFI-A binding, GR transcription and HPA stress responses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These results suggest a direct relation between maternal care, histone acetylation, DNA methylation of the GR-17 promoter, GR expression, and HPA responses to stress.

    “These results suggest a direct relation between maternal care, histone acetylation, DNA methylation of the GR-17 promoter, GR expression and HPA responses to stress.”
    Quote in the paperSubstantial claim

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    Premisecitation

    The maternally regulated decrease in CRF expression is accompanied by an increase in hippocampal GR expression.

    “Baram and colleagues114 showed that this maternally regulated decrease in CRF expression is accompanied by an increase in hippocampal GR expression.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] Avishai-Eliner S., 2001, J Neuroendocrinol. source

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    Premisecitation

    The effect of NGFI-A is eliminated by a site-directed mutation within the NGFI-A response element of the exon 17 promoter, revealing that physical interaction of NGFI-A with its response element triggers increased transcriptional activity.

    “The effect of NGFI-A is eliminated by a site-directed mutation within the NGFI-A response element of the exon 17 promoter83 revealing that it is the physical interaction of NGFI-A with its response element that triggers the increase in transcriptional activity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Weaver IC., 2007, J Neuroscience. source

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    Premisereasoning

    Artificial tactile stimulation of pups increases hippocampal NGFI-A expression and NGFI-A binding to the exon 17 promoter.

    “Perhaps most convincingly, artificial tactile stimulation of pups increases hippocampal NGFI-A expression and NGFI-A binding to the exon 17 promoter.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Maternal separation of neonatal mice produces enduring hypomethylation of the Pomc gene, increased Pomc mRNA expression, and increased basal and CRF-induced ACTH.

    “Maternal separation of neonatal mice produces an enduring hypomethylation of the Pomc gene, which encodes for the ACTH pro-hormone, proopiomelanocortin,119 increased Pomc mRNA expression and increased basal and CRF-induced levels of ACTH.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [119] Wu Y., 2014, Endocrinology. source

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  • May combine two claims.

    Interpretationreasoning

    Variations in parent-offspring interactions epigenetically program hippocampal GR expression and thus the nature of the HPA response to stress.

    “These findings suggest that variations in parent-offspring interactions epigenetically “program” hippocampal GR expression and thus the nature of the HPA response to stress.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    These findings bear considerable similarity to the maternal effect in the rat and are suggestive of early-environment regulation of the neural epigenome in humans.

    “These findings bear considerable similarity to the maternal effect in the rat and are suggestive of early-environment regulation of the neural epigenome in humans.”
    Quote in the paperSubstantial claim

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    Premisecitation

    The interaction between FKBP5 polymorphisms and childhood trauma was associated with stable DNA demethylation, which in turn predicted increased FKBP5 expression.

    “At the molecular level this interaction was associated with stable DNA demethylation, which in turn predicted increased FKBP5 expression.”
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    • cites [133] Klengel T., 2013, Nat Neurosci. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The Quebec Suicide Brain Bank program is strengthened by a validated forensic interview that establishes developmental history and mental health status.

    “The program is strengthened by a validated forensic interview that establishes developmental history and mental health status.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Polymorphisms in FKBP5 influence the position of the nucleosome, which when combined with childhood trauma resulted in an increased risk of PTSD.

    “This study demonstrated that polymorphisms in FKBP5 influence the position of the nucleosome, which when combined with childhood trauma (postulated to increase circulating Cortisol) resulted in an increased risk of post-traumatic stress disorder (PTSD).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Klengel T., 2013, Nat Neurosci. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    These findings are consistent with a working hypothesis that links the early social environment to epigenetic modifications of the GR gene and GR expression, and HPA function.

    “These findings are thus consistent with a working hypothesis that links the early social environment to epigenetic modifications of the GR gene and GR expression, and HPA function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Decreased FKBP5 methylation and increased FKBP5 expression are associated with symptoms of glucocorticoid resistance.

    “Since FKBP5 sequesters activated GR and prevents nuclear binding, the decreased FKBP5 methylation and increased FKBP5 expression associated with symptoms of glucocorticoid resistance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Klengel T., 2013, Nat Neurosci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The exon 1F sequence is the homolog of rat exon 17, is highly expressed in brain, and contains an NGFI-A response element.

