Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms

In the paper

“Maternal age at Holocaust exposure and maternal PTSD were found to independently influence urinary cortisol levels and cortisol metabolism in adult offspring, with the strongest effects in offspring of mothers who were children during World War II 167”

What the sources say

• Disputed

  Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Checked by a reasoning model — may be wrong.

  cites [167] 167. Bader HN, Bierer LM, Lehrner A et al. Maternal age at holocaust exposure and maternal PTSD independently influence urinary cortisol levels in adult offspring. Front Endocrinol 2014;5:103. sourceExperimental — accuracy not yet measured

In the paper

“Specifically, maternal PTSD was associated with lower urinary cortisol levels as well as greater GR sensitivity as measured by the lysozyme inhibition test (an in vitro measure of that sensitivity in peripheral tissue) as well as the dexamethasone suppression test (DST).”

What the sources say

• Supported

  The Discussion reports lower urinary cortisol excretion and greater glucocorticoid sensitivity on both the lysozyme suppression test (LST) and dexamethasone suppression test (DST) in offspring associated with maternal PTSD. The cited finding concerns offspring of Holocaust survivors; no page number is provided in our copy. (LLM, conf=0.94)

  cites [63] 63. Lehrner A, Bierer LM, Passarelli V et al. Maternal PTSD associates with greater glucocorticoid sensitivity in offspring of Holocaust survivors. Psy- choneuroendocrinology 2014;40:213-20. source

In the paper

“However, interestingly, they were directionally distinct (when compared to their respective control groups), with Holocaust offspring showing lower methylation at this site compared to demographically-matched controls, and Holocaust survivors demonstrating higher methylation compared to respective controls.”

What the sources say

• Supported

  The Abstract reports that FKBP5 methylation at bin 3/site 6 was higher in Holocaust survivors than in controls, but lower in their offspring than in offspring controls. The Discussion likewise describes changes at the same site in opposite directions. (LLM, conf=0.94)

  cites [127] 127. Yehuda R, Daskalakis NP, Bierer LM et al. Holocaust exposure induced in- tergenerational effects on FKBP5 methylation. Biol Psychiatry 2016;80: 372-80. source

In the paper

“The interaction demonstrated that, in the absence of maternal PTSD, offspring with paternal PTSD showed higher GR promoter methylation, whereas offspring with both maternal and paternal PTSD showed lower methylation of this promoter region.”

What the sources say

• Supported

  The Results section (‘Maternal PTSD, Paternal PTSD and GR-1F promoter methylation’) reports a significant interaction: offspring with paternal PTSD only had higher GR-1F promoter methylation, while those with both maternal and paternal PTSD had lower methylation. This directly matches the claim. (LLM, conf=0.95)

  cites [126] 126. Yehuda R, Daskalakis NP, Lehrner A et al. Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid recep- tor gene in Holocaust survivor offspring. Am J Psychiatry 2014;171: 872-80. source

In the paper

“The first documented study of the GR promoter in humans showed higher methylation of the hippocampal GR 1F promoter in post-mortem tissue of adult suicide victims with a history of childhood abuse, similar to findings in rodent pups raised by mothers who provided low levels of licking and grooming 121,122 .”

What the sources say

• Partly supported

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

  cites [121] 121. McGowan PO, Sasaki A, D'alessio AC et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 2009;12:342-8. sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [122] 122. Labonte B, Yerko V, Gross J et al. Differential glucocorticoid receptor exon 1(B), 1(C), and 1(H) expression and methylation in suicide completers with a history of childhood abuse. Biol Psychiatry 2012;72:41-8. sourceExperimental — accuracy not yet measured

In the paper

“indicating that maternal mood and offspring HPA axis reactivity may be linked through epigenetic processes and sensitive to fetal developmental stage”

What the sources say

• Supported

  The Conclusion says newborn NR3C1 methylation may link antenatal maternal mood with altered infant HPA stress reactivity. The Discussion reports associations between maternal mood in the second and third trimesters and methylation at different CpG sites, supporting the qualified point about sensitivity to developmental timing. The indexed copy provides section labels but no page numbers. (LLM, conf=0.88)

  cites [141] 141. Oberlander TF, Weinberg J, Papsdorf M et al. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 2008;3:97-106. source

In the paper

“Among mice exposed to stress during early, mid and late gestation, male F1 with early gestation prenatal stress exposure demonstrated behavioral indicators of stress responsivity and anhedonia, as well as alterations in GR and corticotrophin-releasing factor (CRF) expression and increased HPA axis responsivity, with corresponding alteration in CRF and nr3c1 gene methylation 159”

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 [159] 159. Mueller BR, Bale TL. Sex-specific programming of offspring emotionality after stress early in pregnancy. J Neurosci 2008;28:9055-65. source

In the paper

“In animal models, prenatal stress has been shown to lower expression of 11β-HSD2 mRNA and 11B-HSD2 activity, both of which are associated with increased 11β-HSD2 methylation in the placenta 140 .”

