Placental CpG Methylation on HPA Axis Genes Caused by Conflict-Zone Stress
Introduction. When pregnant people experience stress, the glucocorticoids they produce to manage their own stress response cross the placenta and enact epigenetic changes on fetal neurodevelopment.1-4 These epigenetic changes include CpG methylation and are prominent in the hypothalamic-pituitary-adrenocortical (HPA) axis,1-4 leading to altered responses to stress throughout the fetus’ life.1,2,4-6 As the hormones cross the placenta, they cause methylation changes in the placental genome similar to those in the fetal brain,7 thereby leaving a sort of record of their effects in the placental methylome.1-4 Studies have shown that different types of stress induce different patterns of methylation changes,1,4 and variations in responses to treatment based on different methylation patterns have been observed.8 While research has evaluated stress-induced methylation changes in pregnant populations and in individuals exposed to conflict-zone stress, few studies have investigated pregnant individuals experiencing conflict-zone stress. One study found that exposure to conflict-zone stress during pregnancy was associated with methylation in HPA axis genes CRH, CRHBP, NR3C1, and FKBP5, low birth weight, and altered stress-response behaviors in neonates.5 Possible Treatment Directions. There is currently no research investigating effective treatment plans in this population. Therefore, future research should evaluate possible treatments by investigating both prenatal and postnatal options. Treatments should be evaluated for application to specific methylation patterns, and they must be evaluated for potential harm to the fetus or breastfeeding child. One study showed that using coping mechanisms during stress reduced the amount of vasopressin released in the hypothalamus to levels comparable to the non-stress control, suggesting a potential reduction in the amount of glucocorticoids that crossed the placenta and altered fetal neuodevelopment.9 Additionally, studies found that prenatal SSRIs reversed stress-induced changes in maternal behavior,10,11 reduced effects on fetal neurodevelopment,10 and decreased anxiety and depression behaviors in male offspring.11 Postnatal treatments may address the parent and child’s needs separately. One study found that dexamethasone reversed fold changes in FKBP5 mRNA when given several days after stress, and dexamethasone also reduced fear extinction by altering methylation to levels comparable to the non-stress control.12 In children with anxiety disorders, one study indicated that cognitive behavioral therapy reduced methylation in FKBP5 genes.13 Conclusions. Research is necessary to tailor treatment plans to the needs of pregnant individuals experiencing conflict-zone stress. Although various treatment methods that have been successful in similar treatment groups provide good places to start, they must be evaluated for effectiveness in patients with conflict-zone stress-specific methylation patterns.
- Lester BM, Marsit CJ. Epigenetic mechanisms in the placenta related to infant neurodevelopment. 2018;10(3): 321-333. doi: 10.2217/epi-2016-0171. Accessed February 27, 2020.
- Chan JC, Nugent BM, Bale TL. Parental advisory: maternal and paternal stress can impact offspring neurodevelopment. Biol Psychiatry. 2018;83(10): 886-894. doi: 1016/j.biopsych.2017.10.005. Accessed February 27, 2020.
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- Kertes DA, Kamin HS, Hughes DA, et al. Prenatal maternal stress predicts methylation of genes regulating the hypothalamic-pituitary-adrenocortical system in mothers and newborns in the democratic republic of Congo. Child Dev. 2016;87(1): 61-72. doi: 10.1111/cdev.12487. Accessed February 27, 2020.
- Paquette AG, Houseman EA, Green BB, et al. Regions of variable DNA methylation in human placenta associated with newborn neurobehavior. 2016;11(8): 603-613. doi: 10.1080/15592294.2016.1195534. Accessed February 28, 2020.
- Meakin CJ, Martin EM, Fry RC, et al. Placental CpG methylation of HPA-axis genes is associated with cognitive impairment at age 10 among children born extremely preterm. Horm Behav. 2018;29-35. doi: 10.1016/j.yhbeh.2018.02.007. Accessed April 6, 2020.
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- Roberts S, Keers R, Breen G et al. DNA methylation of FKBP5 and responseto exposure-based psychological therapy. Am J Med Genet B Neuropsychiatr Genet. 2019 ;180(2):150-158. doi: 10.1002/ajmg.b.32650. Accessed April 6, 2020.
- Kubo K, Kotachi M, Suzuki A, et al. Chewing during prenatal stress prevents prenatal stress-induced suppression of neurogenesis, anxiety-like behavior and learning deficits in mouse offspring. Int J Med Sci. 2018;15(9):849-858. doi: 10.7150/ijms.25281. Accessed April 6, 2020.
- Velasquez JC, Zhao Q, Chan Y, et al. In UteroExposure to Citalopram Mitigates Maternal Stress Effects on Fetal Brain Development. ACS Chem Neurosci. 2019;10(7):3307-3317. doi: 10.1021/acschemneuro.9b00180. Accessed April 6, 2020.
- Salari AA, Fatehi-Gharehlar L, Motayagheni N et al. Fluoxetine normalizes the effects of prenatal maternal stress on depression- and anxiety-like behaviors in mouse dams and male offspring. Behav Brain Res. 2016;311:354-367. doi: 10.1016/j.bbr.2016.05.062. Accessed April 6, 2020.
- Sawamura T, Klengel T, Armario A et al. Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala. 2016;41(3):832-46. doi: 10.1038/npp.2015.210. Accessed April 6, 2020.
- Roberts S, Keers R, Lester KJ, et al. HPA axis related genes and response to psychological therapies: genetics and epigenetics. Depress Anxiety. 2015;32(12), 861-870. doi: 10.1002/da.22430. Accessed February 28, 2020.