Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation

In the paper

“Enduring behavioral responses to stress and epigenetic alterations in adult offspring have been demonstrated to be mediated by changes in gametes (10)(11)(12)(13), in utero effects (14), variations in early postnatal care (15,16), and/or other early life experiences (17) that are influenced by parental exposure (18).”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [10] Dias, 2014, Parental olfactory experience influences behavior and neural structure in subsequent generations, Nat Neurosci source
• ?Not checked — no full text of the sourcecites [11] Zaidan, 2013, Prereproductive stress to female rats alters corticotropin releasing factor type 1 expression in ova and behavior and brain corticotropin releasing factor type 1 expression in offspring, Biol Psychiatry source
• Supported

  Citation 18 is attached to the claim that parental exposure influences outcomes in offspring, not to the separately cited list of mediating mechanisms. The Abstract reports that early stress in male mice was followed by behavioral alterations and DNA-methylation changes in their offspring; the Results say those offspring were raised under normal conditions. (LLM, conf=0.88)

  cites [12] Franklin, 2010, Epigenetic transmission of the impact of early stress across generations, Biol Psychiatry source
• Supported

  The citation is attached to the point that parental exposure can influence offspring outcomes. The Introduction (page unavailable) says parental environmental exposures can shape offspring neurodevelopment and identifies changes in the intrauterine environment, lactation, and maternal behavior as relevant pathways. The paper does not need to establish every separately cited mechanism in the sentence to support this point. (LLM, conf=0.86)

  cites [13] Rodgers, 2013, Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation, J Neurosci source
• Supported

  Citation (14) is attached to the in utero effects, not to the separately cited gamete or postnatal-care pathways. The Experimental set-up and Abstract report gestational stress exposure followed by altered Bdnf expression and DNA methylation in adult rat offspring; the Introduction also describes lasting behavioral effects of prenatal stress. The paper does not itself measure offspring behavior, but it reports that evidence as background. (LLM, conf=0.87)

  cites [14] Boersma, 2014, Prenatal stress decreases Bdnf expression and increases methylation of Bdnf exon IV in rats, Epigenetics source
• ?Not checked — no full text of the sourcecites [15] Champagne, 2006, Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring, Endocrinology source
• ?Not checked — no full text of the sourcecites [16] Weaver, 2004, Epigenetic programming by maternal behavior, Nat Neurosci source

In the paper

“Differential methylation of the glucocorticoid receptor (GR) gene associated with maternal behavior has been observed in F1 in rodents at Nr3c1 exon 1 7 promoter (16) and in human offspring with parental PTSD at the ortholog NR3C1 exon 1 F promoter (24).”

What the sources say

• ?Not checked — no full text of the sourcecites [16] Weaver, 2004, Epigenetic programming by maternal behavior, Nat Neurosci source
• Supported

  The citation is attached to the human-offspring portion of the sentence. The Results (Maternal PTSD, Paternal PTSD and GR-1F promoter methylation) report differences in NR3C1 exon 1F promoter methylation associated with parental PTSD in offspring of Holocaust survivors; the Introduction identifies this human promoter as orthologous to the rat promoter. (LLM, conf=0.93)

  cites [24] Yehuda, 2014, Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring, Am J Psychiatry source

In the paper

“Animal models have demonstrated that stress exposure can result in epigenetic alterations in the next generation, and such mechanisms have been hypothesized to underpin vulnerability to symptoms in offspring of trauma survivors (6)(7)(8)(9).”

