Epigenetic modifications and transgenerational inheritance in women victims of violence (EWVV)

Abstract

Female survivors of physical or psychological violence, including sexual violence, report significant long-term consequences defined as post-traumatic stress disorder (PTSD). Among these, depression, affective difficulties, anomalous behaviours, and worsened reproductive health may also affect offspring through transgenerational transmission involving primordial germ cells (PGCs) and/or through social transmission and acquisition of behavioural patterns from parent(s) to children. The concept of epigenomic modification involves several molecular targets that are sensitive to environmental stressors, which tune gene activity and expression. DNA methylation, histone acetylation, ncRNAs, telomere attrition, and mitochondrial dysfunction cooperate in maintaining homeostasis and may affect genes involved in key pathways, such as the hypothalamic-pituitary-adrenal axis, mediating the integrated homeostatic response to stressors. The most investigated genes were those implicated in neuroendocrine stress responses; dopamine, norepinephrine, and serotonin signalling; apoptosis; insulin secretion; neuroplasticity; reproduction; foetal growth; and cancer (e.g. MAOA, BRSK2, ADCYAP1, BDNF, DRD2, IGF2, H19). Additional investigated genes were those involved in other important functions, such as neuropeptide binding, immunoregulation, histone deacetylase/demethylase, inflammatory response, and serotonin uptake, yielding interesting but preliminary or not completely replicated findings (e.g. CRHR1, FKBP5, KDM1A, NR3C1, PRTFDC1, and SLC6A4). The assumption that epigenetic traits induced by negative experiences can be reversed by appropriate social, psychological, and pharmacological interventions has prompted the scientific community to investigate the relationship between epigenetic mechanisms and physical and psychological violence. This can help to identify direct links or epigenetic marks useful for optimizing personalized interventions encompassing the genetic, neuropsychiatric, social, and forensic medicolegal fields. Future research should be conducted with extreme caution to evaluate the long-term effects of such strategies and assess whether the immediate observed effects are maintained.

Keywords: PTSD; coping; epidrugs; epigenetics; gender-based violence; methylome; resilience; stress response; women violence.

Graphical Abstract

Figure 1.

Landscape of normal and aberrant epigenetic modifications occurring from fertilization to adulthood: periconception, pregnancy, perinatal, and infancy (first 1000 days of life). On the left, DNA demethylation processes occurring during fertilization. Continuous pink line and blue dashed line indicate the female and male hemigenomes, respectively. De novo global genome methylation during the blastocyst phase is indicated by a dark dashed line. Modified from [94] created using BioRender.com.

Figure 2.

Intergenerational and transgenerational inheritance after exposure to environmental stressors. If a gestating mother (F0, right side) is directly exposed to environmental stressors, exposure may also affect the developing foetus (yellow) and its developing germ line (green), resulting in intergenerational effects (possible inheritance) in the F1 and F2 generations, since the affected generations were directly exposed. The third generation (F3, blue) is the first nondirectly exposed generation; therefore, an observed phenotype in F3 (or beyond) could result from transgenerational epigenetic inheritance. If a male or nonpregnant female (F0, left side) is directly exposed to environmental stressors, germ cells may also be directly affected, influencing the F1 generation (green). The F2 generation would be the first not directly exposed to trauma/stressors, and the appearance of the phenotype in F2 (or beyond) could result from transgenerational epigenetic inheritance. Nonetheless, to confirm transgenerational epigenetic inheritance, it is essential to exclude the effect of other confounding factors for a germline-mediated mechanism. Created using BioRender.com.

Figure 3.

Snapshot of the vicious relationships among violence, epigenetics, and health. Violence against women may have direct and indirect effects on their psychological and physical status, well-being, and health. The resulting epigenetic modifications may (a) affect DNA structure and functionality, putting women’s health at risk; (b) alter methylation and acetylation of the relevant epigenetic mechanisms involved in traumatic stress; (c) generate transgenerational trauma effects, including traits of depression, anxiety, helplessness, and anger in newborns; (d) favour eating disorders and increase the risk of obesity and diabetes; (e) cause chronic stress response, HPA activation, high oxidative stress, and inflammation, increasing the risk of chronic diseases and death; and (f) favour the engagement of harmful behaviours. Created using BioRender.com.