What the sources say

• Partly supported

  Section 6.1 reports that prenatal stress decreases placental 11β-HSD2 mRNA in rats and that reduced expression is associated with increased promoter methylation. It also reports reduced 11β-HSD2 in female mouse placentas, but does not specify reduced enzyme activity or associate an activity measurement with methylation. No page number is available in our copy. (LLM, conf=0.87)

  cites [140] 140. Nugent BM, Bale TL. The omniscient placenta: metabolic and epigenetic regulation of fetal programming. Front Neuroendocrinol 2015;39:28-37. sourceExperimental — accuracy not yet measured

In the paper

“The gestational stage of the fetus is an important determinant of the impact of prenatal exposures on offspring, indicative of developmentally sensitive windows of fetal development 146,147 .”

What the sources say

• Supported

  The Discussion states that effects of stress-related glucocorticoid exposure during pregnancy on offspring are partly dependent on fetal gestational age. It also reports particularly strong cortisol effects among babies whose mothers were exposed in the third trimester, supporting the claim about developmentally sensitive timing. (LLM, conf=0.86)

  cites [146] 146. Yehuda R, Engel SM, Brand SR et al. Transgenerational effects of posttrau- matic stress disorder in babies of mothers exposed to the World Trade Center attacks during pregnancy. J Clin Endocrinol Metab 2005;90:4115-8. source
• ?Not checked — no full text of the sourcecites [147] 147. Glover V, O'connor T, O'Donnell K. Prenatal stress and the programming of the HPA axis. Neurosci Biobehav Rev 2010;35:17-22. source

In the paper

“For example, a preliminary study examining FKBP5 intron 7 methylation in Holocaust survivors and their children demonstrated alterations at the same site within intron 7 in both parents and their children, with no specific consideration of parental gender or PTSD 127 .”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [127] 127. Yehuda R, Daskalakis NP, Bierer LM et al. Holocaust exposure induced in- tergenerational effects on FKBP5 methylation. Biol Psychiatry 2016;80: 372-80. sourceExperimental — accuracy not yet measured

In the paper

“Because of a phenomenon called imprinting, maternal and paternal genomes are differentially marked and re-programmed, and a small number of regions from the DNA of the parent of origin may remain with DNA methylation intact 173,189,191”

What the sources say

• Supported

  The Cytosine methylation section describes different treatment of paternal and maternal methylation after fertilization: most paternal methylation is erased, while maternal methylation is protected. It also says a subset of paternal methylation marks, including marks at some imprinted genes, is maintained. (LLM, conf=0.90)

  cites [173] 173. Rando OJ. Daddy issues: paternal effects on phenotype. Cell 2012;151: 702-8. source
• ?Not checked — no full text of the sourcecites [189] 189. Lane N, Dean W, Erhardt S et al. Resistance of IAPs to methylation repro- gramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis 2003;35:88-93. source
• ?Not checked — no full text of the sourcecites [191] 191. Buiting K, Groß S, Lich C et al. Epimutations in Prader-Willi and Angel- man syndromes: a molecular study of 136 patients with an imprinting de- fect. Am J Hum Genet 2003;72:571-7. source

In the paper

“Among the epigenetic mechanisms that have been implicated in paternal transmission of stress effects via sperm are DNA methylation, oxidative damage to sperm DNA, histone modifications, and changes in small noncoding RNA [175][176][177][178][179] , including microRNA 180,181”

What the sources say

• Partly supported

  The Results (page unavailable) report altered sperm DNA methylation after paternal odor-fear conditioning and discuss noncoding RNA as a possible mechanism. They found no difference in the histone modifications tested; the paper does not identify oxidative sperm-DNA damage or microRNA as mechanisms in this experiment. Thus it supports part, but not the full list attributed to it. (LLM, conf=0.88)

  cites [175] 175. Dias BG, Ressler KJ. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci 2014;17: 89-96. sourceExperimental — accuracy not yet measured
• Partly supported

