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Transgenerational stress inheritance

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Transgenerational stress inheritance is the transmittance of deleterious effects of stress in parents to their offspring through epigenetic mechanisms.

Stress-exposure in parents lead to possible negative outcomes in future generations through transgenerational mechanisms. Stress-induced epigenetic alterations, particularly in regards to programmed HPA axis modifications, persists into future generations, impacting stress reactivity and related behaviors. Early life experiences, even when generations removed, can permanently alter gene expression, endocrine function, metabolism, and epigenetic modification of DNA.[1]

Epigenetic modification in response to stress results in molecular and genetic alterations that in turn results in mis-regulated or silenced genes. For example, epigenetic modifications to the gene BDNF (brain derived neurotrophic factor) as a result of stress can be passed on to offspring. Chronic variable stress induces offspring hypothalamic gene expression modifications, including elevated methylation levels of the BDNF promoter in the hippocampus.[2] Maternal separation and postnatal maternal abuse also increases DNA methylation at regulatory regions of BDNF genes in the prefrontal cortex and hippocampus, leading to potential stress vulnerability in future generations.[3]

Stress and the HPA axis

Gene regulation as it relates to the HPA axis has been implicated in transgenerational stress effects. Environmental prenatal stress exposure, for example, alters glucocorticoid receptor gene expression, gene function, and future stress response in F1 and F2 generations.[4][1] Maternal care likewise contributes to HPA-related epigenetic modifications. Epigenetic re-programming of gene expression alters stress response in offspring later in life when exposed to decreased maternal care. Inattentive mothering has led to increased levels of gene methyl marks, compared to attentive mothers.[4] Female offspring with low licking-grooming mothers have decreased promoter methylation and increased histone acetylation, leading to increased glucocorticoid receptor expression.[4] Epigenetic modifications as a result of absent maternal care lead to decreased estrogen receptor alpha expression, due to increased methylation at the gene’s promoter.[4]

Paternal stress inheritance

Arguably the most interesting example of transgenerational stress inheritance in animal work is the study of offspring born of stressed male rodents, as rodent offspring are fostered mono-parentally and have no direct exposure with their fathers. Recent studies demonstrate that direct injection of sperm RNAs to wild type oocytes results in reproducible stress-related modifications.[5] Small non-coding RNAs may serve as a potential mechanism for stress-related genetic changes in offspring. Mouse models of traumatic early life stress exposure result in microRNA modifications and subsequent differences in gene expression and metabolic function.[5] This effect was reproducible by sperm RNA injection, leading to similar gene modifications in future generations. The novelty of this research suggests direct mechanisms capable of altering epigenetics by stress-related factors.

Phenotypic effects

Recent animal research has investigated transgenerational inheritance as it relates to developing offspring behavior. Early life experiences and environmental factors may lead to epigenetic modification at specific gene loci, leading to altered neuronal plasticity, function, and subsequent behavior.[3] Evidence suggests chromatin remodeling in rodent offspring and altered gene expression within the limbic brain regions that may contribute to depression, stress, and anxiety-related disorders in future generations.[3] Variations in maternal care, such as maternal licking and grooming as previously discussed, indicates reduced HPA axis reactivity in subsequent generations.[4] Such HPA axis modifications lead to decreased anxiety-like behavior in adulthood and increased glucocorticoid receptor levels leading to negative feedback on HPA reactivity and further behavioral modifications.[4][1] Rodent models of maternal separation also reveal increased depressive-like behavior in offspring, decreased stress coping abilities, and changes in DNA methylation.[1]

Stress inheritance in humans

Human models illustrating transgenerational stress effects are limited due to relatively novel exploration of the topic of epigenetics as well as lengthy follow-up intervals required for multi-generational studies. Several models, however, have investigated the role of epigenetic inheritance and transgenerational stress effects. Transgenerational stress in humans, as in animal models, induces effects influencing social behavior, reproductive success, cognitive ability, and stress response.[2] Similar to animal models, human studies have investigated the role of epigenetics and transgenerational inheritance molecularly as it relates to the HPA system. Prenatal influences, such as emotional stress, nutrition depravation, toxin exposure, hypoxia, increased maternal HPA activity, and cortisol levels may activate or affect HPA axis activity of offspring, despite placental barrier.[6]

