Transmission

Previous research assumed that the trauma transmission was mainly caused by the parents' child-rearing behavior, however, it may have been also epigenetically transferred. Epigenetics studies how cellular function is influenced by the regulation of gene expression. An epigenetics study published in 2015 suggested that a parent's experience of trauma may change a child's stress hormone profiles. The theory of trauma transmission via epigenetics has also been researched by other parties. Trauma can be transferred via a repeated environment, triggering the reformation of a gene in each generation; this is the most indirect form of epigenetic imprinting. One's environment and external experiences impact cellular activity and epigenetic processes, making it possible for victims of trauma to pass their symptoms and effects to their children and so on, especially if the environment does not change. However, the epigenome may also be passed through the gametes. For this to occur, the epigenome must be present in the germline. However, the epigenome is extensively reprogrammed during germ cell differentiation and post-fertilization to create totipotent cells, erasing many changes that occur during an individual's lifetime. ^[1] Therefore the best candidates for heritable epigenetic marks are located at repeat/ transposable sequences or regulatory elements that are resistant to reprogramming. ^[2]

Non-coding RNA is currently one of the most investigated epigenetic mechanisms in the study of transgenerational trauma inheritance. Small ncRNAs guide DNA and histone methylation and post-transcriptionally regulate mRNA. ^[3] In C. elegans, starvation-induced stress triggers the expression of small RNAs that cause heritable gene silencing and persist for several generations. These generational effects have been correlated with behavioral phenotypes in some studies. When microRNA (miRNA) from F1 sperm was injected into fertilized oocytes, these offspring exhibited similar phenotypes. ^[2] Although the mechanism of this transmittance across generations is complex, one hypothesis is that piwi-interacting RNA (piRNA) and exogenous RNAi may be involved in a pathway with secondary small RNAs and chromatin regulatory complexes that results in stable transgenerational inheritance. ^[4] DNA methylation is another mechanism studied for transgenerational epigenetic inheritance. 5-methylcytosine (5mC) is the form of methylated DNA linked to gene repression in mammals and N6-Methyladenosineto promotion of activity. Trauma has been shown to alter methylation patterns in the offspring of survivors in various empirical studies, predominantly at the glucocorticoid receptor (NR3C1) gene. ^[5] For DNA methylation to be inherited, it has to be stable enough to undergo mitosis and meiosis, and it must escape the epigenetic reprogramming that occurs during germ cell formation and after fertilization. 5mc in regions of the genome like repeat sequences and rare regulatory elements are resistant to reprogramming. ^[2] However, it has been hard to find methylated regions that are stable over multiple generations, and there has been a lot of discrepancies across studies. These discrepancies may be due to method of methylation analysis used or due to variations in the epigenome between individuals. Recent evidence suggests that histone modifications may also be inherited across generations. Histones tend to be preserved at sites of housekeeping and developmentally regulated genes in sperm but are preserved everywhere in oocytes. ^[2] Although it isn’t confirmed, if changes in the histone modification machinery were to cause phenotypic changes, a second epigenetic mechanism may be involved.

Another major way that stress can be transmitted across generations biologically is through the uterine environment. The gestational stage is a developmentally sensitive stage in an individual’s lifespan. Exposure to harmful stimuli during this stage can have long-lasting, detrimental effects. ^[6] The uterine environment with its unique blend of the mother’s cellular secretions and proteins is a major source of stimuli. ^[7] Empirical evidence has shown that trauma experienced by a mother during pregnancy can affect offspring’s physiology and psychology. ^[5] One possible method of transmission is through transport vesicles transferring amino acids and microRNA from the uterine fluid to the fetus. ^[6] These molecules may then alter gene expression in a way that affects the developmental trajectory of the fetus. Most biological research on transgenerational trauma has focused on the hypothalamic-pituitary-adrenal (HPA) axis, which is the center of the body’s stress response system. One way the HPA axis responds to stress is by triggering the production of glucocorticoids, primarily cortisol. ^[5] Cortisol triggers “fight-or-flight” physiological symptoms like increased blood pressure and heart rate. In animal models, maternal stress and trauma during pregnancy has been shown to reduce the expression of placental enzyme 11B-hydroxysteroid dehydrogenase type 2 (11 β-HSD2), which converts the mother’s cortisol to inactive cortisone. This leads to increased fetal exposure to the mother’s glucocorticoids, which affects the development of glucocorticoid-sensitive systems like the HPA axis. In some studies, abnormal cortisol levels compared to controls and alterations in DNA methylation were observed in infants of mothers who endured trauma while pregnant, particularly in the NR3C1 glucocorticoid receptor gene. ^[7]

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