  The paper’s Abstract reports altered sperm small noncoding RNAs, including microRNAs, after early-life trauma in mice, and sperm-RNA injection reproduced effects in offspring. It mentions DNA methylation and histone modifications only as possible later mechanisms, not as demonstrated mechanisms in this study. Our copy does not support the attributed role of oxidative damage to sperm DNA. (LLM, conf=0.88)

  cites [176] 176. Gapp K, Jawaid A, Sarkies P et al. Implication of sperm RNAs in transge- nerational inheritance of the effects of early trauma in mice. Nat Neurosci 2014;17:667-9. sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract and Introduction (pages not provided) describe transgenerational sperm DNA-methylation changes after environmental toxicant exposure; the Introduction also notes a correlation between histone marks and regions where methylation changes occur. The Discussion speculates about altered noncoding-RNA expression, but the paper does not establish paternal transmission of stress effects through oxidative sperm-DNA damage, histone modifications, or sperm microRNA changes. (LLM, conf=0.86)

  cites [177] 177. Guerrero-Bosagna C, Weeks S, Skinner MK. Identification of genomic fea- tures in environmentally induced epigenetic transgenerational inherited sperm epimutations. PLoS One 2014;9:e100194. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [178] 178. Milekic MH, Xin Y, O'Donnell A et al. Age-related sperm DNA methylation changes are transmitted to offspring and associated with abnormal be- havior and dysregulated gene expression. Mol Psychiatry 2015;20:995- 1001. source
• Supported

  The citations to this paper follow “including microRNA,” so the relevant attribution is the microRNA mechanism, not every mechanism in the preceding list. The Discussion reports stress-related changes in sperm microRNA content consistent with altered offspring stress responsivity; the supplied passages do not give page numbers. (LLM, conf=0.93)

  cites [179] 179. Rodgers AB, Morgan CP, Bronson SL et al. Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regu- lation. J Neurosci 2013;33:9003-12. source
• Partly supported

  The Introduction discusses sperm DNA methylation, histone modifications, and RNA transcripts as aspects of the paternal epigenome that may influence embryonic development. The Conclusions and future directions section discusses environmental effects on sperm epigenetics, but does not establish paternal transmission of stress effects or identify oxidative sperm-DNA damage as a mechanism. The sentence cites other sources specifically for microRNA, so that detail is not assessed against this paper. (LLM, conf=0.85)

  cites [180] 180. Jenkins TG, Carrell DT. The sperm epigenome and potential implications for the developing embryo. Reproduction 2012;143:727-34. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [181] 181. Szyf M. Nongenetic inheritance and transgenerational epigenetics. Trends Mol Med 2015;21:134-44. source

In the paper

“female offspring exposed to prenatal stressors had higher HPA axis reactivity than did similarly exposed males, with differences in placental expression of 11β-HSD enzymes”

What the sources say

• Supported

  The Abstract states that female offspring exposed to stressors had increased HPA-axis reactivity compared with males and reports changes in placental 11β-HSD enzyme expression. The Discussion describes sex-specific differences in 11β-HSD1 and 11β-HSD2 expression, while noting that not every stressor or reactivity test showed a sex difference. (LLM, conf=0.92)

  cites [163] 163. Carpenter T, Grecian S, Reynolds R. Sex differences in early-life program- ming of the hypothalamic-pituitary-adrenal axis in humans suggest in- creased vulnerability in females: a systematic review. J Dev Orig Health Dis 2017;8:244-55. source

In the paper

“Although all of a female's oocytes are present at birth, they can be affected by environmental exposures, particularly during childhood 165”

What the sources say

• Partly supported

  The Human studies section (page unavailable) proposes childhood as a period of vulnerability for female oocytes and says environmental insults may potentially disturb their epigenetic state. It does not state that all oocytes are present at birth, and it presents the exposure effect as a possibility rather than an established fact. (LLM, conf=0.86)

  cites [165] 165. Cortessis VK, Thomas DC, Levine AJ et al. Environmental epigenetics: prospects for studying epigenetic mediation of exposure-response rela- tionships. Hum Genet 2012;131:1565-89. sourceExperimental — accuracy not yet measured

In the paper

“In vitro fertilization was also used to implant the F0 sperm into a naïve female.This produced similar behavioral and biological findings in the F1, further pointing to biological inheritance through sperm.”

What the sources say

• Partly supported

  The Results (section “Inheritance of effects in the F2 and IVF-derived generations”) report that IVF using F0 sperm produced F1 offspring with altered olfactory anatomy, supporting the inference of biological inheritance. But the authors explicitly state that they could not perform behavioral analyses on IVF-generated offspring, so the claim that IVF produced similar behavioral findings is unsupported. (LLM, conf=0.93)

  cites [175] 175. Dias BG, Ressler KJ. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci 2014;17: 89-96. sourceExperimental — accuracy not yet measured

In the paper

“Although significant sex differences were noted in endocrine and behavioral measures, there was no interaction between sex and paternal stress in the offspring of those exposed at puberty or adulthood.”

