Entwicklungsfolgen pränataler Exposition gegenüber endokrin wirksamen Umweltgiften - Untersuchung epigenetischer Mechanismen in der Duisburger Kohortenstudie
Zusammenfassung der Projektergebnisse
Prenatal exposure to EDCs can interfere with developmental processes, and it has been suggested that longterm effects of in utero exposure to EDCs might be caused by the influence of EDCs on basic gene regulatory mechanism. Altered DNA methylation levels as epigenetic mark might be functionally involved in these processes. The present project aimed to investigate in a Western urban-industrial population whether prenatal low-dose exposure to congeners of PCB and PCCD/F is associated with altered DNA methylation patterns in cord blood and whether these alterations might mediate potential associations between the prenatal exposure and developmental outcomes of the brain and body during childhood and adolescence in a sex-stratified manner. Using sex-stratified epigenome-wide association analyses, DNA methylation of 32 DMPs and eight significantly, DMRs were significantly associated with levels of six of the 16 PCB and PCDD/F congeners in the male and female subjects at FDR-corrected threshold of less than .05. Constructed by a weighted gene correlation network of co-methylated CpG sites in the female subsample, six of 31 modules, that were significantly associated with the exposure level of PCDF130 after adjustment for multiple testing, were significantly enriched in gene pathways (FDR < .05). Using mediation models, seven congeners of PCB and PCDD/F significantly (ps < .05) predicted the child´s cognitive ability or longitudinal pubertal development during childhood and adolescence. Neither epigenome-wide differentially methylated DNA marks nor the locus-specific DNA methylation of CpGs in the promoter regions of AR, ERS1, or ERS2 significantly (ps > .05) mediated the associations between the prenatal exposure and outcome of the cognitive ability or the longitudinal pubertal development. However, the child´s sex significantly (ps < .05) moderated the exposureoutcome associations revealing significant effects in the male subsample. The present findings on epigenome-wide differentially methylated DNA levels of single CpG sites, regions and modules indicate that specific congeners of PCB and PCDD/F induce epigenetic changes that are associated with neurodevelopment, gene expression and immune functioning. Furthermore, the present findings on facilitated cognitive ability and accelerated longitudinal pubertal development of boys indicate that prenatal exposure to specific congeners of PCB and PCDD/F exert effects on the developing brain and body during childhood and adolescence in sex-dependent manner. The absent mediating effects by the epigenomewidely identified DNA methylation marks suggest that epigenetic changes in genes associated with neurodevelopment, gene expression and immune functioning are not directly involved in the underlying mechanisms that result from the effects of the prenatal to PCB- and PCDD/F on the developing body and brain during childhood and adolescence. Furthermore, the absent mediating effects of the locus-specific DNA methylation in the promoter regions of the genes AR, ESR1, and ESR2 coding for the androgen, estrogen α and β receptor indicate that the effects of the specific of PCB- and PCCD/F-congeners on the developing body and brain are not directly related to epigenetic marks at these steroid receptors. To conclude, a better understanding of the epigenetic mechanisms of DNA methylation involved in the exposure-outcome relationship between EDCs and altering outcomes in the developing body and brain continues to be an important research aim.
Projektbezogene Publikationen (Auswahl)
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Effects of prenatal exposure to PCBs and PCDD/Fs on DNA methylation and development across childhood and adolescence (Dissertation, Ruhr-University Bochum, Germany).
Mattonet, K.
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Prenatal exposure to endocrine disrupting chemicals is associated with altered DNA methylation in cord blood. Epigenetics, 17(9), 935-952.
Mattonet, Katharina; Nowack-Weyers, Nikola; Vogel, Vanessa; Moser, Dirk; Tierling, Sascha; Kasper-Sonnenberg, Monika; Wilhelm, Michael; Scherer, Michael; Walter, Jörn; Hengstler, Jan G.; Schölmerich, Axel & Kumsta, Robert
