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Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function
Open accessAbstract
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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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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88 Not checked yet · 15 Own interpretation · 8 No basis given · 7 Own result · 1 Own method
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In the paper
“Lactating female Long-Evans rats (an outbred strain of rattus norvegicus) exhibit considerable variation in the frequency of pup licking/grooming (LG).”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
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In the paper
“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”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
What the sources say
- Not checked yetcites [66] Liu D., 1997, Science. source
- Not checked yetcites [67] Caldji C., 1998, Proc Nat Acad Sci U S A. source
- Not checked yetcites [68] Francis D., 1999, Science. source
- Not checked yetcites [69] Menard J., 2004, Neuroscience. source
- Not checked yetcites [70] Weaver IC., 2004, Nat Neurosci. source
- Not checked yetcites [71] Weaver IC., 2005, J Neurosci. source
- Not checked yetcites [72] Zhang TY., 2006, Biol Psychiatry. source
- Not checked yetcites [73] Bagot RC., 2012, Biol Psychiatry. source
- Not checked yetcites [74] Toki S., 2007, Eur J Neurosci. source
- Not checked yetcites [75] Kurata A., 2009, Horm Behav source
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In the paper
“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”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
What the sources say
- Not checked yetcites [92] Zhang TY., 2013, Neuropsychopharmacology. source
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In the paper
“We65,120 showed decreased hippocampal GR expression in samples from suicide completers with histories of childhood maltreatment compared with controls (sudden, involuntary fatalities).”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Epigenetic regulation of glucocorticoid receptor expression in humans
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“In contrast, 5-methylcytosine-dependent immunoprecipitation revealed no differences across the exon 17 GR promoter.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
What the sources say
- Not checked yetcites [92] Zhang TY., 2013, Neuropsychopharmacology. source
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In the paper
“Instead, the differences in hippocampal GR expression were unique to suicide completers with a history of childhood maltreatment.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Epigenetic regulation of glucocorticoid receptor expression in humans
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In the paper
“TSA infusion also eliminated the effect of maternal care on HPA responses to acute stress.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
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In the paper
“Preliminary studies revealed greater methylation across the entire exon 17 GR promoter sequence in the hippocampus of adult offspring of Low LG mothers.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
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In the paper
“The same relation was apparent across the exon 17 GR promoter, where the decreased level of DNA methylation was associated with an increased level of H3K4me3.92”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
What the sources say
- Not checked yetcites [92] Zhang TY., 2013, Neuropsychopharmacology. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“H3K9ac associates with increased transcription and we found increased H3K9ac of the exon 17 GR promoter in hippocampus from the adult offspring of High compared with Low LG mothers.70,83,92”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
What the sources say
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In the paper
“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.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
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In the paper
“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.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
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In the paper
“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.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
What the sources say
- Not checked yetcites [109] Weaver IC., 2006, Proc Natl Acad Sci U S A. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
What the sources say
- Not checked yetcites [92] Zhang TY., 2013, Neuropsychopharmacology. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
What the sources say
- Not checked yetcites [70] Weaver IC., 2004, Nat Neurosci. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Epigenetic regulation of glucocorticoid receptor expression in humans
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In the paper
“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”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Summary
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In the paper
“Moreover, the exon 1F sequence shows increased DNA methylation and decreased NGFI-A binding in samples from suicide victims with a history of maltreatment.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Epigenetic regulation of glucocorticoid receptor expression in humans
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Epigenetic regulation of glucocorticoid receptor expression in humans
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In the paper
“The increase in basal cortisol levels was particularly marked in melancholic and psychotic depression,43 but not in atypical depression.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Hypothalamic-pituitary-adrenal axis function and Major Depressive Disorder
What the sources say
- Not checked yetcites [43] Gold PW., 2002, Mol Psychiatry. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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“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”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Hypothalamic-pituitary-adrenal axis function and Major Depressive Disorder
What the sources say
- Not checked yetcites [40] Pariante CM., 2008, Trends Neurosci. source
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“Interestingly Cushing's disease or prolonged corticosteroid therapy can precipitate Major Depressive Disorder (MDD), but also mania.44”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Hypothalamic-pituitary-adrenal axis function and Major Depressive Disorder
What the sources say
- Not checked yetcites [44] Starkman MN., 1981, Psychosom Med. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Since elevated levels of cortisol act to inhibit subsequent HPA activity, this finding suggests impaired glucocorticoid negative feedback in depressed patients.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Hypothalamic-pituitary-adrenal axis function and Major Depressive Disorder
What the sources say
- Not checked yetcites [44] Starkman MN., 1981, Psychosom Med. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Introduction
What the sources say
- Not checked yetcites [16] Ammerman RT., 1986, Clini Psychol Rev.