What the sources say

• Supported

  The Results (Analysis of offspring physiology & behavior; page unavailable) report significant sex differences in corticosterone measures, with no sex-by-paternal-stress interaction. They also report a significant sex difference in light–dark box behavior. The study compared offspring of sires stressed during puberty or adulthood. (LLM, conf=0.90)

  cites [179] 179. Rodgers AB, Morgan CP, Bronson SL et al. Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regu- lation. J Neurosci 2013;33:9003-12. source

In the paper

“Early maternal separation resulted in decreased nr3c1 DNA methylation in the hippocampus and sperm cells, as well as poor coping behavior.”

What the sources say

• Partly supported

  The Effects of MSUS and EE on GR Expression and Promoter Methylation section reports decreased GR (nr3c1) methylation in the hippocampus of exposed males and their offspring, and in sperm of exposed males. But the intervention combined maternal separation with unpredictable maternal stress, and the Effects of MSUS on Coping Behaviors in Aversive Conditions section reports more active coping in offspring, not poor coping. (LLM, conf=0.90)

  cites [205] 205. Gapp K, Bohacek J, Grossmann J et al. Potential of environmental enrich- ment to prevent transgenerational effects of paternal trauma. Neuropsy- chopharmacology 2016;41:2749-58. sourceExperimental — accuracy not yet measured

In the paper

“was later found to be associated with reduced sperm count, motility and morphology, and altered sperm microRNA, mitochondria and protein in the smoker parent 201,202”

What the sources say

• Partly supported

  The Results and Discussion (page numbers unavailable) report lower sperm count and motility in smokers, describe reduced normal morphology, and identify altered sperm nuclear proteins. The paper does not report altered sperm microRNA or mitochondria in smokers, so those parts of the claim are unsupported. (LLM, conf=0.90)

  cites [201] 201. Hamad MF, Shelko N, Kartarius S et al. Impact of cigarette smoking on histone (H2B) to protamine ratio in human spermatozoa and its relation to sperm parameters. Andrology 2014;2:666-77. sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion reports altered sperm microRNA expression in smokers. But the Study population section reports no significant difference in sperm count, motility, or morphology between smokers and non-smokers. The cited passages do not establish altered sperm mitochondria or protein; the reported Ston1 and TRIM26 changes concern mRNA expression. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  cites [202] 202. Marczylo EL, Amoako AA, Konje JC et al. Smoking induces differential miRNA expression in human spermatozoa: a potential transgenerational epigenetic concern? Epigenetics 2012;7:432-9. sourceExperimental — accuracy not yet measured

In the paper

“Changes in DNA methylation were observed in sperm from men with alcohol or opioid dependence 199,200 , but effects in offspring were not measured.”

What the sources say

• ?Not checked — no full text of the sourcecites [199] 199. Ouko LA, Shantikumar K, Knezovich J et al. Effect of alcohol consumption on CpG methylation in the differentially methylated regions of H19 and IG-DMR in male gametes -Implications for fetal alcohol spectrum dis- orders. Alcohol Clin Exp Res 2009;33:1615-27. source
• Supported

  The Results report significantly increased sperm-DNA methylation at one OPRM1 CpG site in opioid-dependent men, while the overall sperm-DNA difference was not significant. The Discussion treats effects in offspring as a possibility rather than a measured outcome. This source supports the opioid portion of the sentence; the alcohol portion is not attributed to it alone because the sentence cites two sources. (LLM, conf=0.90)

  cites [200] 200. Chorbov VM, Todorov AA, Lynskey MT et al. Elevated levels of DNA methylation at the OPRM1 promoter in blood and sperm from male opi- oid addicts. J Opioid Manag 2011;7:258. source

In the paper

“These mice (F0) demon-strated behavioral changes in response to the stressor, and also changes in several specific sperm microRNA.”

