Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms

In the paper

“Lower cortisol and blunted cortisol reactivity were present in preadolescent boys and girls with maternal PTSD, even after controlling for youth traumatic event history and mental health symptoms 73 .”

What the sources say

• Partly supported

  The Results (§3.3) report a flat, blunted cortisol response in offspring of mothers with PTSD, with group differences maintained after controlling for youth traumatic event history, depressive symptoms, and physical anxiety symptoms. The Discussion (§4) describes low stress-provoked cortisol levels. However, the Methods (§2.1) give an age range of 9–15 years, so describing the entire sample as preadolescent is too narrow. (LLM, conf=0.86)

  cites [73] 73. Danielson CK, Hankin BL, Badanes LS. Youth offspring of mothers with posttraumatic stress disorder have altered stress reactivity in response to a laboratory stressor. Psychoneuroendocrinology 2015;53:170-8. sourceExperimental — accuracy not yet measured

In the paper

“An interaction of maternal and paternal PTSD on urinary cortisol and the DST demonstrated a decreased glucocorticoid sensitivity in offspring with paternal, but not maternal, PTSD.”

What the sources say

• Supported

  The Abstract states that the interaction of maternal and paternal PTSD on the DST and 24-hour urinary cortisol showed decreased glucocorticoid sensitivity in offspring with paternal, but not maternal, PTSD. The Discussion clarifies that this pattern occurred with paternal PTSD only; when maternal PTSD was also present, offspring showed increased sensitivity. (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

“Epigenetic modifications impact gene function by altering gene regulatory elements that affect the action of gene transcription factors 91 .”

What the sources say

• Supported

  In “The chemistry of DNA methylation” (page not provided), the paper explains that methylation within a transcription-factor response element reduces the factor’s binding affinity. The section on site-specific methylation of the NGFIA response element likewise reports that methylation interferes with NGFIA binding, supporting the claimed effect on gene regulation. (LLM, conf=0.92)

  cites [91] 91. Meaney MJ, Szyf M. Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environ- ment and a fixed genome. Dialogues Clin Neurosci 2005;7:103-23. source

In the paper

“For example, lower cortisol levels were observed in the adult offspring of combat veterans with PTSD compared to offspring of combat veterans without PTSD 65 .”

What the sources say

• Partly supported

  The Discussion’s Table 5 reports lower afternoon cortisol in offspring of veterans with a PTSD history than in offspring of veterans without one, following a post-hoc regrouping. But the Discussion says the offspring groups were, on average, adolescents, so the claim’s description of them as adult offspring is not supported. (LLM, conf=0.90)

  cites [65] 65. Yahyavi ST, Zarghami M, Naghshvar F et al. Relationship of cortisol, nor- epinephrine, and epinephrine levels with war-induced posttraumatic stress disorder in fathers and their offspring. Rev Bras Psiquiatr 2015;37:93-8. sourceExperimental — accuracy not yet measured

In the paper

“A blunted cortisol reactivity to stress was observed in even younger offspring, toddlers aged 12-48 months, in association with maternal PTSD occurring as a result of interpersonal violence 74 .”

What the sources say

• Supported

  The Abstract identifies the toddlers as 12–48 months old and reports that children of mothers with interpersonal violence-related PTSD showed blunted cortisol reactivity to the laboratory stressor. The Children's cortisol section also reports a blunted stress response, though it describes the children's ages there as 12–42 months. (LLM, conf=0.92)

  cites [74] 74. Cordero MI, Moser DA, Manini A et al. Effects of interpersonal violence- related post-traumatic stress disorder (PTSD) on mother and child diur- nal cortisol rhythm and cortisol reactivity to a laboratory stressor involv- ing separation. Horm Behav 2017;90:15-24. source

In the paper

“In another study, maternal exposure to child abuse was associated with smaller intracranial volume, due to differences in cortical gray matter, in newborns examined within two weeks of birth 75 .”

What the sources say

• Partly supported

  The Results (Global brain and tissue volumes; page unavailable) associate maternal childhood maltreatment with smaller newborn intracranial volume, principally reflecting lower cortical gray-matter volume. But the Methods (Procedures; page unavailable) report scans at 5–64 days after birth, with a mean of 26 days—not within two weeks. The exposure measure also included childhood neglect as well as abuse. (LLM, conf=0.93)

  cites [75] 75. Moog NK, Entringer S, Rasmussen JM et al. Intergenerational effect of ma- ternal exposure to childhood maltreatment on newborn brain anatomy. Biol Psychiatry 2018;83:120-7. sourceExperimental — accuracy not yet measured

In the paper

“In another study, several measures of GR sensitivity were found to be directionally different in offspring of mothers vs. fathers with PTSD 63 .”

What the sources say

• Supported

  The Results report lower IC50-DEX, indicating greater glucocorticoid sensitivity, in offspring with maternal PTSD than in those with paternal PTSD alone. The Discussion says maternal and paternal PTSD effects were distinguishable and sometimes in opposing directions across three measures of HPA-axis regulation. (LLM, conf=0.91)

  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

“The increased prevalence of PTSD in Holocaust offspring in response to their own traumatic exposures was later found to be associated with maternal PTSD in Holocaust survivors 28 .”

What the sources say

• Supported

  The Results report a higher prevalence of lifetime PTSD in Holocaust survivors’ offspring than in controls and a specific association between offspring PTSD and maternal PTSD. The Introduction also discusses offspring PTSD in relation to their own trauma histories. The Discussion clarifies that Holocaust-offspring status alone did not increase PTSD risk; maternal PTSD was the relevant association. Page numbers were not available in our copy. (LLM, conf=0.90)

  cites [28] 28. Yehuda R, Bell A, Bierer LM et al. Maternal, not paternal, PTSD is related to increased risk for PTSD in offspring of Holocaust survivors. J Psychiatr Res 2008;42:1104-11. source

In the paper

“The effects in adulthood were determined to be directly related to the early postnatal environmental exposures to variations in maternal care, since they were prevented by cross-fostering neonatal rat pups to mothers displaying different behavioral characteristics 81,86,90,91 .”

