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. 2015 Jun 2;112(22):6807-13.
doi: 10.1073/pnas.1408355111. Epub 2014 Nov 10.

DNA Methylation of BDNF as a Biomarker of Early-Life Adversity

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Free PMC article

DNA Methylation of BDNF as a Biomarker of Early-Life Adversity

Marija Kundakovic et al. Proc Natl Acad Sci U S A. .
Free PMC article

Abstract

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.

Keywords: BDNF; biomarker; bisphenol A; early life; epigenetics.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Design of the animal study.
Fig. 2.
Fig. 2.
Sex-specific changes in hippocampal Bdnf gene expression and DNA methylation at P28 after prenatal BPA exposure. Gene expression analysis of (A) Bdnf, (B) Grin2b, and (C) Gadd45b in the P28 hippocampus of males and females prenatally exposed to BPA (200 µg/kg per day) or vehicle (CTL). Schematic representation of transcriptionally relevant CpG sites in Bdnf IV (D) and Grin2b (E) promoters in the vicinity of CREB-binding sites (purple box). BPA induced a sex-specific effect on DNA methylation of Bdnf IV CpG2 (F) that was primarily driven by hypermethylation induced in males (G). No CpG methylation changes were observed in the Grin2b promoter at P28 (H). *P < 0.05, **P < 0.01.
Fig. 3.
Fig. 3.
Lasting Bdnf gene expression and DNA methylation changes in the P60 hippocampus of BPA-treated animals. Gene expression analysis of (A) Bdnf, (B) Grin2b, (C) Gadd45b, and (D) Dnmt1 in the P60 hippocampus of males and females prenatally exposed to BPA (200 µg/kg per day) or vehicle (CTL). BPA induced sex-specific effect on DNA methylation of Bdnf IV CpG sites 3 and 4 (E) that were primarily driven by hypermethylation induced in males (G and H) as well as on Grin2b sites 1 and 2 (F) that were primarily driven by hypermethylation in males (I and J). Sex-specific changes in gene expression and DNA methylation correspond with BPA-induced changes in the novel object recognition test performed before animals were killed for molecular analyses (K). *P < 0.05, **P < 0.01, ***P < 0.001.
Fig. 4.
Fig. 4.
Bdnf DNA methylation patterns in the human and mouse blood mirror Bdnf DNA methylation patterns in the mouse hippocampus. In mice, BPA induced sex-specific effect on DNA methylation of Bdnf IV CpG4 in the blood (A) that was primarily driven by hypermethylation induced in males (B). CpG4 methylation in the blood and CpG4 methylation in the hippocampus are significantly correlated (C). The sequence of the human BDNF promoter IV having 96% homology with the mouse Bdnf IV (CREB-binding site; purple box) (D). In the human cord blood, high maternal BPA levels are associated with altered DNA methylation of two CpG sites in the BDNF IV promoter (D) (low BPA < 1 µg/L; high BPA > 4 µg/L).
Fig. 5.
Fig. 5.
BDNF as biomarker of early-life adversity. Various early-life exposures, such as prenatal stress, maternal toxicological exposures, and maternal neglect, can induce lasting epigenetic changes in the BDNF gene in the brain that contribute to behavioral vulnerability and psychiatric risk. These changes may be reflected in the peripheral blood starting from early life and can be used to predict psychiatric risk.

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