What the sources say

• ?Not checked — no full text of the sourcecites [6] Gapp, 2014, Early life epigenetic programming and transmission of stress-induced traits in mammals: How and when can environmental factors influence traits and their transgenerational inheritance?, Bioessays source
• Partly supported

  The section “Cytosine Methylation in Response to Variations in Maternal Care: A Behavioral Model” (page unavailable) reports altered DNA methylation in rat pups receiving different levels of maternal care and says associated biological effects were transmitted to a third generation. It does not clearly demonstrate that stress exposure in one generation caused epigenetic alterations in the next; the animal model described is one of variation in maternal care. (LLM, conf=0.82)

  cites [7] Yehuda, 2009, The relevance of epigenetics to PTSD: Implications for the DSM-V, J Trauma Stress sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [8] Bale, 2015, Epigenetic and transgenerational reprogramming of brain development, Nat Rev Neurosci source
• ?Not checked — no full text of the sourcecites [9] Dias, 2015, Epigenetic mechanisms underlying learning and the inheritance of learned behaviors, Trends Neurosci source

In the paper

“For example, lower 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2) activity was observed in Holocaust survivors compared with control subjects, presumably reflecting an enduring adaptive response to extreme nutritional deprivation (19).”

What the sources say

• Supported

  The Results report a significantly elevated urinary F/E ratio in Holocaust survivors compared with controls, suggesting lower 11β-HSD-2 activity. The Discussion describes this change as potentially beneficial during starvation or salt depletion and associates it with starvation or other Holocaust-specific trauma, consistent with the claim’s hedged interpretation. (LLM, conf=0.91)

  cites [19] Yehuda, 2009, Enduring effects of severe developmental adversity, including nutritional deprivation, on cortisol metabolism in aging Holocaust survivors, J Psychiatr Res source

In the paper

“FKBP5 effectively decreases glucocorticoid binding to GR, impeding GR translocation to the nucleus (29,30).”

What the sources say

• ?Not checked — no full text of the sourcecites [29] Pratt, 1997, Steroid receptor interactions with heat shock protein and immunophilin chaperones, Endocr Rev source
• Partly supported

  The Discussion reports reduced hormone binding and demonstrates that FKBP51 delays GR nuclear translocation. But it describes impaired translocation as an additional effect: the 'FKBP51 Inhibits Nuclear Translocation of GR' section finds a delay even at saturating hormone concentrations, when the binding-affinity effect is excluded. The claim's implication that reduced binding causes the translocation delay is therefore too broad. (LLM, conf=0.83)

  cites [30] Wochnik, 2005, FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells, J Biol Chem sourceExperimental — accuracy not yet measured

In the paper

“Early abuse induced demethylation in the presence of the FKBP5 risk allele was demonstrated for three of the sites (3 to 5) in adult peripheral blood (38).”

What the sources say

• Supported

  The Results report that, in DNA from peripheral blood cells, three CpGs in FKBP5 intron 7 showed an average 12.3% decrease in methylation among childhood-abuse-exposed risk-allele carriers compared with the other groups. The Methods identify peripheral blood as the DNA source. (LLM, conf=0.91)

  cites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source

In the paper

“Epigenetic effects in maternal or paternal gametes are a potential explanation for epigenetic effects in offspring (10-13), but blood samples will not permit ascertainment of gamete-dependent transmission.”

What the sources say

• Supported

  The Results section says the authors investigated sperm for epigenetic changes because their data suggested inheritance via parental gametes; they found reduced methylation at an olfactory-receptor locus in sperm from exposed fathers. This supports the cited proposition that gamete-based epigenetic effects are a potential explanation for effects in offspring. The statement about what blood samples can establish follows the citation and is not attributed to this source. (LLM, conf=0.88)

  cites [10] Dias, 2014, Parental olfactory experience influences behavior and neural structure in subsequent generations, Nat Neurosci source
• ?Not checked — no full text of the sourcecites [11] Zaidan, 2013, Prereproductive stress to female rats alters corticotropin releasing factor type 1 expression in ova and behavior and brain corticotropin releasing factor type 1 expression in offspring, Biol Psychiatry source
• Supported

  The citation attaches to the proposed gamete-based explanation, not the subsequent statement about blood samples. The Results report altered DNA methylation in the male germline that may be passed to offspring, supporting a paternal-gamete mechanism; the paper need not establish a maternal mechanism to support this possibility. (LLM, conf=0.91)

  cites [12] Franklin, 2010, Epigenetic transmission of the impact of early stress across generations, Biol Psychiatry source
• Supported