What the sources say

• ?Not checked — no full text of the sourcecites [81] 81. Liu D, Diorio J, Tannenbaum B et al. Maternal care, hippocampal gluco- corticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 1997;277:1659-62. source
• ?Not checked — no full text of the sourcecites [86] 86. Weaver IC, Cervoni N, Champagne FA et al. Epigenetic programming by maternal behavior. Nat Neurosci 2004;7:847-54. source
• ?Not checked — no full text of the sourcecites [90] 90. Champagne F, Meaney MJ. Like mother, like daughter: evidence for non-genomic transmission of parental behavior and stress responsivity. Prog Brain Res 2001;133:287-302. source
• 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 [91] 91. Meaney MJ, Szyf M. Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environ- ment and a fixed genome. Dialogues Clin Neurosci 2005;7:103-23. source

In the paper

“In a recent study, grandmaternal stress during pregnancy was associated with genome-wide methylation changes in offspring and grandchildren 154 .”

What the sources say

• Partly supported

  The Abstract and Discussion report an association between grandmaternal stress during pregnancy and DNA methylation in grandchildren. The Materials and methods section says maternal-generation samples were not part of the present study, so this paper does not establish the claimed association in both offspring and grandchildren. (LLM, conf=0.91)

  cites [154] 154. Serpeloni F, Radtke K, de Assis SG et al. Grandmaternal stress during preg- nancy and DNA methylation of the third generation: an epigenome-wide association study. Transl Psychiatry 2017;7:e1202. sourceExperimental — accuracy not yet measured

In the paper

“It has now been shown that stressful experiences such as adult trauma change methylation of the GR gene in blood cells, whether primed by early experience or not 118,119,129,130 .”

What the sources say

• Partly supported

  The Results and Discussion report lower GR-promoter methylation in blood T lymphocytes from people with lifetime PTSD than in trauma-unexposed controls. The study included both childhood and adult trauma, but does not establish that adult trauma changes methylation regardless of early experience; it reports an association in a PTSD group, not that broader causal finding. Page numbers were not available in our copy. (LLM, conf=0.86)

  cites [118] 118. Labonte B, Azoulay N, Yerko V et al. Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder. Transl Psychiatry 2014;4:e368. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction reports prior findings of GR-gene hypomethylation in the peripheral blood of veterans with PTSD, and the Discussion says methylation may change throughout life, perhaps with trauma. But the paper does not establish that adult trauma causes the change regardless of early experience. Its own study used saliva rather than blood and did not replicate the prior finding of lower methylation in veterans with PTSD (Discussion; page unavailable). (LLM, conf=0.84)

  cites [119] 119. McNerney MW, Sheng T, Nechvatal JM et al. Integration of neural and epigenetic contributions to posttraumatic stress symptoms: the role of hip- pocampal volume and glucocorticoid receptor gene methylation. PLoS One 2018;13:e0192222. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section reports that trauma exposure during deployment was associated with increased GR-1F methylation in blood cells. It also reports no significant association between childhood trauma and the main methylation measures, but does not establish that the deployment-related change occurred regardless of early experience. The study was limited to Dutch male military personnel. (LLM, conf=0.84)

  cites [129] 129. Schur RR, Boks MP, Rutten BPF et al. Longitudinal changes in gluco- corticoid receptor exon 1F methylation and psychopathology after mili- tary deployment. Transl Psychiatry 2017;7:e1181. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [130] 130. Yehuda R, Flory JD, Bierer LM et al. Lower methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of veterans with posttrau- matic stress disorder. Biol Psychiatry 2015;77:356-64. source

In the paper

“In parallel with the neuroendocrine observations, the results of these analyses indicated a significant interaction of maternal and paternal PTSD on GR gene methylation 126 .”

What the sources say

• Supported

  The Results section, “Maternal PTSD, Paternal PTSD and GR-1F promoter methylation,” reports a significant interaction of maternal and paternal PTSD on GR-1F promoter methylation (F1,86=5.97, p=.017). This directly supports the citing sentence’s paraphrase about GR gene methylation. (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

“Higher levels of NR3C1 methylation were observed in offspring aged 10-19 of mothers who experienced intimate partner violence during, but not prior to or following, pregnancy 155 .”

What the sources say

• Supported

  The Results (Impact of IPV on methylation patterns in offspring; page unavailable) report an association between offspring GR-promoter methylation and maternal IPV during pregnancy, but not before or after pregnancy. The Results (Maternal stress profiling; page unavailable) state that the children were aged 10–19. The claim describes an observed association, not a causal effect. (LLM, conf=0.92)

  cites [155] 155. Radtke KM, Ruf M, Gunter HM et al. Transgenerational impact of intimate partner violence on methylation in the promoter of the glucocorticoid receptor. Transl Psychiatry 2011;1:e21. source

In the paper

“Higher methylation in the promoter of the NR3C1 gene was also observed in newborns of mothers in the Democratic Republic of Congo exposed to severe prenatal stress, with the strongest effect for maternal warzone stress experiences 156 ,”

What the sources say

• Supported

  Materials and Methods places the mother–newborn pairs in eastern Democratic Republic of Congo. Results and Discussion reports the strongest correlation between maternal war stress and newborn NR3C1 promoter methylation, measured by the first principal component (PC1), and describes higher newborn PC1 as associated with higher mean methylation. The reported association is for PC1, not total methylation. (LLM, conf=0.88)

  cites [156] 156. Mulligan C, D'Errico N, Stees J et al. Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight. Epigenetics 2012;7:853-7. source

In the paper

“This possibility is consistent with clinical, neuroendocrine and epigenetic findings, in which maternal and paternal PTSD predicted different psychiatric and biological outcomes in offspring 28,126 .”