What the sources say

• Partly supported

  The Results section, “Analysis of sperm miR environment” (page unavailable), reports significant increases in nine specific sperm microRNAs in stressed males. The paper does not report behavioral changes in those F0 males in response to the stressors; its behavioral tests concern their offspring. (LLM, conf=0.88)

  cites [179] 179. Rodgers AB, Morgan CP, Bronson SL et al. Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regu- lation. J Neurosci 2013;33:9003-12. sourceExperimental — accuracy not yet measured

In the paper

“in a social defeat model of stress, male and female F1 mice exhibited altered behaviors, and male F1 had a broader range of affected behaviors 204”

What the sources say

• Supported

  The Results (page not provided) report altered behavior in offspring of both sexes, including changes in the elevated plus maze and forced swim tests. They also report an altered response to novelty in male but not female offspring, consistent with a broader range of affected behaviors in males; the Discussion describes the male phenotype as more robust. (LLM, conf=0.91)

  cites [204] 204. Dietz DM, Laplant Q, Watts EL et al. Paternal transmission of stress- induced pathologies. Biol Psychiatry 2011;70:408-14. source

In the paper

“Furthermore, F3 offspring of these animals continued to show phenotypic differences, indicating conservation of stress effects through sperm.”

What the sources say

• Partly supported

  The paper states that F3 MSUS mice had behavioral symptoms similar to F1 and F2 mice (passage [3], section labeled Abstract; page unavailable). It does not establish that sperm carried the effects into F3: it reports normal sperm miRNA levels in F2 males and proposes other epigenetic marks as a possible means of further transmission. (LLM, conf=0.85)

  cites [176] 176. Gapp K, Jawaid A, Sarkies P et al. Implication of sperm RNAs in transge- nerational inheritance of the effects of early trauma in mice. Nat Neurosci 2014;17:667-9. sourceExperimental — accuracy not yet measured

In the paper

“Research on possible intergenerational transmission of stress effects through epigenetic marks in sperm has been conducted in rodents, and includes preconception exposures at various developmental stages to stressful and adverse social experiences 149,175,176,179,181,203,204”

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 [149] 149. Bale TL. Lifetime stress experience: transgenerational epigenetics and germ cell programming. Dialogues Clin Neurosci 2014;16:297. source
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [175] 175. Dias BG, Ressler KJ. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci 2014;17: 89-96. sourceExperimental — accuracy not yet measured
• 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 [176] 176. Gapp K, Jawaid A, Sarkies P et al. Implication of sperm RNAs in transge- nerational inheritance of the effects of early trauma in mice. Nat Neurosci 2014;17:667-9. source

In the paper

“However, these results were not observed when offspring were generated by in vitro fertilization, implicating behavioral, rather than germ cell epigenetic, influence.”

What the sources say

• Partly supported

  The Results report that most behavioral differences seen after natural breeding were absent in IVF offspring, and the Discussion interprets this as suggesting that most transmission occurs through behavioral mechanisms. But the Results also report a small, significant IVF effect in the forced swim test, and the Discussion allows a limited epigenetic role. The claim overstates the finding by saying the results were not observed with IVF and contrasting behavioral with germ-cell epigenetic influence without that qualification. Page numbers were not supplied in our copy. (LLM, conf=0.88)

  cites [204] 204. Dietz DM, Laplant Q, Watts EL et al. Paternal transmission of stress- induced pathologies. Biol Psychiatry 2011;70:408-14. sourceExperimental — accuracy not yet measured

In the paper

“The odorant acetophenone paired with an electric shock resulted in behavioral sensitivity in the fear conditioned mice, with an accompanying change in DNA methylation in brain and sperm of the M71 receptor, which is involved in sensing acetophenone.An increased size in the M71 specific glomeruli in the olfactory epithelium and bulb was also observed 175”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [175] 175. Dias BG, Ressler KJ. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci 2014;17: 89-96. sourceExperimental — accuracy not yet measured

In the paper

“early life stress, modeled by unpredictable maternal separation and maternal stress, led to depressive-like behavioral patterns upon exposure to novel environments and changes in sncRNAs in F1 sperm.”

What the sources say

• Partly supported

  The paper reports that F1 mice exposed to unpredictable maternal separation and maternal stress showed depressive-like behavior on the forced swim test, and that several sncRNAs changed in F1 sperm. It does not describe the response to an unfamiliar space on the elevated plus maze as depressive-like; it interprets that result as reduced avoidance and fear (behavioral-results passage [1]; sperm-RNA passage [3], both labeled Abstract in our copy). (LLM, conf=0.83)

  cites [176] 176. Gapp K, Jawaid A, Sarkies P et al. Implication of sperm RNAs in transge- nerational inheritance of the effects of early trauma in mice. Nat Neurosci 2014;17:667-9. sourceExperimental — accuracy not yet measured

In the paper

“Males were bred with naïve females and produced offspring with blunted HPA axis responsivity as well as changes in transcription of GR genes in the paraventricular nucleus 179”