  The Introduction (page not provided) proposes epigenetic marks in germ cells as a mechanism by which parental exposures affect offspring, while discussing both maternal and paternal studies. The citation is attached to that proposed gamete-dependent mechanism; the statement about what blood samples can establish is the citing authors’ uncited qualification. (LLM, conf=0.91)

  cites [13] Rodgers, 2013, Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation, J Neurosci source

In the paper

“FKBP5 single nucleotide polymorphisms have additionally been shown to interact with early trauma to predict both PTSD and major depression (36,37), possibly through involvement of allelespecific, environmentally dependent changes in methylation of specific cytosine-phosphate-guanine (CpG) sites (38).”

What the sources say

• Partly supported

  The COMMENT reports that FKBP5 SNPs interacted with child abuse to predict adult PTSD symptoms. The “FKBP5 and Child Abuse Interaction” section reports no significant genotype-by-child-abuse interaction for depression outcome after correction for multiple testing. This source therefore supports the PTSD part, but not the claim about major depression. (LLM, conf=0.90)

  cites [36] Binder, 2008, Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults, JAMA sourceExperimental — accuracy not yet measured
• Partly supported

  The main text reports that FKBP5 SNP rs9470080 interacted with childhood adversity to predict PTSD risk in African-American participants; the interaction was not significant in European Americans. It does not report an FKBP5–early-trauma interaction predicting major depression. The depression study listed in the References concerns CRHR1, not FKBP5. (LLM, conf=0.87)

  cites [37] Koenen, 2010, FKBP5 polymorphisms modify the effects of childhood trauma, Neuropsychopharmacology sourceExperimental — accuracy not yet measured

In the paper

“alterations of which have been associated with both PTSD and intergenerational effects (27,28).”

What the sources say

• ?Could not verify

  The Results report an association between maternal PTSD and offspring glucocorticoid sensitivity, and the Discussion considers possible intergenerational mechanisms. Neither section identifies FKBP5 or links alterations of it to PTSD or intergenerational effects (searched: FKBP5 and FK506-binding protein 5). (LLM, conf=0.72)

  cites [27] Lehrner, 2014, Maternal PTSD associates with greater glucocorticoid sensitivity in offspring of Holocaust survivors, Psychoneuroendocrinology sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [28] Daskalakis, 2013, Endocrine aspects of post-traumatic stress disorder and implications for diagnosis and treatment, Endocrinol Metab Clin North Am source

In the paper

“Intron 7 sites are located within, or in proximity to, functional consensus glucocorticoid response elements (GREs) and are demethylated by glucocorticoids, particularly during developmentally sensitive periods (38).”

What the sources say

• Supported

  The Methods (page not supplied) locate the intron 7 CpG sites within or near consensus GREs. The Results (page not supplied) report dexamethasone-induced demethylation of those sites and a sensitive period during which glucocorticoid exposure produced the effect. (LLM, conf=0.94)

  cites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source

In the paper

“FKBP5 gene expression has been shown to be altered in PTSD and major depression (32)(33)(34)(35).”

What the sources say

• Supported

  The Abstract (page unavailable) reports genotype-specific gene-expression changes in PTSD. The Stimulated FKBP5 mRNA expression section (page unavailable) reports a significant difference in FKBP5 mRNA induction between depressed patients and controls carrying the same risk allele. Together, these passages support the broad claim that FKBP5 expression is altered in both conditions. (LLM, conf=0.88)

  cites [32] Menke, 2013, Genetic variation in FKBP5 associated with the extent of stress hormone dysregulation in major depression, Genes Brain Behav source
• Partly supported