What the sources say

• Supported

  The Results report different psychiatric associations: maternal PTSD predicted offspring PTSD, while paternal PTSD was associated with depression and anxiety. The Introduction also reports a study finding that low plasma cortisol in offspring was associated with maternal PTSD after controlling for paternal PTSD. The biological finding is reported from prior work, not measured in this study. (LLM, conf=0.86)

  cites [28] 28. Yehuda R, Bell A, Bierer LM et al. Maternal, not paternal, PTSD is related to increased risk for PTSD in offspring of Holocaust survivors. J Psychiatr Res 2008;42:1104-11. source
• Supported

  The Results (Phenotypic clustering) report different clinical characteristics associated with maternal versus paternal PTSD. The Discussion also describes differing biological patterns in offspring, including cortisol and GR-1F promoter methylation; the effects depend in part on whether one or both parents have PTSD. (LLM, conf=0.92)

  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

“Among offspring of women pregnant during the 1998 Quebec ice storm, those whose mothers experienced objective hardship, but not subjective distress, had methylation alterations in genes related to immune function 157 .”

What the sources say

• Supported

  The Abstract’s Results report that maternal objective hardship correlated with offspring DNA methylation at genes predominantly related to immune function, while subjective distress was uncorrelated. The Methods identify the cohort as children of women recruited in connection with the 1998 Quebec ice storm. (LLM, conf=0.92)

  cites [157] 157. Cao-Lei L, Massart R, Suderman MJ et al. DNA methylation signatures triggered by prenatal maternal stress exposure to a natural disaster: pro- ject ice storm. PLoS One 2014;9:e107653. source

In the paper

“These behaviors were transmitted to the next generation through the male germ line.”

What the sources say

• ?Could not verify

  The Materials and Methods section reports depressive-like behaviors in male offspring exposed to stress during gestation. Neither that section nor the Results and Discussion passages establish transmission to another generation through the male germ line; searches for germline, sperm, paternal inheritance, and F2 offspring found no such evidence. Page numbers were not available in our copy. (LLM, conf=0.76)

  cites [159] 159. Mueller BR, Bale TL. Sex-specific programming of offspring emotionality after stress early in pregnancy. J Neurosci 2008;28:9055-65. sourceExperimental — accuracy not yet measured

In the paper

“methylation levels were associated with salivary cortisol stress responses in the newborns at 3 months”

What the sources say

• Supported

  The Results passage on neonatal methylation and infant HPA stress reactivity reports that greater NR3C1 methylation at CpG3 in newborns predicted greater cortisol stress responses at three months. The Discussion confirms the association and specifies that it was observed at CpG3, not the other CpG sites analyzed. Page numbers are not provided in our copy. (LLM, conf=0.94)

  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

“Phenotypic and epigenetic changes were observed in adults who were exposed in utero to the Dutch famine of 1944-45, but only among those exposed at the time of conception and during the first half of gestation, compared to those exposed in the third trimester or early postnatal period 150,151 .”

What the sources say

• Partly supported

  The Results and Discussion report lower IGF2 methylation in adults exposed to famine around conception, but not in those exposed late in gestation. The paper does not establish the same finding across the first half of gestation or compare an early-postnatal exposure group. Nor does it report adult phenotypic changes confined to early exposure; it notes lower birth weight after late-gestational exposure and says the phenotypic consequences of the epigenetic changes remain to be assessed. (LLM, conf=0.89)

  cites [150] 150. Heijmans BT, Tobi EW, Stein AD et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA 2008;105:17046-9. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [151] 151. Ravelli GP, Stein ZA, Susser MW. Obesity in young men after famine ex- posure in utero and early infancy. N Engl J Med 1976;295:349-53. source

In the paper

“FKBP5 methylation in parents and their children were positively correlated.”

What the sources say

• Supported

  The section “F0 FKBP5 Intron 7 Methylation at Bin 3 Predicts F1 FKBP5 Intron 7 Methylation at Bin 3” reports a positive parent–offspring correlation at bin 3/site 6 (r = .441, p = .010). It says the association was primarily driven by Holocaust-exposed families. (LLM, conf=0.93)

  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

“third trimester maternal depression/anxiety associated with higher methylation of NR3C1 at a predicted NGF1-A binding site 141”

What the sources say

• Supported

  The Discussion reports that increased third-trimester depressed maternal mood was associated with increased neonatal methylation at CpG3, within the potential NGFI-A binding site of NR3C1. The results identify the neonatal DNA analyzed as coming from cord blood mononuclear cells; the paper describes the exposure as depressed/anxious maternal mood. (LLM, conf=0.93)

  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

“prenatal stress has different effects in male vs. female offspring 143,159-161”

What the sources say

• ?Not checked — no full text of the sourcecites [143] 143. O'Donnell KJ, Meaney MJ. Fetal origins of mental health: the develop- mental origins of health and disease hypothesis. Am J Psychiatry 2017; 174:319-28. source
• Supported

  The Discussion reports that stress early in gestation altered behavioral stress-coping responses in male offspring but did not further alter those responses in females. The Results also report a decrease in whole-brain NF-1 in males but no corresponding effect in females. These passages support sex-specific effects of prenatal stress; page numbers were not provided. (LLM, conf=0.93)

  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
• ?Not checked — no full text of the sourcecites [160] 160. McCormick CM, Smythe JW, Sharma S et al. Sex-specific effects of pre- natal stress on hypothalamic-pituitary-adrenal responses to stress and brain glucocorticoid receptor density in adult rats. Brain Res 1995;84: 55-61. source
• ?Not checked — no full text of the sourcecites [161] 161. Weinstock M. Gender differences in the effects of prenatal stress on brain development and behaviour. Neurochem Res 2007;32:1730-40. source

In the paper

“Lower GR 1F promoter methylation was significantly associated with greater GR sensitivity, as indicated by greater post-dexamethasone cortisol suppression.”

