Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms

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.

“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 .”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

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

“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.”

• 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. sourceSupported

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

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

• 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. sourceSupported

Lower cortisol levels were observed in the adult offspring of combat veterans with PTSD compared to offspring of combat veterans without PTSD.

“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 .”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

A blunted cortisol reactivity to stress was observed in toddlers aged 12-48 months in association with maternal PTSD occurring as a result of interpersonal violence.

“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 .”

• 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. sourceSupported

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.

“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 .”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

Several measures of GR sensitivity were directionally different in offspring of mothers vs. fathers with PTSD.

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

• 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. sourceSupported

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.

“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 .”

• 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. sourceSupported

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.

“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 .”

• cites [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. sourceNot checked — no full text of the source
• cites [86] 86. Weaver IC, Cervoni N, Champagne FA et al. Epigenetic programming by maternal behavior. Nat Neurosci 2004;7:847-54. sourceNot checked — no full text of the source
• cites [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. sourceNot checked — no full text of the source
• 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. sourceSupported

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

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

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

Stressful experiences such as adult trauma change methylation of the GR gene in blood cells, whether primed by early experience or not.

“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 .”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured
• 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. sourcePartly 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)

  Experimental — accuracy not yet measured
• 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. sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [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. sourceNot checked — no full text of the source

Results indicated a significant interaction of maternal and paternal PTSD on GR gene methylation.

“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 .”

• 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. sourceSupported

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.

“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 .”

• 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. sourceSupported

Higher methylation in the promoter of the NR3C1 gene was 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.

“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 ,”

• 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. sourceSupported

Maternal and paternal PTSD predicted different psychiatric and biological outcomes in offspring.

“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 .”

• 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. sourceSupported
• 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. sourceSupported

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.

“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 .”

• 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. sourceSupported

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

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

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

  Experimental — accuracy not yet measured

Methylation levels in newborns were associated with salivary cortisol stress responses at 3 months.

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

• 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. sourceSupported

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.

“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 .”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [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. sourceNot checked — no full text of the source

FKBP5 methylation in parents and their children were positively correlated.

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

• 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. sourceSupported

Third trimester maternal depression/anxiety is associated with higher methylation of NR3C1 at a predicted NGF1-A binding site in newborn cord blood.

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

• 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. sourceSupported

Prenatal stress has different effects in male vs. female offspring.

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

• cites [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. sourceNot checked — no full text of the source
• cites [159] 159. Mueller BR, Bale TL. Sex-specific programming of offspring emotionality after stress early in pregnancy. J Neurosci 2008;28:9055-65. sourceSupported
• cites [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. sourceNot checked — no full text of the source
• cites [161] 161. Weinstock M. Gender differences in the effects of prenatal stress on brain development and behaviour. Neurochem Res 2007;32:1730-40. sourceNot checked — no full text of the source

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

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

• 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. sourceSupported

Fetal sex, or trophoblast cells from the embryo reflecting fetal sex, may differentially regulate epigenetic signals in the placenta, leading to differential signaling that feeds back to the offspring.

“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”

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

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.

“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 .”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

In animal models of prenatal stress, exposure to chronic stress in utero increased male, but not female, HPA stress reactivity.

“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”

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

  Experimental — accuracy not yet measured
• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

Early gestational stress exposure led to sex differences in expression and methylation of genes in the placenta associated with growth and nutrient transport.

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

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

  Experimental — accuracy not yet measured

Prenatal stress in humans was associated with alterations in diurnal cortisol secretion in males that were not apparent in females.

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

• 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. sourceSupported

The compelling data demonstrating heritable epigenetic alterations come from animal models.

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

• 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. sourceSupported
• cites [181] 181. Szyf M. Nongenetic inheritance and transgenerational epigenetics. Trends Mol Med 2015;21:134-44. sourceNot checked — no full text of the source

Several observational studies demonstrate that environmental exposures in males-such as famine, obesity, smoking, alcohol consumption, exposure to toxins, and exposure to stress-result in subsequent behavioral and biologic effects in offspring.

“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]”

• cites [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. sourceNot checked — no full text of the source
• cites [184] 184. Anway MD, Cupp AS, Uzumcu M. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 2005;308:1466-9. sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [185] 185. Friedler G. Paternal exposures: impact on reproductive and developmen- tal outcome. An overview. Pharmacol Biochem Behav 1996;55:691-700. sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [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 source
• cites [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. sourceNot checked — no full text of the source

Offspring effects may be mediated, in part, by epigenetic changes in parental germ cells resulting from acquired parental stress exposures throughout life.

“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]”

• cites [3] 3. Bohacek J, Mansuy IM. Molecular insights into transgenerational non- genetic inheritance of acquired behaviours. Nat Rev Genet 2015;16: 641-52. sourceNot checked — no full text of the source
• cites [168] 168. Jirtle RL, Skinner MK. Environmental epigenomics and disease suscepti- bility. Nat Rev Genet 2007;8:253-62. sourcePartly 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)

  Experimental — accuracy not yet measured
• 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. sourcePartly 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)

  Experimental — accuracy not yet measured
• 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. sourceSupported

Genomic imprinting patterns can have major effects on the embryonic phenotype.

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

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

In a different paradigm, two groups of male mice were exposed to a wide range of stressors over 42 days at puberty or adulthood.

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

• 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. sourceSupported

The extent of paternal alcoholism has been associated with neurological and behavioral deficits in offspring.

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

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

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

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

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

A cross-fostering study confirmed the absence of maternal effects on the observed offspring phenotype.

“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.”

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

  Experimental — accuracy not yet measured

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

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

• 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. sourceSupported

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

“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”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

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

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

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

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.

“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”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured
• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

When altered microRNAs from sperm of 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.