What the sources say

• Partly supported

  The Breeding Scheme (Materials & Methods) says the males were bred with naïve females, and the Abstract reports reduced HPA stress responsivity in their offspring. The Discussion reports enriched expression of glucocorticoid receptor (GR)-responsive genes in the paraventricular nucleus, not a demonstrated change in transcription of GR genes themselves; the Brain Gene Expression Analysis (Results) says no single gene met its significance criteria. (LLM, conf=0.85)

  cites [179] 179. Rodgers AB, Morgan CP, Bronson SL et al. Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regu- lation. J Neurosci 2013;33:9003-12. sourceExperimental — accuracy not yet measured

In the paper

“The studies described in these reports either failed to find effects in Holocaust offspring, corroborated earlier clinical descriptions, attempted to restrict the observations of damaging effects to a subgroup, or pointed to serious methodological challenges in attempting to address this question empirically [11][12][13] .”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [11][12][13]

In the paper

“While some aspects of intergenerational trauma effects remain contested, discussions about whether there are clinically observable intergenerational effects in offspring have become less contentious in the last several years, with the increasing recognition of the universality of this phenomenon.”

In the paper

“At the current time, the idea that epigenetic mechanisms underlie clinical observations in offspring of trauma survivors represents a hypothesis to be tested.”

In the paper

“In adulthood, the handled rats had altered basal and stress-induced corticosterone levels as well as higher GR sensitivity on the low-dose DST and greater GR number in the hippocampus [77][78][79] .”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [77][78][79]

In the paper

“Although PTSD was found to occur in association with paternal PTSD in a study of Australian Vietnam Veterans and their offspring 29 , the contribution of potential maternal symptoms, even through secondary traumatization, was not assessed.”

What the sources say

• ?Not checked — no full text of the sourcecites [29] 29. O'Toole BI, Burton MJ, Rothwell A et al. Intergenerational transmission of post-traumatic stress disorder in Australian Vietnam veterans' families. Acta Psychiatr Scand 2017;135:363-72. source

In the paper

“Finally, there had been directionally interesting findings of low cortisol and increased glucocorticoid receptor (GR) sensitivity in Holocaust survivors and other trauma exposed individuals with PTSD, suggesting that the experience of trauma might leave long-lasting biological signatures in stress-related biology that could be a catalyst for longer-term adaptations 55 .”

What the sources say

• ?Not checked — no full text of the sourcecites [55] 55. Yehuda R, Kahana B, Binder-Brynes K et al. Low urinary cortisol excretion in Holocaust survivors with posttraumatic stress disorder. Am J Psychiatry 1995;152:982-6. source

In the paper

“There is now converging evidence supporting the idea that offspring are affected by parental trauma exposures occurring before their birth, and possibly even prior to their conception.”

In the paper

“Furthermore, dysregulation of stress neurocircuitry is a fundamental feature of mood and anxiety disorders [52][53][54] , including PTSD, found to be prevalent in offspring.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [52][53][54]

In the paper

“By 22 weeks of gestation, the fetal HPA axis is developed and functioning, although it continues to be sensitive to environmental influence 137,138 .”

What the sources say

• ?Not checked — no full text of the sourcecites [137] 137. Challis JR, Sloboda D, Matthews SG et al. The fetal placental hypothalamic- pituitary-adrenal (HPA) axis, parturition and post natal health. Mol Cell Endocrinol 2001;185:135-44. source
• ?Not checked — no full text of the sourcecites [138] 138. Mastorakos G, Ilias I. Maternal and fetal hypothalamic-pituitary-adrenal axes during pregnancy and postpartum. Ann N Y Acad Sci 2003;997:136-49. source

In the paper

“There may also be different effects on offspring, as well mechanisms underlying these effects, depending on the history of trauma exposure and/or psychiatric symptoms prior to pregnancy.”

In the paper

“The intrauterine environment presents a developmentally potent context 95 , mechanistically distinct from postnatal parenting or family environment, through which maternal trauma or stressful experiences may influence fetal epigenetic programming of the HPA axis 136 .”

What the sources say

• ?Not checked — no full text of the sourcecites [95] 95. Seckl JR, Meaney MJ. Glucocorticoid "programming" and PTSD risk. Ann N Y Acad Sci 2006;1071:351-78. source
• ?Not checked — no full text of the sourcecites [136] 136. Sosnowski DW, Booth C, York TP et al. Maternal prenatal stress and infant DNA methylation: a systematic review. Dev Psychobiol 2018;60:127-39. source

In the paper

“Given the directionality of these findings, which is consistent with elevated cortisol levels, it may be that exposures in mothers which originate during pregnancy result in directionally different epigenetic alterations from those observed in offspring where the maternal (or paternal) trauma occurred prior to conception.”