What the sources say

• Supported

  The Results section reports a significant negative association between GR-1F promoter methylation and cortisol decline after dexamethasone: greater suppression was associated with lower methylation (r=−.249, p=.029). The Discussion interprets this as enhanced glucocorticoid negative feedback, consistent with greater GR sensitivity. (LLM, conf=0.94)

  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 importance of fetal sex, or more specifically, trophoblast cells from the embryo reflecting fetal sex, is that it may differentially regulate epigenetic signals in the placenta, leading to differential signaling that feeds back to the offspring 140”

What the sources say

• Supported

  Section 2.1 says embryo-derived trophoblast cells reflect fetal sex, allowing sex differences in placental signaling. Section 4.1 links sex differences in placental epigenetic regulators to possible differences in placental function, while section 6.2 describes placental signaling as a relay to the developing fetal brain. The claim’s tentative wording is consistent with those passages; page numbers were not provided. (LLM, conf=0.90)

  cites [140] 140. Nugent BM, Bale TL. The omniscient placenta: metabolic and epigenetic regulation of fetal programming. Front Neuroendocrinol 2015;39:28-37. source

In the paper

“More recently, a relatively large epigenetic study of the Dutch hunger cohort (422 exposed and 463 sibling controls) identified alterations in DNA methylation specifically associated with in utero exposure to maternal famine 152 .”

What the sources say

• Partly supported

  The Results (Genome-wide mediation analysis; page not provided) describe a DNA-methylation study of prenatal famine exposure and identify associated CpG sites. But the study reports 348 prenatally exposed individuals, not 422; its 463 unexposed controls included time controls as well as sibling controls, rather than 463 sibling controls. (LLM, conf=0.90)

  cites [152] 152. Tobi EW, Slieker RC, Luijk R et al. DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic dis- ease in adulthood. Sci Adv 2018;4. sourceExperimental — accuracy not yet measured

In the paper

“exposure to chronic stress in utero increased male, but not female, HPA stress reactivity (e.g., behavioral response to the tail suspension test) 159,162”

What the sources say

• Partly supported

  The Prenatal Stress Methods describe chronic variable stress during gestation, and the HPA Axis Stress Response Results report elevated corticosterone after restraint in males exposed to stress early in gestation. The Discussion reports altered tail-suspension behavior in males but not females; however, HPA-axis reactivity was measured only in males, so the source does not establish that female HPA reactivity was unchanged. (LLM, conf=0.87)

  cites [159] 159. Mueller BR, Bale TL. Sex-specific programming of offspring emotionality after stress early in pregnancy. J Neurosci 2008;28:9055-65. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Analysis of adult F2 behavior and physiology; page not supplied) report increased tail-suspension immobility in males, but not females, after paternal prenatal stress exposure. They report no significant effect on HPA-axis corticosterone responses in either sex. The claim conflates the behavioral result with increased HPA reactivity and does not distinguish the F2 offspring from the directly exposed F1 generation. (LLM, conf=0.90)

  cites [162] 162. Morgan CP, Bale TL. Early prenatal stress epigenetically programs dys- masculinization in second-generation offspring via the paternal lineage. J Neurosci 2011;31:11748-55. sourceExperimental — accuracy not yet measured

In the paper

“early gestational stress exposure led to sex differences in expression and methylation of genes in the placenta associated with growth and nutrient transport 159”

What the sources say

• Partly supported

  The Results section reports sex-specific changes in placental expression of genes associated with growth and nutrient transport after early prenatal stress. It also reports changes in expression of the methylation-maintenance enzyme DNMT1, but does not report methylation changes in those placental genes themselves (page numbers unavailable in our copy). (LLM, conf=0.90)

  cites [159] 159. Mueller BR, Bale TL. Sex-specific programming of offspring emotionality after stress early in pregnancy. J Neurosci 2008;28:9055-65. sourceExperimental — accuracy not yet measured

In the paper

“prenatal stress in humans was associated with alterations in diurnal cortisol secretion in males that were not apparent in females 163”

What the sources say

• Supported

  The Static HPA axis measures section reports that males born preterm had a shallower diurnal cortisol decline than term-born males, with no such relationship among females. The Discussion identifies preterm birth as a marker of prenatal stress, so the claim matches the review’s reported finding, specifically for preterm birth. (LLM, conf=0.89)

  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

“Still, the compelling data demonstrating heritable epigenetic alterations come from animal models 179,181”

What the sources say

• Supported

  The Introduction describes rodent studies supporting transmission of paternal experiences through epigenetic marks in sperm. The Discussion reports that stressed male mice had altered sperm microRNA profiles alongside altered offspring stress responses, supporting the claim’s broad characterization of evidence from animal models. (LLM, conf=0.87)

  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
• ?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

“there have been several observational studies demonstrating that environmental exposures in malessuch as famine, obesity, smoking, alcohol consumption, exposure to toxins, and exposure to stressresult in subsequent behavioral and biologic effects in offspring [183][184][185][186][187]”

What the sources say

• ?Not checked — no full text of the sourcecites [183] 183. Fullston T, Teague EMCO, Palmer NO et al. Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete pene- trance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content. FASEB Journal 2013;27:4226-43. source
• Partly supported

  The Abstract reports that endocrine-disruptor exposure in pregnant rats produced reproductive effects in male offspring that persisted through the male germ line. This was an experiment involving exposure of gestating females, not an observational study of exposures in males. Our copy does not support the listed exposures to famine, obesity, smoking, alcohol, or stress, or the claim of behavioral effects. (LLM, conf=0.88)

  cites [184] 184. Anway MD, Cupp AS, Uzumcu M. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 2005;308:1466-9. sourceExperimental — accuracy not yet measured
• Partly supported