  The Results and Comment sections report genotype-dependent changes in FKBP5 expression associated with PTSD symptoms, including a replicated association. The passages do not report altered FKBP5 expression in major depression, so this source supports only the PTSD part of the claim. Page numbers were not provided in our copy. (LLM, conf=0.88)

  cites [33] Mehta, 2011, Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: Evidence from endocrine and gene expression studies, Arch Gen Psychiatry sourceExperimental — accuracy not yet measured
• Partly supported

  The genetic analysis (§3.3; page unavailable) links lower FKBP5 expression to greater PTSD symptom severity. The Discussion (§4; page unavailable) does not establish altered FKBP5 gene expression in major depression: it reports that a depression-associated genotype was not related to FKBP5 mRNA expression, although it was associated with higher protein levels. (LLM, conf=0.88)

  cites [34] Sarapas, 2011, Genetic markers for PTSD risk and resilience among survivors of the World Trade Center attacks, Dis Markers sourceExperimental — accuracy not yet measured
• Supported

  The Results report significantly decreased FKBP5 expression in participants with PTSD. The Discussion also reports that FKBP5 expression in recurrent depression was altered in the opposite direction; the paper does not present that depression finding as its own experiment. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites [35] Yehuda, 2009, Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks, Biol Psychiatry source

In the paper

“Indeed, for the NR3C1 gene, associations of individual sites with exposures to several types of adversity are increasingly recognized (52).”

What the sources say

• Supported

  The GR-1F promoter site-specific methylation section reviews site-specific NR3C1 methylation findings across 16 studies. It identifies associations with several forms of adversity, including prenatal maternal mood, childhood abuse, parental loss, and other early stressful events. The supplied passages do not provide page numbers. (LLM, conf=0.93)

  cites [52] Daskalakis, 2014, Site-specific methylation changes in the glucocorticoid receptor exon 1F promoter in relation to life adversity: Systematic review of contributing factors, Front Neurosci source

In the paper

“The main finding in this study is that Holocaust survivors and their offspring have methylation changes on the same site in a functional intronic region of the FKBP5 gene, a GR-binding sequence in intron 7, but in the opposite direction.”

In the paper

“Neither parental PTSD (β 5 .134,ns) nor the presence of the FKBP5 risk allele (β 5 2.044, ns) contributed to the model.”

In the paper

“However, like the CTQ total score, emotional abuse was not significantly associated with bin 3/site 6 methylation (β 5 .018,ns) and did not alter the significance of Holocaust exposure at this site (β 5 2.375, p 5 .045).”

In the paper

“Adding childhood adversity as measured by the CTQ total score did not alter the predictive significance of parental exposure (β 5 2.359, p 5 .049)and was not a predictor of bin 3/site 6 methylation (β 5 2.034, ns).”

In the paper

“The mechanism of intergenerational transmission of epigenetic effects at bin 3/site 6 is not known but does not appear to be mediated by childhood adversity, as is the case for bin 2.”

In the paper

“In contrast to the findings at bin 3/site 6, which relate to parental exposure, bin 2/sites 3 to 5 methylation was associated with offspring trauma exposure (childhood physical and sexual abuse), but the direction depended on the presence of the FKBP5 risk allele.”

In the paper

“It should be noted that mean CTQ subscale and total scores for the Holocaust offspring were generally lower than reported in other population samples”

In the paper

“Parental trauma exposure is associated with greater risk for posttraumatic stress disorder (PTSD) and mood and anxiety disorders in offspring (1,2).”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Yehuda, 1998, Vulnerability to posttraumatic stress disorder in adult offspring of Holocaust survivors, Am J Psychiatry source
• ?Not checked — no full text of the sourcecites [2] Weissman, 2005, Families at high and low risk for depression: A 3-generation study, Arch Gen Psychiatry source

In the paper

“The finding was unchanged without covariation (F 1,29 5 4.91, p 5 .035)and when presence of lifetime PTSD in offspring (p 5 .036)or severity of childhood trauma (p 5 .049)were added, respectively, as additional covariates.”