Biological vulnerability and HPA axis alterations may be observed after maternal epigenetic programing during pregnancy, leading to similar modifications in future generations.[7] Child abuse exposure, for example, is associated with lower baseline infant cortisol levels as well as modified HPA axis function. Human studies investigating PTSD and its effects on offspring have illustrated similar molecular and HPA axis modification and function.[8] PTSD patients who experienced trauma from genocides or terrorist attacks frequently exhibited aggressive or neglectful behavior toward offspring during critical developmental periods, possibly contributing to permanent glucocorticoid deregulation in offspring.[7] PTSD mothers and children illustrate lower basal cortisol levels and glucocorticoid receptors and increased mineralcorticoid receptors when exposed to stress.[8] Therefore, developmental experiences, such as stress exposure, may have critical effects on neuromodulatory mechanisms transgenerationally.[6]

Strong relationships between maternal care and subsequent epigenetic modification in offspring, similar to that found in animal models, has been observed in humans. Severe emotional trauma in the mother, for example, often leads to modified methylation patterns of DNA in subsequent offspring generations.[9] PTSD exposed offspring illustrate epigenetic modifications similar to that seen in PTSD mothers, with an increased NR3C2 methylation in exon 1 and increased CpG methylation in the NR3C2 coding sequence, leading to alterations in mineralcorticoid receptor gene expression.[8] Additionally, investigation of post mortem hippocampal tissue indicates decreased levels of neuron-specific glucocorticoid receptor mRNA and decreased DNA methylation in promoter regions among suicidal individuals with lifelong stress and/or abuse exposure.

Epigenetic mechanisms as a result of early life stress may be responsible for neuronal and synaptic alterations in the brain. Developmental stress exposure has been shown to alter brain structure and behavioral functions in adulthood. Evidence of decreased complexity in the CA1 and CA3 region of the hippocampus in terms of dendritic length and spine density after early-life stress exposure indicates transgenerational stress inheritance.[3] Therefore, environmental and experience-dependent synaptic reorganization and structure modifications may lead to increased stress vulnerability and brain dysfunction in future generations.[3]

References

  1. ^ a b c d Matthews SG, Phillips DI (January 2012). "Transgenerational inheritance of stress pathology". review. Experimental Neurology. 233 (1): 95–101. doi:10.1016/j.expneurol.2011.01.009. PMID 21281632.
  2. ^ a b Gudsnuk K, Champagne FA (2012). "Epigenetic influence of stress and the social environment". review. ILAR Journal. 53 (3–4): 279–88. doi:10.1093/ilar.53.3-4.279. PMID 23744967.
  3. ^ a b c d e Vialou V, Feng J, Robison AJ, Nestler EJ (2013). "Epigenetic mechanisms of depression and antidepressant action". review. Annual Review of Pharmacology and Toxicology. 53: 59–87. doi:10.1146/annurev-pharmtox-010611-134540. PMID 23020296.
  4. ^ a b c d e f Szyf M, Weaver I, Meaney M (July 2007). "Maternal care, the epigenome and phenotypic differences in behavior". review. Reproductive Toxicology. 24 (1): 9–19. doi:10.1016/j.reprotox.2007.05.001. PMID 17561370.
  5. ^ a b Hodes GE, Walker DM, Labonté B, Nestler EJ, Russo SJ (January 2017). "Understanding the epigenetic basis of sex differences in depression". review. Journal of Neuroscience Research. 95 (1–2): 692–702. doi:10.1002/jnr.23876. PMID 27870456.
  6. ^ a b Li SC (November 2013). "Neuromodulation and developmental contextual influences on neural and cognitive plasticity across the lifespan". review. Neuroscience and Biobehavioral Reviews. 37 (9 Pt B): 2201–8. doi:10.1016/j.neubiorev.2013.07.019. PMID 23973556.
  7. ^ a b Yahyavi ST, Zarghami M, Marwah U (2013). "A review on the evidence of transgenerational transmission of posttraumatic stress disorder vulnerability". review. Revista Brasileira De Psiquiatria. 36 (1): 89–94. doi:10.1590/1516-4446-2012-0995. PMID 24402183.
  8. ^ a b c Daskalakis NP, Cohen H, Nievergelt CM, Baker DG, Buxbaum JD, Russo SJ, Yehuda R (October 2016). "New translational perspectives for blood-based biomarkers of PTSD: From glucocorticoid to immune mediators of stress susceptibility". review. Experimental Neurology. 284 (Pt B): 133–140. doi:10.1016/j.expneurol.2016.07.024. PMID 27481726.
  9. ^ Kellermann NP (2013). "Epigenetic transmission of Holocaust trauma: can nightmares be inherited?". review. The Israel Journal of Psychiatry and Related Sciences. 50 (1): 33–9. PMID 24029109.


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