A human-relevant mixture of endocrine disrupting chemicals induces changes in hippocampal DNA methylation correlating with hyperactive behavior in male mice

Humans are ubiquitously exposed to endocrine disrupting chemicals (EDCs), substances that interfere with endogenous hormonal signaling. Exposure during early development is of particular concern due to the programming role of hormones during this period. A previous epidemiological study has shown as...

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Bibliographic Details
Published in:	Chemosphere (Oxford) Vol. 313; p. 137633
Main Authors:	Di Criscio, Michela, Lodahl, Jennifer Ekholm, Stamatakis, Antonios, Kitraki, Efthymia, Bakoyiannis, Ioannis, Repouskou, Anastasia, Bornehag, Carl-Gustaf, Gennings, Chris, Lupu, Diana, Rüegg, Joëlle
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-02-2023
Subjects:	Adult Alkylation Animals Behavioral research Brain Chemical mixtures Child DNA DNA Methylation Endocrine disrupters Endocrine disrupting chemicals endocrine disruptor Endocrine Disruptors - metabolism Exposed to Female Folkhälsovetenskap Gene expression Genes expression Hippocampus Hippocampus - metabolism hormone Hormones HPA axis Human relevant mixture Humans Hyperactive behavior Hypothalamo-Hypophyseal System Hypothalamus-pituitary-adrenal axis Male Male mouse Mammals Methylation Mice Pituitary-Adrenal System Pregnancy Prenatal Exposure Delayed Effects - metabolism Public Health Science Receptors, Glucocorticoid - genetics Receptors, Glucocorticoid - metabolism DNA methylation HPA axis Human relevant mixture Hyperactive behavior Hippocampus Endocrine disrupting chemicals
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Summary:	Humans are ubiquitously exposed to endocrine disrupting chemicals (EDCs), substances that interfere with endogenous hormonal signaling. Exposure during early development is of particular concern due to the programming role of hormones during this period. A previous epidemiological study has shown association between prenatal co-exposure to 8 EDCs (Mixture N1) and language delay in children, suggesting an effect of this mixture on neurodevelopment. Furthermore, in utero exposure to Mixture N1 altered gene expression and behavior in adult mice. In this study, we investigated whether epigenetic mechanisms could underlie the long term effects of Mixture N1 on gene expression and behavior. To this end, we analyzed DNA methylation at regulatory regions of genes whose expression was affected by Mixture N1 in the hippocampus of in utero exposed mice using bisulfite-pyrosequencing. We show that Mixture N1 decreases DNA methylation in males at three genes that are part of the hypothalamus-pituitary-adrenal (HPA) axis: Nr3c1, Nr3c2, and Crhr1, coding for the glucocorticoid receptor, the mineralocorticoid receptor, and the corticotropin releasing hormone receptor 1, respectively. Furthermore, we show that the decrease in Nr3c1 methylation correlates with increased gene expression, and that Nr3c1, Nr3c2, and Crhr1 methylation correlates with hyperactivity and reduction in social behavior. These findings indicate that an EDC mixture corresponding to a human exposure scenario induces epigenetic changes, and thus programming effects, on the HPA axis that are reflected in the behavioral phenotypes of the adult male offspring. [Display omitted] •In utero exposure to a human-relevant EDC mixture affects hippocampal DNAm in males.•DNAm changes at the Nr3c1 gene correlate with altered expression.•DNAm changes correlate with hyperactivity and decreased social behavior.
ISSN:	0045-6535 1879-1298 1879-1298
DOI:	10.1016/j.chemosphere.2022.137633