Copyright ©The Author(s) 2021.
World J Psychiatr. Oct 19, 2021; 11(10): 711-735
Published online Oct 19, 2021. doi: 10.5498/wjp.v11.i10.711
Table 1 Studies of transgenerational epigenetic inheritance in Caenorhabditis elegans of relevance to neuropsychiatric conditions and mammalian preclinical models
Type of stress (if applicable to study)
Transgenerational shifts in progeny phenotypes
Epigenetic modifications implicated in the inheritance process
Psychiatric conditions with similar epigenetic pathology
Elevated temperatureTemperature-induced transcriptome changes potentially up to F14 generationHeat shock reduces H3K9me3 to facilitate de-repression of endogenously repressed repeats (DNA transposons)Klosin et al[43], 2017Repetitive elements as etiological factors for schizophrenia (SZ), bipolar disorder and major depression (review)Darby and Sabunciyan 2014[44]
No difference in another repressive mark, H3K27me3Altered expression of human endogenous retroviruses associated with autism spectrum disorder and SZ (review)Misiak et al[169], 2019
Active histone marks H3K36me3 and H3K4me2 both unchangedTissue-specific repetitive elements expression differences in Parkinson’s diseaseBillingsley et al[170], 2019
Heat shockMaternal heat shock altered survival of F1 progeny through 5-HT dependent HSF-1 recruitment to heat shock protein gene promotors. Persistence of phenotypic changes not investigatedHistone H3 occupancy at hsp70 genes decreased following heat shockDas et al[9], 2020 MDD associated with increased hsp70 expression in post mortem dorsolateral prefrontal cortexMartín-Hernández et al[53], 2018
Elevated serum HSP70 levels predicted development of MDD for premenopausal women. Serum HSP70 decreased over time for women who did not develop MDDPasquali et al[54], 2018
Decreased Hsp70 expression in CA4 associated with complete seizure remission for temporal lobe epilepsyKandratavicius et al[171], 2014
NANATransgenerational inheritance of H3K36me3 is regulated by two distinct histone methyltransferases, MES-4 and MET-1Kreher et al[172], 2018 H3K36me3 implicated in SZ susceptibility SNPs. But histone lysine methyltransferases yet to be investigated in the context of SZNiu et al[65], 2019
NANALifespan regulated by the H3K9me2 methyltransferase MET-2Lee et al[49], 2019 H3K9me2 elevated in post-mortem SZ brains and peripheral blood cells. Treatment with histone methyltransferase inhibitor BIX-01294 decreased H3K9me2 levels and rescued expression of SZ risk genesChase et al[50], 2019
Reduced H3K9me2 at oxytocin and arginine vasopressin gene promotors in a rodent model of stress-induced depression. Rescued by physical exerciseKim et al[51], 2016
Cdk-5 targeted H3K9me2 attenuates cocaine-induced locomotor behaviour and conditioned place preference in a rodent model of addictionHeller et al[52], 2016
NADecline in fertilityH3K4me2 demethylase spr-5Greer et al[173], 2014 Treatment with antipsychotic drug olanzapine increased H3K4me2 binding on gene loci associated with adipogenesis and lipogenesis in a rat modelSu et al[174], 2020
KDM5C gene that encodes the H3K4me2/3 histone demethylase linked to autism and intellectual disabilityVallianatos et al[175], 2018
Heavy metal (arsenite) stressIncreased resistance to oxidative stress up to F2 generation; no change in reproduction or lifespanH3K4me3 complex components (wdr-5.1, ash-2, set-2), and transcription factors daf-16 and hsf-1Kishimoto et al[10], 2017 Increased H3K4me3 associated with three synapsin gene variants in bipolar disorder and major depressionCruceanu et al[63], 2013
SZ risk variants are over-represented in association with H3K4me3 in human frontal lobeGirdhar et al[64], 2018
H3K4me3 implicated in SZ susceptibility SNPsNiu et al[65], 2019
Increased H3K4me3 associated with increased Oxtr gene expression in a rat model of methamphetamine addictionAguilar-Valles et al[68], 2014
Hyperosmotic stressIncreased resistance to oxidative stress up to F2 generationNot further investigated in studyKishimoto et al[10], 2017Relevance to human health presently unclear