  The Summary and Conclusions (page unavailable) reports epidemiologic associations between paternal exposures and offspring outcomes, including neurobehavioral and biological abnormalities. The paper discusses smoking, alcohol, and occupational chemicals, but the passages found do not address famine, obesity, or stress. It also describes the epidemiologic evidence as associations, rather than demonstrating that those exposures cause the outcomes. (LLM, conf=0.88)

  cites [185] 185. Friedler G. Paternal exposures: impact on reproductive and developmen- tal outcome. An overview. Pharmacol Biochem Behav 1996;55:691-700. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [186] 186. Cicero TJ. Effects of paternal exposure to alcohol on offspring develop- ment. Alcohol Res Health 1994;18:37.
• ?Not checked — no full text of the sourcecites [187] 187. Ji BS, Shu XO, Zheng W et al. Paternal cigarette smoking and the risk of childhood cancer among offspring of nonsmoking mothers. J Natl Cancer Inst 1997;89:238-43. source

In the paper

“Offspring effects may be mediated, in part, by epigenetic changes in parental germ cells resulting from acquired parental stress exposures throughout life 3,[168][169][170]”

What the sources say

• ?Not checked — no full text of the sourcecites [3] 3. Bohacek J, Mansuy IM. Molecular insights into transgenerational non- genetic inheritance of acquired behaviours. Nat Rev Genet 2015;16: 641-52. source
• Partly supported

  The paper discusses environmentally induced epigenetic changes in germ cells as a possible route to offspring effects, including after postnatal exposure (Abstract, page unavailable). It does not establish that acquired parental stress exposures throughout life act through that route. Its Behavioural transmission discussion instead says the maternal-care effects on offspring stress responses are not germline inherited. (LLM, conf=0.86)

  cites [168] 168. Jirtle RL, Skinner MK. Environmental epigenomics and disease suscepti- bility. Nat Rev Genet 2007;8:253-62. sourceExperimental — accuracy not yet measured
• Partly supported

  Section 2 (page unavailable) says environmental exposures can alter the germ-line epigenome and affect subsequent generations. Section 3 identifies stress as a factor that can influence phenotypes transgenerationally. But the paper places germ-line epigenetic alteration in a narrow developmental window, rather than supporting the claim that parental exposures throughout life produce those changes. (LLM, conf=0.87)

  cites [169] 169. Guerrero-Bosagna C, Skinner MK. Environmentally induced epigenetic transgenerational inheritance of phenotype and disease. Mol Cell Endo- crinol 2012;354:3-8. sourceExperimental — accuracy not yet measured
• Supported

  The Introduction says that studies of parental experiences before conception, termed lifetime exposures, suggest transmission through epigenetic reprogramming of germ cells. The Epigenetic signatures of stress experience section reports altered offspring phenotypes after paternal stress at prenatal, postnatal, adolescent, or adult stages. The source supports the claim as a proposed mechanism, not as a certainty; page numbers were not supplied. (LLM, conf=0.93)

  cites [170] 170. Rodgers AB, Bale TL. Germ cell origins of posttraumatic stress disorder risk: the transgenerational impact of parental stress experience. Biol Psychiatry 2015;78:307-14. source

In the paper

“Genomic imprinting patterns can have major effects on the embryonic phenotype 192,193”

What the sources say

• Supported

  The Introduction (page unavailable) says imprinting plays an important role in early development, explicitly including embryonic development. It also describes parent-of-origin-dependent phenotypic effects, supporting the claim that imprinting can substantially affect embryonic phenotype. (LLM, conf=0.88)

  cites [192] 192. Lawson HA, Cheverud JM, Wolf JB. Genomic imprinting and parent-of- origin effects on complex traits. Nat Rev Genet 2013;14:609-17. source
• Supported

  The paper’s introductory discussion (page not specified in our copy) reports large-scale effects involving imprinted genes, including embryonic or fetal lethality. This supports the claim that imprinting can have major effects on embryonic phenotype, although the examples involve major genetic alterations such as knockouts or uniparental disomies. (LLM, conf=0.87)

  cites [193] 193. Wolf JB, Hager R, Cheverud JM. Genomic imprinting effects on complex traits: a phenotype-based perspective. Epigenetics 2008;3:295-9. source

In the paper

“two groups of male mice were exposed to a wide range of stressors over 42 days at puberty or adulthood 179”

What the sources say

• Supported

  The Materials & Methods section (‘Chronic Variable Stress’) describes two experimental groups of male mice: one received 42 days of stress throughout puberty and the other 42 days in adulthood. It lists seven different stressors administered in varying order. (LLM, conf=0.95)

  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

“The extent of paternal alcoholism has also been associated with neurological and behavioral deficits in offspring 198”

What the sources say

• Partly supported

  The Multigenerational Effects section (page unavailable) reports behavioral abnormalities in offspring following paternal alcohol exposure. It does not establish an association with the extent of paternal alcoholism or specifically report neurological deficits in those offspring; the neurological and cognitive deficits discussed in the Prenatal Alcohol Exposure section concern prenatal exposure rather than paternal drinking. (LLM, conf=0.86)

  cites [198] 198. Boschen KE, Keller SM, Roth TL et al. Epigenetic mechanisms in alcohol- and adversity-induced developmental origins of neurobehavioral func- tioning. Neurotoxicol Teratol 2018;66:63-79. sourceExperimental — accuracy not yet measured

In the paper

“When the F1 males were themselves mated, changes in brain persisted in the F2 male offspring, demonstrating conservation of the effect through two generations.”

