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The long-term impact of adverse caregiving environments on epigenetic modifications and telomeres.

Blaze J, Asok A, Roth TL - Front Behav Neurosci (2015)

Bottom Line: Early childhood is a sensitive period in which infant-caregiver experiences have profound effects on brain development and behavior.Interestingly, telomeric enzymes and subtelomeric regions are subject to epigenetic modifications-a factor which may play an important role in regulating telomere length and contribute to future mental health.This review will focus on clinical and animal studies that highlight the long-term epigenetic and telomeric changes produced by adverse caregiving in early-life.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychological and Brain Sciences, University of Delaware Newark, DE, USA.

ABSTRACT
Early childhood is a sensitive period in which infant-caregiver experiences have profound effects on brain development and behavior. Clinical studies have demonstrated that infants who experience stress and adversity in the context of caregiving are at an increased risk for the development of psychiatric disorders. Animal models have helped to elucidate some molecular substrates of these risk factors, but a complete picture of the biological basis remains unknown. Studies continue to indicate that environmentally-driven epigenetic modifications may be an important mediator between adverse caregiving environments and psychopathology. Epigenetic modifications such as DNA methylation, which normally represses gene transcription, and microRNA processing, which interferes with both transcription and translation, show long-term changes throughout the brain and body following adverse caregiving. Recent evidence has also shown that telomeres (TTAGGG nucleotide repeats that cap the ends of DNA) exhibit long-term changes in the brain and in the periphery following exposure to adverse caregiving environments. Interestingly, telomeric enzymes and subtelomeric regions are subject to epigenetic modifications-a factor which may play an important role in regulating telomere length and contribute to future mental health. This review will focus on clinical and animal studies that highlight the long-term epigenetic and telomeric changes produced by adverse caregiving in early-life.

No MeSH data available.


Related in: MedlinePlus

Disruptions in infant care produce DNA methylation alterations in the rodent brain. Both maternal deprivation and aberrant care in rodents lead to altered DNA methylation profiles at numerous gene loci important in stress, emotion, and cognition. For example, offspring that experience this stress display hypomethylation of corticotropin releasing hormone (CRH) in the hippocampus, arginine vasopressin (AVP) in the hypothalamus, and pro-opiomelanocortin (Pomc) in the pituitary. Conversely, the same stress produces hypermethylation of the glucocorticoid receptor (gene) in the hippocampus and brain derived neurotrophic factor (Bdnf) in the prefrontal cortex (PFC).
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Figure 1: Disruptions in infant care produce DNA methylation alterations in the rodent brain. Both maternal deprivation and aberrant care in rodents lead to altered DNA methylation profiles at numerous gene loci important in stress, emotion, and cognition. For example, offspring that experience this stress display hypomethylation of corticotropin releasing hormone (CRH) in the hippocampus, arginine vasopressin (AVP) in the hypothalamus, and pro-opiomelanocortin (Pomc) in the pituitary. Conversely, the same stress produces hypermethylation of the glucocorticoid receptor (gene) in the hippocampus and brain derived neurotrophic factor (Bdnf) in the prefrontal cortex (PFC).

Mentions: Later studies revealed prominent methylation alterations in the adult mPFC, dorsal and ventral hippocampus, and central/basolateral nucleus of the amygdala (Blaze et al., 2013; Roth et al., 2014). We have also demonstrated that the epigenetic effects of maltreatment (at least at the level of bdnf DNA methylation and gene expression) can be reversed in the adult rat PFC by zebularine treatment, an inhibitor of DNA methylation (Roth et al., 2009). Finally, we have also highlighted dynamic (i.e., alterations that are short-lived) and later-emerging (not present early in early development but later) DNA methylation alterations following exposure to caregiver maltreatment, effects that are not common in the early-life stress literature (Roth et al., 2009, 2014; Blaze and Roth, 2013; Blaze et al., 2013). For example, while bdnf exon IV PFC methylation was lower in adolescent maltreated-females compared to controls, it was higher in adult maltreated-females (Blaze et al., 2013). While infant and adolescent maltreated-females show higher levels of methylation associated with bdnf IV in the ventral hippocampus, this effect is not present in adults (Roth et al., 2014). While infant and adolescent maltreated-males do not show any changes in methylation associated with bdnf IV in the amygdala, adults show lower levels of methylation (Roth et al., 2014). Further, we have also observed lower levels of mRNA for key epigenetic regulatory genes in maltreated-animals when adult, an effect not detected earlier in development (Blaze and Roth, 2013). Together, our data and that of others make it clear that early-life stress in the form of disrupted caregiving has the capacity to alter central nervous system DNA methylation and gene expression (Figure 1). But, are these changes detectable in the periphery?