- Not checked yetcites [17] Trickett PK., 1995, Dev Rev. source
- Not checked yetcites [18] Repetti RL., 2002, Psychol Bull. source
- Not checked yetcites [19] Lupien SJ., 2009, Nat Rev Neurosci. source
- Not checked yetcites [20] Hill J., 2001, Br J Psychiatry. source
- Not checked yetcites [21] Holmes SJ., 1987, J Child Psychol Psychiatry. source
- Not checked yetcites [22] Canetti L., 1997, Adolescence.
- Not checked yetcites [23] Parker G., 1989, Psychiatr Dev.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Moreover, childhood maltreatment also associates with an increased severity of illness, reduced treatment responsivity, and increased comorbidity.14,15”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Introduction
What the sources say
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“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”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Hypothalamic-pituitary-adrenal axis function and Major Depressive Disorder
What the sources say
- Not checked yetcites [42] Stetler C., 2011, Psychosom Med. source
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In the paper
“Thus, warm, nurturing families tend to promote resistance to stress and to diminish vulnerability to stress-induced illness.18,25”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Introduction
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Parental influences on stress reactivity
What the sources say
- Not checked yetcites [18] Repetti RL., 2002, Psychol Bull. source
- Not checked yetcites [33] Flinn MV., 1995, Curr Anthropology. source
- Not checked yetcites [34] Luecken LJ., 2000, Psychol Health. source
- Not checked yetcites [35] Pruessner JC., 2004, J Neurosci. source
- Not checked yetcites [36] Taylor SE., 2006, Biol Psychiatry. source
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In the paper
“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”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Hypothalamic-pituitary-adrenal axis function and Major Depressive Disorder
What the sources say
- Not checked yetcites [45] Laue L., 1990, J Clin Endocrinol & Metab. source
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In the paper
“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”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and HPA function
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and HPA function
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and HPA function
What the sources say
- Not checked yetcites [58] Heim C., 2000, JAMA. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
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In the paper
“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”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and HPA function
What the sources say
- Not checked yetcites [58] Heim C., 2000, JAMA. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and HPA function
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
What the sources say
- Not checked yetcites [67] Caldji C., 1998, Proc Nat Acad Sci U S A. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one. The quote only partly states this claim.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
What the sources say
- Not checked yetcites [114] Avishai-Eliner S., 2001, J Neuroendocrinol. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Pup LG increases hippocampal NGFI-A expression and binding to the exon 17 promoter.70,82,83”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Baram and colleagues114 showed that this maternally regulated decrease in CRF expression is accompanied by an increase in hippocampal GR expression.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
What the sources say
- Not checked yetcites [114] Avishai-Eliner S., 2001, J Neuroendocrinol. source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
What the sources say
- Not checked yetcites [83] Weaver IC., 2007, J Neuroscience. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Perhaps most convincingly, artificial tactile stimulation of pups increases hippocampal NGFI-A expression and NGFI-A binding to the exon 17 promoter.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
What the sources say
- Not checked yetcites [119] Wu Y., 2014, Endocrinology. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings suggest that variations in parent-offspring interactions epigenetically “program” hippocampal GR expression and thus the nature of the HPA response to stress.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Developmental adversity and epigenetic regulation of HPA function
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Epigenetic regulation of glucocorticoid receptor expression in humans
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“At the molecular level this interaction was associated with stable DNA demethylation, which in turn predicted increased FKBP5 expression.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Epigenetic regulation of glucocorticoid receptor expression in humans
What the sources say
- Not checked yetcites [133] Klengel T., 2013, Nat Neurosci. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The program is strengthened by a validated forensic interview that establishes developmental history and mental health status.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Epigenetic regulation of glucocorticoid receptor expression in humans
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Epigenetic regulation of glucocorticoid receptor expression in humans
What the sources say
- Not checked yetcites [133] Klengel T., 2013, Nat Neurosci. source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Epigenetic regulation of glucocorticoid receptor expression in humans
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“Since FKBP5 sequesters activated GR and prevents nuclear binding, the decreased FKBP5 methylation and increased FKBP5 expression associated with symptoms of glucocorticoid resistance.”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Epigenetic regulation of glucocorticoid receptor expression in humans
What the sources say
- Not checked yetcites [133] Klengel T., 2013, Nat Neurosci. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function > Epigenetic regulation of glucocorticoid receptor expression in humans
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.”