What the sources say

• Supported

  The Results section reports that naïve F1 males were mated with naïve females to produce F2 offspring. It then reports significantly enlarged odor-specific glomeruli in the olfactory bulbs of F2 offspring and concludes that the neuroanatomical alterations persisted to at least the F2 generation. Page numbers were not provided in our copy. (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. source

In the paper

“To even more carefully eliminate any maternal contributions to offspring effects, a cross-fostering study was performed, which confirmed the absence of maternal effects on the observed offspring phenotype.”

What the sources say

• Partly supported

  The Results (page not supplied) report that cross-fostering did not reverse the offspring’s behavioral or structural phenotype, supporting an inherited rather than socially transmitted effect. But the authors say the findings “strongly suggest” biological inheritance; they do not confirm the absence of all maternal effects, and they also observe the phenotype in offspring of conditioned mothers. (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

In the paper

“F0 exposed to several unpredictable maternal stressors and separation demonstrated changes that could be observed across two generations 176”

What the sources say

• Supported

  The Methods (Mice treatment; page not supplied) describe maternal separation combined with unpredictable maternal stress and explain how F1 and F2 mice were bred. The results passage labeled Abstract (page not supplied) reports behavioral changes in F1 mice that were also observed in F2 offspring. (LLM, conf=0.90)

  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

“An independent research team also demonstrated that small non-coding RNAs (sncRNAs), common in sperm, can mediate inheritance of environmentally acquired traits or phenotypes in mice 176”

What the sources say

• Partly supported

  The Abstract reports that sperm RNAs from mice exposed to early-life trauma reproduced behavioral and metabolic changes when injected into fertilized oocytes, and says the results strongly suggest sncRNAs contribute to inheritance. But the Methods (RNAs injection in fertilized oocytes; page not provided) specify that the injected material was total sperm RNA, not isolated sncRNAs. The claim therefore overstates direct demonstration of sncRNA mediation. (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

“When environmental enrichment was applied at weaning until adulthood, the behavioral and methylation effects were no longer observed in the F0 or F1.”

What the sources say

• Partly supported

  The Environmental Enrichment section says mice received enrichment from weaning to adulthood. The Reversibility of Altered Responses section reports normalized behavior in enriched F1 males and behavioral changes in their F2 offspring; the GR Expression and Promoter Methylation section reports correction of some methylation changes in F1 sperm and F2 offspring. The claim incorrectly names F0 rather than F2, and overstates the methylation result: an alteration at CpG4 remained in F2 offspring despite paternal enrichment. (LLM, conf=0.87)

  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

“Such studies have produced very compelling data suggesting that exposure to extreme stress in males can affect brain, behavior and sperm in the next generation 176,179”

What the sources say

• Partly supported

  The paper reports altered behavior and hippocampal miRNAs in F2 offspring of mice exposed to early-life traumatic stress. It also reports altered sperm miRNAs in the stressed F1 males, but says miRNAs were not altered in F2 sperm; thus it does not support the claim that sperm was affected in the next generation. (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 Discussion (page unavailable) reports that stress in male mice altered paternal germ cells and offspring HPA-axis regulation, supporting an effect on offspring stress circuitry. But it calls the exposure mild, not extreme; the sperm changes were measured in fathers, not offspring. The Results, “Analysis of offspring physiology & behavior” (page unavailable), found no paternal-stress effect on the behavioral tests reported. (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. sourceExperimental — accuracy not yet measured

In the paper

“When altered microRNAs from sperm of the stressed males were injected into fertilized wild-type oocytes, comparable behavioral, metabolic and molecular outcomes were observed in the F2 offspring, indicating transmission of epigenetic marks.”

What the sources say

• Partly supported

  The injection-results passage (labeled Abstract in our copy) reports comparable behavioral, metabolic and molecular effects in animals produced by injecting sperm RNAs from stressed males into fertilized wild-type oocytes. The Methods specify that the injected material was total sperm RNA, not isolated altered microRNAs. The passage reports depressive-like behavior in the injected animals’ offspring, but does not report the full set of comparable outcomes in those offspring; it also does not identify the injected animals as F2. (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

In the paper

“The offspring (F1) of odor conditioned F0 males mated with naïve females also showed similar changes in brain and sperm.”

What the sources say

• Supported

  The Results state that odor-conditioned F0 males were mated with naive females. They report enlarged odor-specific olfactory structures in F1 offspring and reduced methylation at the relevant olfactory-receptor locus in F1 sperm, similar to F0 sperm. These are the brain and sperm changes described in the claim. (LLM, conf=0.92)

  cites [175] 175. Dias BG, Ressler KJ. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci 2014;17: 89-96. source

In the paper

“another study demonstrated that environmental enrichment following stress exposure in the F0 could reverse and prevent some of the effects 205”

What the sources say

• Partly supported

  The Reversibility of Altered Responses in Aversive Conditions section reports that environmental enrichment after early-life stress reversed some altered responses in male offspring. However, the paper says enrichment was given to F1 males, not the F0 generation; the MSUS Treatment and Breeding section identifies F0 as the parents of those males. Page numbers were not available in our copy. (LLM, conf=0.88)

  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

“In 2002, a seminal paper demonstrated that the rat offspring effects of licking and grooming were associated with an epigenetic change, namely, DNA methylation at a GR (nr3c1) gene promoter in the hippocampus 85,86 .”

What the sources say

• ?Not checked — no full text of the sourcecites [85] 85. Weaver IC, Szyf M, Meaney MJ. From maternal care to gene expression: DNA methylation and the maternal programming of stress responses. En- docr Res 2002;28:699. source
• ?Not checked — no full text of the sourcecites [86] 86. Weaver IC, Cervoni N, Champagne FA et al. Epigenetic programming by maternal behavior. Nat Neurosci 2004;7:847-54. source

In the paper

“This idea was plausible, since the HPA axis is subject to early developmental programming 50,51 .”