In the paper

“However, the limited data suggesting an association of an epigenetic alteration with maternal age at trauma exposure imply potential contributions of both in utero effects and possibly preconception epigenetic changes to gametes.”

In the paper

“paternal exposure to preconception stress at any stage of development might impact gametes but, as with females, there may be critical periods of vulnerability to insult.”

In the paper

“Contrary to initial understanding, it is now believed that some epigenetic changes in germ cells may survive the nearly global erasure of DNA methylation that occurs before implantation of the embryo, or associate with other epigenetic mechanisms 188,189”

What the sources say

• ?Not checked — no full text of the sourcecites [188] 188. Chong S, Whitelaw E. Epigenetic germline inheritance. Curr Opin Genet Dev 2004;14:692-6. source
• ?Not checked — no full text of the sourcecites [189] 189. Lane N, Dean W, Erhardt S et al. Resistance of IAPs to methylation repro- gramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis 2003;35:88-93. source

In the paper

“Germ cells in both females and males can be affected by trauma exposure, but the critical periods for affecting oocytes and sperm may differ.”

In the paper

“Oocytes remain in a haploid de-methylated state until puberty, and are therefore vulnerable to environmental perturbations 166”

What the sources say

• ?Not checked — no full text of the sourcecites [166] 166. Faulk C, Dolinoy DC. Timing is everything: the when and how of environ- mentally induced changes in the epigenome of animals. Epigenetics 2011;6:791-7. source

In the paper

“In an unpublished study, earlier age of maternal Holocaust exposure was also associated with lower FKBP5 methylation at intron 7 in offspring.”

In the paper

“To date, there are no known studies that have directly examined transgenerational effects mediated through sperm in humans.”

In the paper

“DNA methylation marks are re-established following their erasure, allowing developmental processes, including cell differentiation, to occur 190”

What the sources say

• ?Not checked — no full text of the sourcecites [190] 190. Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian de- velopment. Science 2001;293:1089-93. source

In the paper

“Accordingly, the nature of the effects may differ in oocytes and sperm in relation to trauma exposure.”

In the paper

“These effects were observed only when limited food access occurred prior to puberty, supporting the hypothesis that the transmission occurred through epigenetic programming of gametes and may be mediated by the X and Y sex chromosomes 181,195”

What the sources say

• ?Not checked — no full text of the sourcecites [181] 181. Szyf M. Nongenetic inheritance and transgenerational epigenetics. Trends Mol Med 2015;21:134-44. source
• ?Not checked — no full text of the sourcecites [195] 195. Pembrey ME, Bygren LO, Kaati G et al. Sex-specific, male-line transgen- erational responses in humans. Eur J Hum Genet 2006;14:159. source

In the paper

“Unlike oocytes, which are formed in females prior to birth, spermatogenesis in males is initiated in the testes at puberty and continues throughout the lifespan 174”

What the sources say

• ?Not checked — no full text of the sourcecites [174] 174. Desai N, Ludgin J, Sharma R et al. Female and male gametogenesis. In: Falcone T, Hurd WW (eds). Clinical reproductive medicine and surgery. New York: Springer, 2017:43-62. source

In the paper

“The unknown variance associated with unmeasured stress in prior generations and its relevance to any maternal exposures is simply not known and creates a difficulty in ascertaining mechanisms.”

In the paper

“it is methodologically extremely difficult to separate out effects in an oocyte from effects of the fetoplacental environment”

In the paper

“studies examining offspring in close proximity to birth may be particularly informative regarding offspring biology”

In the paper

“They will be less informative with respect to offspring phenotype as it is expressed later in life.”

In the paper

“Restricted nutritional intake in paternal grandfathers affected mortality rates in grandsons only, whereas paternal grandmother access to food was associated with mortality of granddaughters.”

What the sources say

• ?Not checked — no full text of the sourcecites [181] 181. Szyf M. Nongenetic inheritance and transgenerational epigenetics. Trends Mol Med 2015;21:134-44. source
• ?Not checked — no full text of the sourcecites [195] 195. Pembrey ME, Bygren LO, Kaati G et al. Sex-specific, male-line transgen- erational responses in humans. Eur J Hum Genet 2006;14:159. source

In the paper

“the exact nature of the mechanisms involved in transmission through gametes continues to remain obscure”

In the paper

“Scientific studies are rapidly identifying epigenetic mechanisms to explain how an environmental exposure may lead to an enduring change in the function of DNA that can be passed to future generations.”