“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.”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

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

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

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

Environmental enrichment following stress exposure in the F0 could reverse and prevent some of the effects.

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

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

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.

“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 .”

• cites [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. sourceNot checked — no full text of the source
• cites [86] 86. Weaver IC, Cervoni N, Champagne FA et al. Epigenetic programming by maternal behavior. Nat Neurosci 2004;7:847-54. sourceNot checked — no full text of the source

The HPA axis is subject to early developmental programming.

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

• cites [50] 50. Seckl JR. Glucocorticoids, developmental 'programming' and the risk of affective dysfunction. Prog Brain Res 2007;167:17-34. sourceNot checked — no full text of the source
• cites [51] 51. Matthews SG. Early programming of the hypothalamo-pituitary-adrenal axis. Trends Endocrinol Metab 2002;13:373-80. sourceNot checked — no full text of the source

Observed effects in offspring were mediated not by maternal separation or early handling by humans, but by the behavior of the mother upon being reunited with her pups, specifically the extent of licking and grooming of pups.

“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.”

The elimination of offspring effects through cross-fostering is a potent example of social transfer of information through parental behavior-not parental DNA or biological inheritance.

“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.”

Lower cortisol levels in adult Holocaust offspring were associated with maternal, but not paternal, PTSD.

“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 .”

• cites [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. sourceNot checked — no full text of the source

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

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

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

“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 .”

• cites [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. sourceNot checked — no full text of the source

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.

“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] .”

• cites [60][61][62][63][64]Not matched

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

Intergenerational and transgenerational transmission of environmental adversity effects have been established in animal models.

“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”

Holocaust offspring reported higher levels of childhood trauma exposure than demographically similar comparison subjects, particularly if one or more parent had PTSD.

“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 .”

• cites [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. sourceNot checked — no full text of the source

Early childhood maltreatment in itself could result in lower cortisol levels.

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

• cites [67][68][69][70][71]Not matched

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

Maternal and paternal PTSD were associated with different biological outcomes.

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

Yom Kippur war veterans were more likely to develop PTSD in response to combat if they had a Holocaust survivor parent.

“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 .”

• cites [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. sourceNot checked — no full text of the source

Low cortisol in offspring was associated with offspring reports of emotional abuse.

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

• cites [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. sourceNot checked — no full text of the source

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

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

• cites [8] 8. Rakoff V. A long term effect of the concentration camp experience. View- points 1966;1:17-22.Not matched

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

Offspring of mothers that displayed lower vs. higher licking and grooming demonstrated distinct neuroendocrine and behavioral parameters, which persisted from F1 to F2.

“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 .”

• cites [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. sourceNot checked — no full text of the source
• cites [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. sourceNot checked — no full text of the source

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).

“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 .”

• cites [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. sourceNot checked — no full text of the source

Higher methylation in the promoter of the NR3C1 gene was observed in 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.

“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 .”

• cites [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. sourceNot checked — no full text of the source

In a study of pregnancy-related anxiety, methylation at the 1F exon of NR3C1 in offspring was influenced by maternal anxiety only during the first two trimesters.

“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”

• cites [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. sourceNot checked — no full text of the source

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

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

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.

“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 .”

• cites [139] 139. Reynolds RM. Glucocorticoid excess and the developmental origins of disease: two decades of testing the hypothesis. Psychoneuroendocrinol- ogy 2013;38:1-11. sourceNot checked — no full text of the source

Higher GR promoter methylation in circulating leukocytes of healthy adults was found to be associated with disrupted, inadequate, or abusive parenting.

“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] .”

• cites [123][124][125]Not matched

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

• AssumptionRests on an assumption: Peripheral blood methylation findings reflect epigenetic processes relevant to brain or stress biology.

In studies of Holocaust offspring, most differences in offspring phenotype were associated with persistent psychological effects of parents.

“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.”

Exposure to famine during pregnancy had biological and behavioral effects on grandchildren, such as on adiposity.

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

• cites [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. sourceNot checked — no full text of the source

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

“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”

• cites [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. sourceNot checked — no full text of the source

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

“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”

• cites [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. sourceNot checked — no full text of the source

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

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

• cites [181] 181. Szyf M. Nongenetic inheritance and transgenerational epigenetics. Trends Mol Med 2015;21:134-44. sourceNot checked — no full text of the source
• cites [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. sourceNot checked — no full text of the source

There may be slightly different effects according to species and sex, depending on the parameter being measured.

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

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

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

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

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

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

“In primordial germ cells, DNA methylation is again erased and re-established based on the sex of the transmitting parent 190”

• cites [190] 190. Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian de- velopment. Science 2001;293:1089-93. sourceNot checked — no full text of the source

Genomic imprinting 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.

“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.”

Studying transmission through sperm eliminates confounds created by influences of fetoplacental environment, delivery factors, and maternal care.

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

The possibility that trauma-related epigenetic changes in germ cells contribute to offspring phenotype has been demonstrated in association with sperm.

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

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.

“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.”

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.

“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”

• cites [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. sourceNot checked — no full text of the source

Sex-related placental differences may confer protection or vulnerability to the fetus through differential exposure to maternal stress hormones.

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

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.

“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.”

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.

“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.”

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

“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”

• cites [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. sourceNot checked — no full text of the source

Environmental effects which cross the generations do not necessarily predict negative generational consequences.

“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.”

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

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

Evidence is beginning to converge around the role of epigenetic mechanisms.

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

The first category of offspring effects involves accommodations made by offspring in response to their own environmental exposures in early life, or even in utero.

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

Smoking was reported to increase risk of childhood cancer in the offspring of male smokers.

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

• cites [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. sourceNot checked — no full text of the source

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.

“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.”

Not all stressors impact sperm in an intergenerational manner.

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

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

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