Prenatal stress decreases<i>Bdnf</i>expression and increases methylation of<i>Bdnf</i>exon IV in rats

Boersma, Gretha J.; Lee, Richard S.; Cordner, Zachary A.; Ewald, Erin R.; Purcell, Ryan H.; Moghadam, Alexander A.; Tamashiro, Kellie L.K.

doi:10.4161/epi.27558

Cited by 159 publications

(123 citation statements)

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“…However, persistent epigenetic changes in BDNF do not seem to be specific to prenatal BPA or male offspring because comparable epigenetic effects have been observed in both sexes in response to other environmental exposures associated with behavioral and psychiatric risk, including prenatal stress (24), earlylife maternal neglect (22), and perinatal methylmercury exposure (23). These findings suggest that a BDNF DNA methylation signature may be a hallmark of early-life adversity.…”

Section: Discussionmentioning

confidence: 76%

“…We examined two genes that have been associated with neuronal plasticity and psychopathology and are known to be epigenetically regulated in response to environmental exposures: brain-derived neurotrophic factor (Bdnf) (21)(22)(23)(24) and NMDA receptor 2b subunit (Grin2b) (25,26). In addition, we also examined expression of the epigenetic regulators implicated in DNA (de) methylation in the brain: growth arrest and DNA damage-inducible beta (Gadd45b) (27) at P28 and P60, and DNA methyltransferases 1 (Dnmt1) and -3a (Dnmt3a) (28) at P60.…”

Section: Resultsmentioning

confidence: 99%

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DNA methylation of BDNF as a biomarker of early-life adversity

Kundaković

Gudsnuk

Herbstman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

368

244

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Early-life adversity increases the risk for psychopathology in later life. The underlying mechanism(s) is unknown, but epigenetic variation represents a plausible candidate. Early-life exposures can disrupt epigenetic programming in the brain, with lasting consequences for gene expression and behavior. This evidence is primarily derived from animal studies, with limited study in humans due to inaccessibility of the target brain tissue. In humans, although there is evidence for DNA methylation changes in the peripheral blood of psychiatric patients, a fundamental question remains as to whether epigenetic markers in the blood can predict epigenetic changes occurring in the brain. We used in utero bisphenol A (BPA) exposure as a model environmental exposure shown to disrupt neurodevelopment and exert long-term effects on behavior in animals and humans. We show that prenatal BPA induces lasting DNA methylation changes in the transcriptionally relevant region of the Bdnf gene in the hippocampus and blood of BALB/c mice and that these changes are consistent with BDNF changes in the cord blood of humans exposed to high maternal BPA levels in utero. Our data suggest that BDNF DNA methylation in the blood may be used as a predictor of brain BDNF DNA methylation and gene expression as well as behavioral vulnerability induced by early-life environmental exposure. Because BDNF expression and DNA methylation are altered in several psychiatric disorders that are associated with early-life adversity, including depression, schizophrenia, bipolar disorder, and autism, BDNF DNA methylation in the blood may represent a novel biomarker for the early detection of psychopathology.epigenetics | biomarker | BDNF | bisphenol A | early life

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Section: Discussionmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

DNA methylation of BDNF as a biomarker of early-life adversity

Kundaković

Gudsnuk

Herbstman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

368

244

View full text Add to dashboard Cite

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“…The mechanisms by which early life experience, especially stress, is able to program brain development seem to involve epigenetic modulation of individual genes or large gene clusters. As an example, adult male mice exposed to early prenatal stress show altered expression and DNA methylation in CRF, glucocorticoid receptors (Mueller and Bale, 2008;Nemeroff, 1992) or BDNF (Boersma et al, 2013). Since recent studies have shown that methylation plays a pivotal role in the onset of puberty in female rodent (Ojeda and Lomniczi, 2014), one can hypothesize that early exposure to stress could alter methylationmediated programming of puberty.…”