What the sources say

• ?Not checked — no full text of the sourcecites [50] 50. Seckl JR. Glucocorticoids, developmental 'programming' and the risk of affective dysfunction. Prog Brain Res 2007;167:17-34. source
• ?Not checked — no full text of the sourcecites [51] 51. Matthews SG. Early programming of the hypothalamo-pituitary-adrenal axis. Trends Endocrinol Metab 2002;13:373-80. source

In the paper

“However, it subsequently became clear that the observed effects in offspring were mediated not by the maternal separation or the early handling by humans, but rather by the behavior of the mother upon being reunited with her pups in the home cage, specifically the extent of licking and grooming of pups.”

In the paper

“The elimination of offspring effects through cross-fostering is a potent example of social transfer of information through parental behaviornot parental DNA or biological inheritance.”

In the paper

“A post-hoc analysis of cortisol circadian rhythm data indicated that lower cortisol levels in adult Holocaust offspring were associated with maternal, but not paternal, PTSD 61 .”

What the sources say

• ?Not checked — no full text of the sourcecites [61] 61. Yehuda R, Teicher MH, Seckl JR et al. Parental posttraumatic stress dis- order as a vulnerability factor for low cortisol trait in offspring of holocaust survivors. Arch Gen Psychiatry 2007;64:1040-8. source

In the paper

“studies in humans have not yet demonstrated that the effects of trauma are heritable through non-genomic (i.e., epigenetic) mechanisms.”

In the paper

“A higher prevalence of PTSD, mood and anxiety disorders was also observed in Holocaust offspring, largely selected from a convenience sample of people seeking treatment for Holocaust-related problems, compared with controls 26 .”

What the sources say

• ?Not checked — no full text of the sourcecites [26] 26. Yehuda R, Schmeidler J, Wainberg M et al. Vulnerability to posttraumatic stress disorder in adult offspring of Holocaust survivors. Am J Psychiatry 1998;155:1163-71. source

In the paper

“Studies published over the next decade demonstrated that, in the absence of their own traumatic exposures, offspring of Holocaust survivors were more likely to show HPA axis alterations associated with PTSD, such as lower cortisol levels and enhanced GR responsiveness [60][61][62][63][64] .”

What the sources say

• ?Not matched

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

  cites [60][61][62][63][64]

In the paper

“Although both intergenerational (from F0 to F1) and transgenerational (from F0 to F3 or F4) transmission of environmental adversity effects have been established in animal models”

In the paper

“Supporting this idea were findings that Holocaust offspring reported higher levels of childhood trauma exposure than demographically similar comparison subjects, particularly if one or more parent had PTSD 66 .”

What the sources say

• ?Not checked — no full text of the sourcecites [66] 66. Yehuda R, Halligan SL, Grossman R. Childhood trauma and risk for PTSD: relationship to intergenerational effects of trauma, parental PTSD, and cortisol excretion. Dev Psychopathol 2001;13:733-53. source

In the paper

“By then it had been established that early childhood maltreatment in itself could result in lower cortisol levels [67][68][69][70][71] .”

What the sources say

• ?Not matched

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

  cites [67][68][69][70][71]

In the paper

“Subsequent investigations documented that maternal and paternal PTSD were associated with different biological outcomes.”

In the paper

“One the most provocative observations regarding Holocaust offspring was the report that Yom Kippur war veterans were more likely to develop post-traumatic stress disorder (PTSD) in response to combat if they had a Holocaust survivor parent 25 .”

What the sources say

• ?Not checked — no full text of the sourcecites [25] 25. Solomon Z, Kotler M, Mikulincer M. Combat-related posttraumatic stress disorder among second-generation Holocaust survivors: preliminary find- ings. Am J Psychiatry 1988;145:865-8. source

In the paper

“In fact, the low cortisol in offspring was found to be associated with offspring reports of emotional abuse 66 .”

What the sources say

• ?Not checked — no full text of the sourcecites [66] 66. Yehuda R, Halligan SL, Grossman R. Childhood trauma and risk for PTSD: relationship to intergenerational effects of trauma, parental PTSD, and cortisol excretion. Dev Psychopathol 2001;13:733-53. source

In the paper

“The concept of intergenerational trauma was introduced in the psychiatric literature through descriptions of behavioral and clinical problems in offspring of Holocaust survivors 8 .”

What the sources say

• ?Not matched

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

  cites [8] 8. Rakoff V. A long term effect of the concentration camp experience. View- points 1966;1:17-22.

In the paper

“The offspring of mothers that displayed lower vs. higher licking and grooming demonstrated distinct neuroendocrine and behavioral parameters, which persisted from F1 to F2 80,81 .”

What the sources say

• ?Not checked — no full text of the sourcecites [80] 80. Francis D, Diorio J, Liu D et al. Nongenomic transmission across gener- ations of maternal behavior and stress responses in the rat. Science 1999; 286:1155-8. source
• ?Not checked — no full text of the sourcecites [81] 81. Liu D, Diorio J, Tannenbaum B et al. Maternal care, hippocampal gluco- corticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 1997;277:1659-62. source

In the paper

“These findings were replicated in a study assessing the relationship between PTSD in offspring and their own parents, assessed directly by clinical interview of the parent (s) 27 .”

What the sources say

• ?Not checked — no full text of the sourcecites [27] 27. Yehuda R, Schmeidler J, Giller EL et al. Relationship between posttrau- matic stress disorder characteristics of Holocaust survivors and their adult offspring. Am J Psychiatry 1998;155:841-3. source

In the paper

“and in the children of women exposed to the Tutsi genocide during pregnancy compared with non-genocide exposed women of the same ethnicity and pregnant at the same time, and their children 41 .”