In the paper

“In the context of offspring born to two trauma survivors, these two modes of epigenetic influences are likely to interact, and it is indeed very difficult to parse out the many potential contributions to offspring phenotype, not to mention those related to the offspring's own experiences through childhood, adolescence and adulthood.”

In the paper

“The assertion that an effect is truly transgenerational requires ruling out direct exposure of offspring as a causal mechanism.”

In the paper

“a reanalysis of these data showed that the child's early life circumstances were also relevant to findings from father to son but, when childhood factors in sons were controlled in statistical analyses, the transmission effects through the male line were strengthened 194”

What the sources say

• ?Not checked — no full text of the sourcecites [194] 194. Kaati G, Bygren LO, Pembrey M et al. Transgenerational response to nutrition, early life circumstances and longevity. Eur J Hum Genet 2007; 15:784. source

In the paper

“In males, F1 may be influenced via the germ line of the exposed F0 father, but since sperm is not generated in the fetus (as ova are in females), transmission of trauma-associated traits to F2 would be considered transgenerational transmission.”

In the paper

“Overeating in paternal grandfathers was associated with increased risk for diabetes in grandchildren, whereas limited food availability in fathers was associated with protection from cardiovascular death in sons.”

What the sources say

• ?Not checked — no full text of the sourcecites [194] 194. Kaati G, Bygren LO, Pembrey M et al. Transgenerational response to nutrition, early life circumstances and longevity. Eur J Hum Genet 2007; 15:784. source

In the paper

“These findings indicate that stress-induced changes to germ cells are not immutable and can be reversed by alternative environmental perturbations that are directed at stimulating plasticity.”

In the paper

“In the absence of studies examining the effects of trauma through the male germ line in humans, the above findings demonstrate that a wide range of environmental exposures, not only exposure to extreme trauma, can have biological and behavioral effects that persist in one or more generations.”

In the paper

“These changes are likely to be mediated primarily by maternal trauma-related symptoms, but may be affected by multiple inputs, including paternal trauma-related effects.”

In the paper

“Nonetheless, the findings in animal models implicating epigenetic mechanisms in the transmission of stress effects through germ cells have created much excitement for the possibility that similar mechanisms might be operating in humans.”

In the paper

“This series of studies provides a clear demonstration of an epigenetically mediated transgenerational biological inheritance through sperm of a behavioral trait and corresponding neuroanatomical brain changes that persist for two generations.”

In the paper

“Research on epigenetic inheritance of effects of trauma faces many scientific and methodological complexities, not to mention conceptual issues regarding interpretation of transmitted effects.”

In the paper

“Even potentially heritable changes can be modified, because environments change.”

In the paper

“Thus, for females, traits must be observed in F3 females to be considered transgenerational, because the F1 female offspring is exposed to the stressor during gestation through the intrauterine environment.”

In the paper

“The second are the effects of a preconception parental trauma that remain in the germ cell and following conception, affecting the offspring's development in utero and subsequent postnatal phenotype.”

In the paper

“The state of the science in relation to human offspring at present is that, whereas some neuroendocrine and epigenetic alterations have been documented in connection with maternal and paternal trauma exposure and PTSD, studies have not yet conclusively demonstrated epigenetic transmission of trauma effects in humans.”

In the paper

“Epigenetic mechanisms have been favored over genetic explanations (or gene-environment interactions) of intergenerational effects in part because of their potential to explain the phenotypic differences in offspring associated with maternal vs. paternal trauma exposure.”

In the paper

“At the present time, the field has not sufficiently grappled with the meaning of the intergenerational transmission of trauma effects for the offspring.”

In the paper

“However, there is much diversity in effects, and opportunities for modifying even strong effects of non-coding RNAs, chromatin, and DNA methylation.”

In the paper

“These findings confirmed that early or later life exposures in the male mouse can affect germ cell microRNA, and are sufficient to result in a similar phenotype in the subsequent generation, again confirming the transmission through sperm in an independent animal model.”

In the paper

“Ultimately, the potential utility, and possible stability, of an environmentally induced trait transmitted to an offspring will depend on the offspring's environmental context.”

In the paper

“the principle of epigenetic plasticity implies that changes to the epigenome might reset when the environmental insults are no longer present, or when we have changed sufficiently to address environmental challenges in a new way.”

In the paper

“It is the ability to flexibly respond to environmental stimuli that is fundamentally adaptive and the basis of human resilience.”