The long-term impact of adverse caregiving environments on epigenetic modifications and telomeres.

Blaze J, Asok A, Roth TL - Front Behav Neurosci (2015)

Disruptions in infant care produce DNA methylation alterations in the rodent brain. Both maternal deprivation and aberrant care in rodents lead to altered DNA methylation profiles at numerous gene loci important in stress, emotion, and cognition. For example, offspring that experience this stress display hypomethylation of corticotropin releasing hormone (CRH) in the hippocampus, arginine vasopressin (AVP) in the hypothalamus, and pro-opiomelanocortin (Pomc) in the pituitary. Conversely, the same stress produces hypermethylation of the glucocorticoid receptor (gene) in the hippocampus and brain derived neurotrophic factor (Bdnf) in the prefrontal cortex (PFC).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4389567&req=5

Figure 1: Disruptions in infant care produce DNA methylation alterations in the rodent brain. Both maternal deprivation and aberrant care in rodents lead to altered DNA methylation profiles at numerous gene loci important in stress, emotion, and cognition. For example, offspring that experience this stress display hypomethylation of corticotropin releasing hormone (CRH) in the hippocampus, arginine vasopressin (AVP) in the hypothalamus, and pro-opiomelanocortin (Pomc) in the pituitary. Conversely, the same stress produces hypermethylation of the glucocorticoid receptor (gene) in the hippocampus and brain derived neurotrophic factor (Bdnf) in the prefrontal cortex (PFC).
Mentions: Later studies revealed prominent methylation alterations in the adult mPFC, dorsal and ventral hippocampus, and central/basolateral nucleus of the amygdala (Blaze et al., 2013; Roth et al., 2014). We have also demonstrated that the epigenetic effects of maltreatment (at least at the level of bdnf DNA methylation and gene expression) can be reversed in the adult rat PFC by zebularine treatment, an inhibitor of DNA methylation (Roth et al., 2009). Finally, we have also highlighted dynamic (i.e., alterations that are short-lived) and later-emerging (not present early in early development but later) DNA methylation alterations following exposure to caregiver maltreatment, effects that are not common in the early-life stress literature (Roth et al., 2009, 2014; Blaze and Roth, 2013; Blaze et al., 2013). For example, while bdnf exon IV PFC methylation was lower in adolescent maltreated-females compared to controls, it was higher in adult maltreated-females (Blaze et al., 2013). While infant and adolescent maltreated-females show higher levels of methylation associated with bdnf IV in the ventral hippocampus, this effect is not present in adults (Roth et al., 2014). While infant and adolescent maltreated-males do not show any changes in methylation associated with bdnf IV in the amygdala, adults show lower levels of methylation (Roth et al., 2014). Further, we have also observed lower levels of mRNA for key epigenetic regulatory genes in maltreated-animals when adult, an effect not detected earlier in development (Blaze and Roth, 2013). Together, our data and that of others make it clear that early-life stress in the form of disrupted caregiving has the capacity to alter central nervous system DNA methylation and gene expression (Figure 1). But, are these changes detectable in the periphery?

Bottom Line: Early childhood is a sensitive period in which infant-caregiver experiences have profound effects on brain development and behavior.Interestingly, telomeric enzymes and subtelomeric regions are subject to epigenetic modifications-a factor which may play an important role in regulating telomere length and contribute to future mental health.This review will focus on clinical and animal studies that highlight the long-term epigenetic and telomeric changes produced by adverse caregiving in early-life.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychological and Brain Sciences, University of Delaware Newark, DE, USA.

ABSTRACT
Early childhood is a sensitive period in which infant-caregiver experiences have profound effects on brain development and behavior. Clinical studies have demonstrated that infants who experience stress and adversity in the context of caregiving are at an increased risk for the development of psychiatric disorders. Animal models have helped to elucidate some molecular substrates of these risk factors, but a complete picture of the biological basis remains unknown. Studies continue to indicate that environmentally-driven epigenetic modifications may be an important mediator between adverse caregiving environments and psychopathology. Epigenetic modifications such as DNA methylation, which normally represses gene transcription, and microRNA processing, which interferes with both transcription and translation, show long-term changes throughout the brain and body following adverse caregiving. Recent evidence has also shown that telomeres (TTAGGG nucleotide repeats that cap the ends of DNA) exhibit long-term changes in the brain and in the periphery following exposure to adverse caregiving environments. Interestingly, telomeric enzymes and subtelomeric regions are subject to epigenetic modifications-a factor which may play an important role in regulating telomere length and contribute to future mental health. This review will focus on clinical and animal studies that highlight the long-term epigenetic and telomeric changes produced by adverse caregiving in early-life.

No MeSH data available.


Related in: MedlinePlus