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?
In the citing paper
“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
In the citing paper
“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
Citations
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Childhood maltreatment and methylation of the glucocorticoid receptor gene NR3C1 in bipolar disorder
Perroud, N., Dayer, A., Piguet, C., Nallet, A., Favre, S., Malafosse, A., & Aubry, J.-M. (2014) · British Journal of Psychiatry · doi:10.1192/bjp.bp.112.120055 · Cited by 89
RetractedFelitti, V. J., Anda, R. F., Nordenberg, D., Williamson, D. F., Spitz, A. M., Edwards, V., Koss, M. P., & Marks, J. S. (1998) · American Journal of Preventive Medicine · doi:10.1016/s0749-3797(98)00017-8 · Cited by 18,943
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Kouzarides, T. (2007) · Cell · doi:10.1016/j.cell.2007.02.005 · Cited by 10,883
Child abuse: Adolescent records vs. adult recall
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Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., McClay, J., Mill, J., Martin, J., Braithwaite, A., et al. (2003) · Science · doi:10.1126/science.1083968 · Cited by 8,120
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Effects of stress throughout the lifespan on the brain, behaviour and cognition
Lupien, S. J., McEwen, B. S., Gunnar, M. R., & Heim, C. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2639 · Cited by 6,256
Epigenetic programming by maternal behavior
Weaver, I. C. G., Cervoni, N., Champagne, F. A., D'Alessio, A. C., Sharma, S., Seckl, J. R., Dymov, S., Szyf, M., & Meaney, M. J. (2004) · Nature Neuroscience · doi:10.1038/nn1276 · Cited by 6,177
Self-citationConversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1
Tahiliani, M., Koh, K. P., Shen, Y., Pastor, W. A., Bandukwala, H., Brudno, Y., Agarwal, S., Iyer, L. M., Liu, D. R., Aravind, L., et al. (2009) · Science · doi:10.1126/science.1170116 · Cited by 5,836
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Cited by
Sorted by citations
Pathogenesis of depression: Insights from human and rodent studies
Ménard, C., Hodes, G. E., & Russo, S. J. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2015.05.053 · Cited by 593
“Victims of childhood abuse or parental neglect have significantly higher probabilities of developing mood disorders (for review, see (Anacker et al., 2014)) and studies of institutionalized children indicate that global deprivation induces persistent behavioral and cognitive deficits (Chugani et…”
BackgroundWalker, C., Bath, K. G., Joëls, M., Kőrösi, A., Larauche, M. H., Lucassen, P. J., Morris, M. J., Raineki, C., Roth, T. L., Sullivan, R. M., et al. (2017) · Stress · doi:10.1080/10253890.2017.1343296 · Cited by 432
“The value of a naturalistic approach is that it can explore normal variations in maternal care within an undisturbed situation, i.e. high/low licking mothers or communal nesting (Anacker, O ’ Donnell, & Meaney, 2014; Blanchard, Summers, & Blanchard, 2013).”
BackgroundUvnäs-Moberg, K., Handlin, L., & Petersson, M. (2015) · Frontiers in Psychology · doi:10.3389/fpsyg.2014.01529 · Cited by 351
“It is well known that early exposure to stress, during pregnancy or in early life, may lead to lifelong sensitivity to stress and stressors and also to an inhibition of social interactive behaviors (Anacker et al., 2014).”
BackgroundWhy are some individuals more resilient than others: the role of social support
Southwick, S. M., Sippel, L. M., Krystal, J. H., Charney, D. S., Mayes, L. C., & Pietrzak, R. (2016) · World Psychiatry · doi:10.1002/wps.20282 · Cited by 400
The enemy between us: The psychological and social costs of inequality
Wilkinson, R. G., & Pickett, K. E. (2017) · European Journal of Social Psychology · doi:10.1002/ejsp.2275 · Cited by 280
Metadata
- 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.
- 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
- 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
- diamond
- doi.org
- 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.
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