Section: Stress and Timing Of Puberty: Mechanisms Of Actionmentioning

confidence: 99%

Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: Revision of human observations and mechanistic insight from rodents

Parent

Franssen

Fudvoye

et al. 2015

Frontiers in Neuroendocrinology

160

140

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Puberty presents remarkable individual differences in timing reaching over 5 years in humans. We put emphasis on the two edges of the age distribution of pubertal signs in humans and point to an extended distribution towards earliness for initial pubertal stages and towards lateness for final pubertal stages. Such distortion of distribution is a recent phenomenon. This suggests changing environmental influences including the possible role of nutrition, stress and endocrine disruptors. Our ability to assess neuroendocrine effects and mechanisms is very limited in humans. Using the rodent as a model, we examine the impact of environmental factors on the individual variations in pubertal timing and the possible underlying mechanisms. The capacity of environmental factors to shape functioning of the neuroendocrine system is thought to be maximal during fetal and early postnatal life and possibly less important when approaching the time of onset of puberty.

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“…28 In animal studies, maternal stress during pregnancy induces increased bdnf promoter IV DNA methylation and decreased BDNF expression in the amygdala and hippocampus in offspring that persist into adulthood. 29 Persistent epigenetic changes in bdnf, within the cortex of offspring, are also observed in response to abusive caregiving during the postnatal period. [29][30][31][32] We have recently found that increased BDNF promoter IV DNA methylation in peripheral blood may be a significant biomarker of prenatal adversity that is relevant for both animals and humans.…”

Section: Introductionmentioning

confidence: 99%

Maternal prenatal depressive symptoms predict infantNR3C11F andBDNFIV DNA methylation

et al. 2015

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Abbreviations: BDNF, gene encoding the brain-derived neurotrophic factor protein, BPA, bisphenol A, GR, glucocorticoid receptor, HPA, hypothalamic-pituitary adrenal, NR3C1, gene encoding the glucocorticoid receptor.Prenatal maternal psychological distress increases risk for adverse infant outcomes. However, the biological mechanisms underlying this association remain unclear. Prenatal stress can impact fetal epigenetic regulation that could underlie changes in infant stress responses. It has been suggested that maternal glucocorticoids may mediate this epigenetic effect. We examined this hypothesis by determining the impact of maternal cortisol and depressive symptoms during pregnancy on infant NR3C1 and BDNF DNA methylation. Fifty-seven pregnant women were recruited during the second or third trimester. Participants self-reported depressive symptoms and salivary cortisol samples were collected diurnally and in response to a stressor. Buccal swabs for DNA extraction and DNA methylation analysis were collected from each infant at 2 months of age, and mothers were assessed for postnatal depressive symptoms. Prenatal depressive symptoms significantly predicted increased NR3C1 1F DNA methylation in male infants (b D 2.147, P D 0.044). Prenatal depressive symptoms also significantly predicted decreased BDNF IV DNA methylation in both male and female infants (b D ¡3.244, P D 0.013). No measure of maternal cortisol during pregnancy predicted infant NR3C1 1F or BDNF promoter IV DNA methylation. Our findings highlight the susceptibility of males to changes in NR3C1 DNA methylation and present novel evidence for altered BDNF IV DNA methylation in response to maternal depression during pregnancy. The lack of association between maternal cortisol and infant DNA methylation suggests that effects of maternal depression may not be mediated directly by glucocorticoids. Future studies should consider other potential mediating mechanisms in the link between maternal mood and infant outcomes.

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Prenatal stress decreasesBdnfexpression and increases methylation ofBdnfexon IV in rats

Cited by 159 publications

References 50 publications

DNA methylation of BDNF as a biomarker of early-life adversity

DNA methylation of BDNF as a biomarker of early-life adversity

Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: Revision of human observations and mechanistic insight from rodents

Maternal prenatal depressive symptoms predict infantNR3C11F andBDNFIV DNA methylation

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