Abstract
While biological alterations associated with childhood maltreatment (CM) have been found in affected individuals, it remains unknown to what degree these alterations are biologically transmitted to the next generation. We investigated intergenerational effects of maternal CM on DNA methylation and gene expression in N = 113 mother-infant dyads shortly after parturition, additionally accounting for the role of the FKBP5 rs1360780 genotype. Using mass array spectrometry, we assessed the DNA methylation of selected stress-response-associated genes (FK506 binding protein 51 [FKBP5], glucocorticoid receptor [NR3C1], corticotropin-releasing hormone receptor 1 [CRHR1]) in isolated immune cells from maternal blood and neonatal umbilical cord blood. In mothers, CM was associated with decreased levels of DNA methylation of FKBP5 and CRHR1 and increased NR3C1 methylation, but not with changes in gene expression profiles. Rs1360780 moderated the FKBP5 epigenetic CM-associated regulation profiles in a gene × environment interaction. In newborns, we found no evidence for any intergenerational transmission of CM-related methylation profiles for any of the investigated epigenetic sites. These findings support the hypothesis of a long-lasting impact of CM on the biological epigenetic regulation of stress-response mediators and suggest for the first time that these specific epigenetic patterns might not be directly transmitted to the next generation.
Highlights
Childhood maltreatment (CM) is so far an underestimated global phenomenon present in all societies and social classes
Mounting evidence suggests that childhood maltreatment (CM) is associated with alterations in DNA methylation within the glucocorticoid receptor gene (NR3C1)[9,10,11,12,13] and its regulatory co-chaperone FK506-binding protein 51 (FKBP51), which is encoded by the FKBP5 gene[13,14]
Our results suggest that CM induces long-lasting alterations in the DNA methylation pattern of genes regulating the HPA axis, namely FKBP5, CRHR1, and NR3C1, which are, not found in immune cells of the offspring
Summary
Childhood maltreatment (CM) is so far an underestimated global phenomenon present in all societies and social classes. Epigenetic alterations within key player genes of the hypothalamic-pituitary-adrenal (HPA) axis, the main coordinator of the physiological stress response (Fig. 1), are discussed to biologically contribute to health consequences observed in CM-affected individuals[7,8]. FKBP51 is essential for a normal physiological stress response Another important regulator of HPA axis activity is the corticotropin-releasing hormone receptor 1 (CRH-R1, codified by the CRHR1 gene; Fig. 1)[15,16]. While rodent studies suggested that epigenetic alterations associated with early life adversity might be stably inherited through the germ cells[25,26,27], evidence for an intergenerational transmission of CM consequences[28] via germ cells in humans is lacking so far
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