Transgenerational epigenetic influences of paternal environmental exposures on brain function and predisposition to psychiatric disorders

Yeshurun, Shlomo; Hannan, Anthony J.

doi:10.1038/s41380-018-0039-z

Cited by 99 publications

(81 citation statements)

References 116 publications

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“…As reviewed in Ref. , there are data for transgenerational inheritance of diseases/dysfunctions including reproduction, obesity, psychiatric disorders from a variety of environmental stressors including vinclozolin, bisphenol A, atrazine bisphenol A plus phthalates (DEHP and DBP), permethrin plus DEET, methoxychlor, Jet fuel 8, phthalate (DEHP),dioxin, DDT, PCBs, tributyltin, nicotine, alcohol, calorie restriction, high‐fat diets, folate and stress. Mechanisms currently focus on a variety of epigenetic changes including DNA methylation, histone changes and non‐coding RNAs .…”

Section: Transgenerational Inheritancementioning

confidence: 99%

The developmental basis of disease: Update on environmental exposures and animal models

Heindel

2018

Basic Clin Pharma Tox

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At the Prenatal Programming and Toxicity (PPTox) Conference I in 2008, I presented an overview of the developmental origins of health and disease field focusing on environmental chemical exposures and disease outcomes. At that time, I noted that the field was getting off the ground with a focus on developmental exposure to a small number of endocrine disrupting chemicals (EDCs) and disease outcomes across the lifespan in animal models. In this update, I note that the DOHaD field has changed significantly over the last decade. There are new windows of susceptibility including preconception, prepuberty, a focus on the mother and not just the offspring, and a significant focus on the new field of epigenetic transgenerational inheritance. New disease focus areas have sprung up including obesity, type 2 diabetes and fatty liver disease, all with a connection to developmental exposures to EDCs. There is also a focus on the study of new EDCs, molecular mechanisms, the development of new biomarkers of exposure and disease outcomes and studies focusing on intervention and prevention studies.

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Section: Transgenerational Inheritancementioning

confidence: 99%

The developmental basis of disease: Update on environmental exposures and animal models

Heindel

2018

Basic Clin Pharma Tox

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“…Adverse experiences can have long-lasting transgenerational effects on mental and physical health, and often increase disease risk 4,5 . Traumatic stress in early life in particular, can induce pathologies like psychosis, depression and metabolic dysfunctions in adulthood across generations 6 .…”

Section: Introductionmentioning

confidence: 99%

Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma

Gapp

Steenwyk

Germain

et al. 2018

Preprint

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30Psychiatric diseases have a strong heritable component known to not be restricted to 31 DNA sequence-based genetic inheritance alone but to also involve epigenetic factors in 32 germ cells 1,2 . Initial evidence suggested that sperm RNA is causally linked 2,3 to the 33 transmission of symptoms induced by traumatic experiences. Here we show that 34 alterations in long RNA in sperm contribute to the inheritance of specific trauma 35 symptoms. Injection of long RNA fraction from sperm of males exposed to postnatal 36 trauma recapitulates the effects on food intake, glucose response to insulin and risk-37 taking in adulthood whereas the small RNA fraction alters body weight and behavioral 38 despair. Alterations in long RNA are maintained after fertilization, suggesting a direct 39 link between sperm and embryo RNA. 40 41 42 43 Adverse experiences can have long-lasting transgenerational effects on mental and 46 physical health, and often increase disease risk 4,5 . Traumatic stress in early life in 47 particular, can induce pathologies like psychosis, depression and metabolic 48 dysfunctions in adulthood across generations 6 . To examine the biological factors 49 involved, we recapitulated heritable behavioural and metabolic effects of postnatal 50 trauma across several generations using a previously established model of 51 unpredictable maternal separation combined with unpredictable maternal stress 52(MSUS) in the mouse, that shows symptoms through up to three generations ( Fig.1) 2,7-53 13 . We have shown that such postnatal trauma alters small RNA in sperm and that 54 injection of total sperm RNA from exposed male mice into naïve fertilized oocytes elicits 55 symptoms reminiscent of those observed in natural offspring of exposed fathers 2 . Other 56 studies have demonstrated that adult stress 14,15 and environmental insults like altered 57 diet or vinclozolin exposure, or positive factors such as exercise or environmental 58 enrichment can affect small RNA in sperm 16-21 and somatic tissues 22 in the offspring.59Recently, tRNA fragments and their modifications were also found to be affected by 60 nutritional insult, and unmodified or modified sperm small RNA injected into fertilized 61 oocytes could mimic metabolic changes resulting from altered parental diet in the 62 progeny 18,23,24 . These studies therefore suggest that small RNA in sperm can be 63 carrier of heritable information. Here we sought to determine whether long RNA in 64 sperm also contributes to the transmission of the effects of previous exposure. 66 Materials and Methods 68Mice. C57BL/6J mice were housed in a temperature and humidity-controlled facility 69 under a reverse light-dark cycle, and food and water were provided ad libitum. 70 Experimental procedures were performed during the animals' active cycle. All71 experiments were approved by the cantonal veterinary office, Zurich (license 55/12 then 72 57/15).73 74 MSUS paradigm. C57BL/6J primiparous females and males were mated at 2.5-3 75 months of age. Randomly selected dams and litt...

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“…Specific transgenerational benefits of EE exposed fathers have been reported for offspring in rodent models of epilepsy via reduced seizure frequency (Dezsi et al, 2016) and maternal separation, as indicated by a mitigation of anxiety-like behavior (Gapp et al, 2016). Overall, these basic research findings underscore the importance of environmental factors in mediating parental contributions to offspring outcomes through behavioral and potentially epigenetic mechanisms (Yeshurun & Hannan, 2018; described in the next section). This is important to note given that the clinical application of EE in pediatric settings is typically administered by parents (Downs et al, 2018;Morgan et al, 2013Morgan et al, , 2015Purpura et al, 2014;Woo & Leon, 2013;Woo et al, 2015) and not surprisingly, at least for children with autism, therapy is more likely to be beneficial if parents are adherent to the intervention procedures (Aronoff et al, 2016).…”

Section: Harnessing the Environment To Promote Resiliency To Early mentioning

confidence: 77%

Resilience priming: Translational models for understanding resiliency and adaptation to early life adversity

Kentner

Cryan

Brummelte

2018

Developmental Psychobiology

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Despite the increasing attention to early life adversity and its long‐term consequences on health, behavior, and the etiology of neurodevelopmental disorders, our understanding of the adaptations and interventions that promote resiliency and rescue against such insults are underexplored. Specifically, investigations of the perinatal period often focus on negative events/outcomes. In contrast, positive experiences (i.e. enrichment/parental care//healthy nutrition) favorably influence development of the nervous and endocrine systems. Moreover, some stressors result in adaptations and demonstrations of later‐life resiliency. This review explores the underlying mechanisms of neuroplasticity that follow some of these early life experiences and translates them into ideas for interventions in pediatric settings. The emerging role of the gut microbiome in mediating stress susceptibility is also discussed. Since many negative outcomes of early experiences are known, it is time to identify mechanisms and mediators that promote resiliency against them. These range from enrichment, quality parental care, dietary interventions and those that target the gut microbiota.

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Transgenerational epigenetic influences of paternal environmental exposures on brain function and predisposition to psychiatric disorders

Cited by 99 publications

References 116 publications

The developmental basis of disease: Update on environmental exposures and animal models

The developmental basis of disease: Update on environmental exposures and animal models

Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma

Resilience priming: Translational models for understanding resiliency and adaptation to early life adversity

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