What the sources say

• ?Not checked — no full text of the sourcecites [41] 41. Perroud N, Rutembesa E, Paoloni-Giacobino A et al. The Tutsi genocide and transgenerational transmission of maternal stress: epigenetics and biology of the HPA axis. World J Biol Psychiatry 2014;15:334-45. source

In the paper

“a study of pregnancy-related anxiety found that methylation at the 1F exon of the NR3C1 in offspring was influenced by maternal anxiety only during the first two trimesters 158”

What the sources say

• ?Not checked — no full text of the sourcecites [158] 158. Hompes T, Izzi B, Gellens E et al. Investigating the influence of maternal cortisol and emotional state during pregnancy on the DNA methylation status of the glucocorticoid receptor gene (NR3C1) promoter region in cord blood. J Psychiatr Res 2013;47:880-91. source

In the paper

“These findings suggest enduring epigenetic alterations in offspring associated with maternal trauma during gestation.”

In the paper

“The placenta nourishes and protects the fetus, buffering the effects of maternal glucocorticoids through the expression of placental 11B-hydroxysteroid dehydrogenase type 2 (11β-HSD2), an enzyme that converts cortisol to inactive cortisone 139 .”

What the sources say

• ?Not checked — no full text of the sourcecites [139] 139. Reynolds RM. Glucocorticoid excess and the developmental origins of disease: two decades of testing the hypothesis. Psychoneuroendocrinol- ogy 2013;38:1-11. source

In the paper

“Following this observation in post-mortem brain tissue, higher GR promoter methylation in circulating leukocytes of healthy adults was also found to be associated with disrupted, inadequate, or abusive parenting [123][124][125] .”

What the sources say

• ?Not matched

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

  cites [123][124][125]

In the paper

“In studies of Holocaust offspring, perhaps the most salient observation has been that most differences in offspring phenotype were associated with persistent psychological effects of parents.”

In the paper

“Interestingly, exposure to famine during pregnancy had biological and behavioral effects on grandchildren, such as on adiposity 153 .”

What the sources say

• ?Not checked — no full text of the sourcecites [153] 153. Painter RC, Osmond C, Gluckman P et al. Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life. BJOG 2008;115:1243-9. source

In the paper

“Offspring of F1 fathers, but not F1 mothers, who were prenatally exposed to famine had higher body mass index and obesity rates as adults 197”

What the sources say

• ?Not checked — no full text of the sourcecites [197] 197. Veenendaal MV, Painter RC, Rooij S et al. Transgenerational effects of prenatal exposure to the 1944-45 Dutch famine. BJOG 2013;120:548-54. source

In the paper

“Changes in any of these properties in sperm could affect gene expression and other biological processes in the developing embryo and fetus, setting the stage for phenotypic change in offspring 182”

What the sources say

• ?Not checked — no full text of the sourcecites [182] 182. Schagdarsurengin U, Steger K. Epigenetics in male reproduction: effect of paternal diet on sperm quality and offspring health. Nat Rev Urol 2016;13: 584-95. source

In the paper

“In Sweden, limited food supply affected mortality rates of grandchildren in a sex-specific manner through the paternal line.”

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

“Thus there may be slightly different effects according to species and sex, depending on the parameter being measured.”

In the paper

“In studies where offspring are also examined, it is difficult to break down effects of prenatal exposures from postnatal maternal factors”

In the paper

“Some of these exposures have also been associated with alterations in sperm of the exposed father.”

In the paper

“In primordial germ cells, DNA methylation is again erased and re-established based on the sex of the transmitting parent 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

“This provides at least one putative mechanism in addition to parent of origin effects for the transfer of an environmentally-induced epigenetic mark from one generation to another.”

In the paper

“Studying transmission through sperm eliminates confounds created by influences of fetoplacental environment, delivery factors, and maternal care as described above.”

In the paper

“However, the possibility that trauma-related epigenetic changes in germ cells contribute to offspring phenotype has been demonstrated in association with sperm.”

In the paper

“Thus, there is no information about epigenetic changes in sperm of fathers exposed to adversity with examination of potential corresponding changes in the sperm of their sons.”

In the paper

“A three-generational study of obesity in males and females demonstrated different risk and protective factors associated with grandparental and parental food availability during puberty 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

“These sex-related placental differences may confer protection or vulnerability to the fetus through differential exposure to maternal stress hormones.”

In the paper

“The notion that oocytes may be affected by preconception trauma is consistent with findings in Holocaust offspring in association with maternal age of exposure during the Holocaust.”

In the paper

“Regarding exposures during World War II, including the studies of the Dutch famine, it is difficult, if not impossible, to ascertain exactly when the traumatic period began.”

In the paper

“Data from the UK Avon Longitudinal Study of Parents and Children study identified effects of paternal smoking on offspring, but only when smoking occurred before puberty 195”

What the sources say

• ?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

“It is for this reason that environmental effects which cross the generations do not necessarily predict negative generational consequencesposing challenges for interpretation of such effects.”

In the paper

“It is also important to underscore the lack of permanence of effects once environmental conditions are altered.”

In the paper

“Thus, evidence is beginning to converge around the role of epigenetic mechanisms.”

In the paper

“The first involve accommodations made by offspring in response to their own environmental exposures in early life, or even in utero.”

In the paper

“Smoking was reported to increase risk of childhood cancer in the offspring of male smokers 187”

What the sources say

• ?Not checked — no full text of the sourcecites [187] 187. Ji BS, Shu XO, Zheng W et al. Paternal cigarette smoking and the risk of childhood cancer among offspring of nonsmoking mothers. J Natl Cancer Inst 1997;89:238-43. source

In the paper

“The in vitro fertilization study permitted changes to be attributed to sperm and not, for example, maternal reactions to behavior in the conditioned father during mating, or other potential confounds.”

In the paper

“Furthermore, not all stressors impact sperm in an intergenerational manner.”

In the paper

“In both cases, the transmission is a result of parental exposure effects.”