Larval starvationIncreased resistance to oxidative stress up to F2 generationNot further investigated in studyKishimoto et al[10], 2017Relevance to human health presently unclear
Larval starvationNAThirteen miRNAs up-regulated (miR-34-3p, the family of miR-35-3p to miR-41-3p, miR-39-5p, miR-41-5p, miR-240-5p, miR-246-3p and miR-4813-5p); Two miRNAs down-regulated (let-7-3p, miR-85-5p)Garcia-Segura et al[77], 2015 Eight differentially expressed blood miRNAs linked to PTSD. Four up-regulated (miR-19a-3p, miR-101-3p, miR-20a-5p, miR-20b-5p). Four down-regulated (miR-486-3p, miR-125b-5p, miR-128-3p, miR-15b-3p)Martin et al[78], 2017
Deletion of miR-34 family in mice facilitates resilience to stress-induced anxiety and extinction of fear memoryAndolina et al[84], 2016
miR-34 differentially expressed in induced pluripotent stem cells derived from schizophrenia patientsZhao et al[176], 2015
miR-34a regulates expression of p73, a p53-family member, that is implicated in neuronal differentiationAgostini et al[86], 2011
StarvationIncreased longevity of progeny up to F3 generationInheritance of small RNAs through at least 3 generations. Rechavi et al[11], 2014 miRNAs and rRNAs make up the majority of exRNAs in human plasmaDanielson et al[91], 2017
Small RNAs regulating expression of genes involved in nutrition, metabolic health and lipid transport1 specific exRNA predicted diagnosis of Alzheimer’s diseaseYan et al[94], 2020
exRNAs are potentially involved in the paternal intergenerational influence on offspring metabolic health (mouse model)van Steenwyk et al[93], 2020
Table 2 Studies of transgenerational epigenetic inheritance in Drosophila melanogaster of potential relevance to psychiatric conditions and mammalian preclinical models
Type of stress (if applicable to study)
Transgenerational shifts in progeny phenotypes
Epigenetic processes implicated in the inheritance process
Potentially relevant psychiatric conditions
Thermal stress (selection based on intolerance to heat stress)Reduced ability to fly by F2 generation, maintain through to F4 generationEpigenetic mechanism not investigated; aspects of stress physiology that affect flight still unclearKrebs and Thompson[111], 2006Relevance to human health presently unclear.
Mild heat stress(embryos maintained at 29 °C)De-suppression of white gene up to F4 generationDisruption of polycomb group (PcG) protein complex affecting H3K27me3Bantignies et al[114], 2003 Despite multiple reports of altered H3K27me3, the involvement of PcG protein complexes in human psychopathologies has not been established
Heat shock (flies exposed to 37 °C for 1 h)De-suppression of white gene sustained up to F3 generation required repeated exposure to the same paternal stressor. Gradual return to normal upon removal of heat shockDisruption of pATF-2 mediated heterochromatin assemblySeong et al[121], 2011 Rat model of chronic stress reported increased ATF-2 gene expression in the frontal cortex of chronically stressed rats, which is decreased following chronic antidepressant treatmentLaifenfeld et al[122], 2004
pATF-2 levels are increased in post mortem samples of unmedicated vs medicated patients with MDD. No differences detected for bipolar disorder or schizophreniaGourzis et al[177], 2012
Case report of decreased chromosome 1 heterochromatin in FTLD, misdiagnosed as SZ. Altered size distribution of chromosome 1 heterochromatic region in unrelated SZ patients compared to controlsKosower et al[178], 1995
Risperidone inhibition of heterochromatin formation in human liposarcoma cells in vitro, in a process involving PKA signalling; extent of dysregulated heterochromatin in psychosis yet to be exploredFeiner et al[125], 2019
Parental exposure to risperidone led to intergenerational effects on F1 predator avoidance behaviours in zebrafish; potential human effects have not been investigatedKalichak et al[179], 2019
