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

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.epigenetics | biomarker | BDNF | bisphenol A | early life

Maternal prenatal depressive symptoms predict infantNR3C11F andBDNFIV DNA methylation

“…26 While previous studies have indicated increased NR3C1 1F DNA methylation in cord blood samples at birth, here we illustrate that increased NR3C1 1F DNA methylation associated with prenatal depression persists into the postnatal period in infant buccal cells, independent of postnatal depressed maternal mood, and is particularly evident in male infants. Previous studies in humans have not examined the question of sex differences in environmentally-induced NR3C1 1F DNA methylation, [23][24][25][26][27] and although animal studies have primarily examined these effects exclusively in males, there is emerging evidence suggestive of a particular epigenetic vulnerability in males in response to prenatal 33 and postnatal 35 experiences. These findings compliment a body of literature, which suggests that males may more be at risk of adverse outcomes compared to females as a result of exposure to maternal distress during pregnancy.…”

“…41 Although species differences in the regulation of this gene may account for our findings, recent analyses indicate increased DNA methylation in human cord blood samples within the CREB binding site associated with elevated in utero BPA exposure, which is consistent with the direction of reported effects in rodents. 33 An alternative explanation for these findings may involve the biphasic epigenetic changes that have been observed to occur across development. 42 The decreased BDNF methylation we observe in infants exposed to prenatal depression could reflect a molecular basis for the rapid maturation that may be induced by adverse prenatal events.…”

“…The regions of interest within NR3C1 and BDNF were chosen based on previous research that has identified these areas as susceptible to epigenetic regulation following early exposure to adverse environmental influences. 23,26,28,33 Pyrosequencing was performed using a PyroMark Q24 pyrosequencer (Qiagen Ltd, USA) with specific pyrosequencing primers. Before sample analysis, each pyrosequencing assay was validated using standard curves by analyzing 0, 20, 40, 60, 80, and 100% methylated human genomic DNA standards (Fig.…”

“…[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. 33 However, the impact of prenatal psychological distress on infant BDNF IV DNA methylation has yet to be explored.…”

Differential Expression of Long Noncoding RNAs And Targeted MRNAs in Peripheral Blood Lymphocytes of Neurodevelopmental Disorders

“…Expression of this gene is reduced in Alzheimer's, Parkinson's, and Huntington's disease patients. Nowadays, this gene has been demonstrated to possibly be involved in the regulation of the stress response and in the biology of mood disorders [27,28]. It has been hypothesized that BDNF is involved in the pathogenesis of ADHD, although the study results are controversial.…”