BRIEF RESEARCH REPORT published: 03 April 2020 doi: 10.3389/fcell.2020.00216 Edited by: Huiming Zhang, Shanghai Center for Plant Stress Biology (SIBS-CAS), China Reviewed by: Daniel Vaiman, Institut National de la Santé et de la Recherche Médicale (INSERM), France Rodolfo Negri, Sapienza University of Rome, Italy *Correspondence: Candela R. González gonzalez.candela@maimonides.edu; cande.gonz80@gmail.com Specialty section: This article was submitted to Epigenomics and Epigenetics, a section of the journal Frontiers in Cell and Developmental Biology Received: 03 February 2020 Accepted: 12 March 2020 Published: 03 April 2020 Citation: González B, Gancedo SN, Janeir Garazatua SA, Roldán E, Vitullo AD and González CR (2020) Dopamine Receptor D1 Contributes to Cocaine Epigenetic Reprogramming of Histone Modifications in Male Germ Cells. Front. Cell Dev. Biol. 8:216. doi: 10.3389/fcell.2020.00216 Dopamine Receptor D1 Contributes to Cocaine Epigenetic Reprogramming of Histone Modifications in Male Germ Cells Betina González 1 , Samanta N. Gancedo 1 , Sahira A. Janeir Garazatua 2 , Eduardo Roldán 3 , Alfredo D. Vitullo 2 and Candela R. González 2 * 1 Instituto de Investigaciones Farmacológicas, Universidad de Buenos Aires–Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina, 2 Centro de Estudios Biomédicos Básicos, Aplicados y Desarrollo, Universidad Maimónides, Buenos Aires, Argentina, 3 Departamento de Biodiversidad y Biología Evolutiva, Museo Nacional de Ciencias Naturales, Madrid, Spain Paternal environmental perturbations, including cocaine intake, can affect the development and behavior of the offspring through epigenetic inheritance. However, the mechanism by which cocaine alters the male germ cells epigenome is almost unexplored. Here, we report that cocaine-treated male mice showed alterations on specific histone post-translational modifications (PTMs) including increased silent chromatin marks H3K9me3 and H3K27me3 and decreased active enhancer and promoter marks H3K27ac and H3K4me3 in isolated germ cells. Also, cocaine increased H3K9ac and H4K16ac levels, involved in the replacement of histones by protamines that take place at round spermatid stage. Cocaine also altered histones H3/H4 epigenetic enzymes by increasing acetyltransferase KAT8/MOF, deacetylase SIRT1 and methyltransferase KMT1C/G9A, and decreasing deacetylases HDAC1/2 and demethylase KDM1A/LSD1 protein levels. Moreover, a pre-treatment with dopamine receptor 1 (DRD1) antagonist SCH23390 (SCH) blocked cocaine effects on H3K4me3, H3K27me3, and H4K16ac epigenetic marks. Interestingly, treatment with SCH-only was able to modify most of the histone marks tested here, pointing to a dopamine role in controlling histone PTMs in germ cells. Taken together, our data suggest a key role for DRD1 in mediating cocaine-triggered epigenetic modifications related to the silencing of gene transcription and the histone-to-protamine replacement that controls chromatin architecture of maturing sperm cells, and pinpoints a novel role of the dopaminergic system in the regulation of male germ cells reprogramming. Keywords: cocaine, male germ cells, epigenetics, dopamine receptor 1, histone post-traslational modifications INTRODUCTION In the last years, there has been special interest in the characterization of epigenetic mechanisms during spermatogenesis that control the reprogramming of the paternal genome, due to the possible trans-generational transmission of acquired traits (Lacal and Ventura, 2018; Galan et al., 2019). Epigenetic reprogramming involves histones post-translational modifications (PTMs), Frontiers in Cell and Developmental Biology | www.frontiersin.org 1 April 2020 | Volume 8 | Article 216