Heat stress (flies raised at 29 °C)Suppression of BX2 transgene cluster over multiple (50) generationsParamutation of BX2 via maternally inherited piRNAs, triggered by heat stress which resulted in active transcription of piRNAs within that gene locusde Vanssay et al[126], 2012 Paramutation is not regarded as an established epigenetic process in mammals
However, readers should be aware of this proof-of-concept study in miceYuan et al[180], 2015
Casier et al[127], 2019 Paternal transmission of “white-tail-tip” phenotype caused by paramutant allele in mice limited to one generation. Maternal miRNAs and piRNAs regulate (inhibit) germline transmission of paramutation
14 piRNAs differentially expressed in AD prefrontal cortex samples vs controlsQiu et al[128], 2017
Sequencing of CSF-derived exosome sncRNA revealed combination of 3 miRNAs and 3 piRNAs detected AD and predicted the conversion of mild–cognitive impaired (MCI) patients to AD dementia. Greater predictive confidence when combining the smallRNA signature with pTau and Aβ 42/40 ratio pathologyJain et al[129], 2019
Forced cohabitation with predator or endoparasitoid wasps Stressed females shift behaviour to laying eggs on food rich in ethanol, and that preference is inherited through five generationsMaternal inheritance of chromosome III and NPF (Drosophila homolog of NPY) gene locus, reduced NPF expression in the fan shaped body of the adult brain drives ethanol preferenceBozler et al[136], 2019 Dysregulation of NPY levels in the brain is a key pathophysiology of drug addiction. Manipulation of NPY neurotransmission has potentially beneficial behavioural outcomes, depending on the drug in questionGonçalves et al[181], 2016
NPY is implicated in human alcohol misuse disordersMayfield et al[137], 2002
NPY is also implicated in rodent models of alcohol misuse disorderMottagui-Tabar et al[138], 2005
Thorsell and Mathe[139], 2017
Badia-Elder et al[140], 2003
Schroeder et al[142], 2005
Robinson et al[141], 2019
Restraint stressPaternal restraint stress affects epigenome, transcriptome and metabolome of F1 progenyStress-induced up-regulation of Upd3 (Drosophila homolog of IL-6) in somatic cells and testes, activating JAK/STAT pathwaySeong et al[145], 2020 Metabolic dysregulation in the F1 offspring derived from male breeders exposed to early postnatal stressvan Steenwyk et al[146], 2018; van Steenwyk et al[93], 2020
Subsequent p38 activation results in dATF-2 deactivation in germ cells leading to decreased H3K9me2 (repressive mark) at target genes. Repressive histone marks inherited by F1 progenyReview of epigenetic mechanisms proposed to underlie intergenerational transmission of paternal traumaYehuda and Lehrner[182], 2018
Childhood adversity associated with altered DNA methylation of HPA axis and immune system genes; potentially inherited by offspringBick et al[154], 2012
Methylphenidate (MPH) treatmentBehavioural response to MPH is genetically variable and intergenerational effects can be observed in F1 offspringMechanism is unknown but MPH resulted in alterations to expression of many histone modifying genesRohde et al[158], 2019 ADHD is highly heritable, but the reasons are unclear despite the identification of candidate genes. Future studies should attempt to identify transgenerationally heritable epigenetic modifications as the basis for genetic vulnerability
Non-human primate studies indicate that MPH treatment affects normal puberty. The transgenerational implications of this finding for humans needs to be followed-upMattison et al[155], 2011
G418 treatment (toxic stress)Exposure of F0 females to G418 resulted in reduction of Polycomb group gene expression in up till F3 generationMaternal Polycomb group expression in early embryogenesis affects expression of the zygotic genome, which can be inheritedStern et al[168], 2014 G418 has been successfully used to rescue PTC deficiencies in a cell culture model for frontotemporal dementia. However, its broader utility for treating neuropsychiatric conditions remains unknownKuang et al[164], 2020
PTC mutations of neuronal UPF3B gene associated with nonspecific mental retardation with or without austismLaumonnier et al[183], 2010