    “The exon 1F sequence is of particular interest as it is the homolog of the rat exon 17, is highly expressed in brain and contains an NGFI-A response element.65,121”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [65] McGowan PO., 2009, Nat Neurosci. source

      Not checked in the free run.

    • cites [121] Turner JD., 2005, J Mol Endocrinol. source

      Not checked in the free run.

46 of 46

  • The authors state this as an assumption.

    DNA methylation is a reasonable candidate mechanism for the enduring effects of maternal care on hippocampal gene expression in the rat.

    “We focused our initial studies on potential influences on DNA methylation with the assumption that this relatively stable covalent modification was a reasonable candidate mechanism for the enduring effects of maternal care on hippocampal gene expression in the rat.”

  • The paper relies on this without support.

    Approximately a third of individuals who die by suicide have histories of childhood adversity, including childhood sexual and physical abuse, as well as parental neglect.

    “Approximately a third of individuals who die by suicide have histories of childhood adversity, including childhood sexual and physical abuse, as well as parental neglect.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Childhood environments and experiences play a role in epigenetic regulation of many components of physiological stress response systems.

    “Yet, in the past decade we have developed a much stronger appreciation for the role childhood environments and experiences in the epigenetic regulation of many components of physiological stress response systems (Anacker et al., 2014; Tyrka et al., 2013).”

    From Developmental psychoneuroendocrine and psychoneuroimmune pathways from childhood adversity to disease (2017) · cites this paper as Anacker et al., 2014

  • Maternal care in infancy contributes to epigenetic regulation of the glucocorticoid receptor in the hippocampus and in peripheral immune cells.

    “Maternal care in infancy contributes to epigenetic regulation of the glucocorticoid receptor in the hippocampus (Anacker et al., 2014; McGowan et al., 2009) as well as in peripheral immune cells (Miller et al., 2011; Tyrka et al., 2012).”

    From Developmental psychoneuroendocrine and psychoneuroimmune pathways from childhood adversity to disease (2017) · cites this paper as Anacker et al., 2014

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 10

  1. Ammerman RT., 1986, Clini Psychol Rev., 6, 10
  2. Canetti L., 1997, Adolescence., 32, 381
  3. Parker G., 1989, Psychiatr Dev., 7, 317
  4. Rutter M., 1979, Ann Acad Med Singapore., 8, 3243
  5. Nemeroff CB., 1996, Mol Psychiatry., 1, 336
  6. De Bellis MD., 1994, J Clin Endocrinol Metab., 78, 249
  7. McCormick JA., 2000, Mol Endocrinol., 14, 506
  8. Sapolsky RM., 2000, Endo Rev., 21, 55
  9. Romens SE., Child Dev. In press.
  10. Yehuda R., Biol Psychiatry. In press.

Cited by

Sorted by citations

Related

Authors
Anacker, C., O'Donnell, K. J., & Meaney, M. J.
Affiliations
  • Douglas Mental Health University Institute (CA)
  • Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal, Canada
Corresponding author
Meaney, Michael J.
ORCID
Venue
Dialogues in Clinical Neuroscience
Publisher
Informa UK Limited
Published
2014-09-30
Volume
16
Issue
3
Pages
321-333
ISSN
  • 1294-8322 (ISSN-L)
  • 1958-5969
DOI
10.31887/dcns.2014.16.3/canacker
PMC
PMC4214175
OpenAlex
W2135480836
Cited by
237
References
144
Citations by year
2026: 9 · 2025: 17 · 2024: 15 · 2023: 20 · 2022: 14 · 2021: 19 · 2020: 20 · 2019: 24 · 2018: 31 · 2017: 29 · 2016: 23 · 2015: 16
FWCI
11.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Dialogues in Clinical Neuroscience (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
childhood adversity, epigenetic programming, hypothalamic-pituitary-adrenal axis, depression risk, stress response genes, parent-offspring interactions, social adversity, gene expression
MeSH terms
Animals, Child Abuse, Developmental Disabilities, Child, Preschool, Humans, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Epigenesis, Genetic

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

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