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Changes in the expression of genes involved in the ovarian function of rats caused by daily exposure to 3-methylcholanthrene and their prevention by α-naphthoflavone

  • Reproductive Toxicology
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Abstract

Daily exposure to low doses of 3-methylcholanthrene (3MC) during the pubertal period in rats disrupts both follicular growth and ovulation. Thus, to provide new insights into the toxicity mechanism of 3MC in the ovary, here we investigated the effect of daily exposure to 3MC on selected ovarian genes, the role of the aryl hydrocarbon receptor (AhR) and the level of epigenetic remodeling of histone post-transcriptional modifications. Immature rats were daily injected with 3MC (0.1 or 1 mg/kg) and mRNA expression of genes involved in different ovarian processes were evaluated. Of the 29 genes studied, 18 were up-regulated, five were down-regulated and six were not altered. To assess whether AhR was involved in these changes, we used the chromatin immunoprecipitation assay. 3MC increased AhR binding to promoter regions of genes involved in Notch signaling (Hes1, Jag1), activation of primordial follicles (Cdk2), cell adhesion (Icam1), stress and tumor progression (Dnajb6), apoptosis (Bax, Caspase-9) and expression of growth and transcription factors (Igf2, Sp1). Studying the trimethylation and acetylation of histone 3 (H3K4me3 and H3K9Ac, respectively) of these genes, we found that 3MC increased H3K4me3 in Cyp1a1, Jag1, Dnajb6, Igf2, Notch2, Adamts1, Bax and Caspase-9, and H3K9Ac in Cyp1a1, Jag1, Cdk2, Dnajb6, Igf2, Icam1, and Sp1. Co-treatment with α-naphthoflavone (αNF), a specific antagonist of AhR, prevented almost every 3MC-induced changes. Despite the low dose used in these experiments, daily exposure to 3MC induced changes in both gene expression and epigenomic remodeling, which may lead to premature ovarian failure.

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Acknowledgements

We thank Marcela Marquez and Enzo Cuba for their technical assistances in the maintenance and treatments of animals. This work was supported by PIP 112-2008000271 from Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), UBACYT 20020130100156BA from Universidad de Buenos Aires, Argentina, and NIH: 5R01HD084542-02 from the National Institute of Health, USA.

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Authors and Affiliations

  1. Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Facultad de Medicina, Paraguay 2155, 16º P, (C1121ABG) Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina

    Eric Alejandro Rhon-Calderón, Rocío Alejandra Galarza & Alicia Graciela Faletti

  2. Primate Genetics Section, Division of Neuroscience, Oregon National Primate Research Center, OHSU, Beaverton, OR, 97006, USA

    Carlos Alejandro Toro & Alejandro Lomniczi

  3. Universidad de Buenos Aires, Facultad de Medicina, Dto. de Toxicología y Farmacología, Buenos Aires, Argentina

    Rocío Alejandra Galarza & Alicia Graciela Faletti

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  1. Eric Alejandro Rhon-Calderón
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  2. Carlos Alejandro Toro
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  3. Alejandro Lomniczi
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Correspondence to Alicia Graciela Faletti.

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All animals were handled according to the Guiding Principles for the Care and Use of Research Animals, and all studies were approved by the Institutional Committee of the School of Medicine of Buenos Aires University, Argentina (CICUAL).

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Rhon-Calderón, E.A., Toro, C.A., Lomniczi, A. et al. Changes in the expression of genes involved in the ovarian function of rats caused by daily exposure to 3-methylcholanthrene and their prevention by α-naphthoflavone. Arch Toxicol 92, 907–919 (2018). https://doi.org/10.1007/s00204-017-2096-5

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