In the paper

“Bin 3/site 6 methylation was not associated with the FKBP5 risk allele and could not be attributed to the offspring's own trauma exposure, their own psychopathology, or other examined characteristics that might independently affect methylation of this gene.”

In the paper

“in the aforementioned study, the increase in offspring 11β-HSD-2 activity was interpreted as a protective adaptation to mitigate exposure to elevated maternal glucocorticoids associated with reduced maternal 11β-HSD-2 activity (20,50).”

What the sources say

• ?Not checked — no full text of the sourcecites [20] Bierer, 2014, Elevation of 11beta-hydroxysteroid dehydrogenase type 2 activity in Holocaust survivor offspring: Evidence for an intergenerational effect of maternal trauma exposure, Psychoneuroendocrinology source
• ?Not checked — no full text of the sourcecites [50] Yehuda, 2011, Minireview: Stress-related psychiatric disorders with low cortisol levels: A metabolic hypothesis, Endocrinology source

In the paper

“The addition of presence/absence of the FKBP5 risk allele as a covariate did not appreciably alter the finding (p 5 .053),suggesting that bin 3/site 6 methylation changes in F0 were driven more by exposure than genetic variation in this single nucleotide polymorphism.”

In the paper

“We previously reported a directional difference between parents and offspring in 11β-HSD-2 activity, which was interpreted as an accommodation in the offspring during a sensitive developmental window to the biological consequences of parental trauma exposure (20).”

What the sources say

• ?Not checked — no full text of the sourcecites [20] Bierer, 2014, Elevation of 11beta-hydroxysteroid dehydrogenase type 2 activity in Holocaust survivor offspring: Evidence for an intergenerational effect of maternal trauma exposure, Psychoneuroendocrinology source

In the paper

“Like FKBP5, 11β-HSD-2 is a moderator of glucocorticoid action”

In the paper

“The directional difference in bin 3/site 6 methylation between Holocaust survivors and their offspring was unexpected but may reflect an intergenerational biological accommodation.”

In the paper

“In turn, FKBP5 gene expression is regulated by GR binding, forming an intracellular ultrashort glucocorticoid negative-feedback loop that regulates FKBP5 and GR (26,31).”

What the sources say

• ?Not checked — no full text of the sourcecites [26] Binder, 2009, The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders, Psychoneuroendocrinology source
• ?Not checked — no full text of the sourcecites [31] Jaaskelainen, 2011, Steroid up-regulation of FKBP51 and its role in hormone signaling, Curr Opin Pharmacol source

In the paper

“There were no significant differences between the groups in age, gender, years of education, current anxiety or mood disorder diagnoses, or frequency of the FKBP5 risk allele.”

In the paper

“There were no significant differences between the groups in age, gender, years of education, childhood trauma scores, psychiatric diagnoses, frequency of the FKBP5 risk allele, or cortisol levels.”

In the paper

“In contrast, the effect was reduced when controlling for parental PTSD (F 1,23 5 2.59, p 5 .121),suggesting an influence of parental PTSD symptoms.”

In the paper

“Genotypes of rs1360780 were in Hardy-Weinberg equilibrium (p ..05).”

In the paper

“In addition, even within the same cell type, observed global changes reflect diverse changes in single cells, as has been reported in a number of articles using clone-based sequencing for methylation analysis [for example (16,17,54)].”

What the sources say

• ?Not checked — no full text of the sourcecites [16] Weaver, 2004, Epigenetic programming by maternal behavior, Nat Neurosci source
• ?Not checked — no full text of the sourcecites [17] Murgatroyd, 2009, Dynamic DNA methylation programs persistent adverse effects of early-life stress, Nat Neurosci source
• ?Not checked — no full text of the sourcecites [54] Yehuda, 2015, Lower methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of veterans with posttraumatic stress disorder, Biol Psychiatry source

In the paper

“All F1 participants were raised by their biological parents.”

In the paper

“The intra-assay and interassay coefficients of variation were 2.3% and 6.1%, respectively.”