Epigenetic alterations in the mouse testis after chronic cocaine administration: potential involvement in transgenerational cocaineinduced phenotypes

JEAN LUD CADET; ALFREDO VITULLO; BETINA GONZALEZ; EDGAR GARCIA-RILL; VERONICA BISAGNO; JAVIER A. MUÑIZ; FRANCISCO URBANO; CANDELA R. GONZALEZ

San Diego

Congreso; Neuroscience 2016; 2016

Society for Neuroscience

There is growing evidence of epigenetic mechanisms contributing to the transgenerational transmission of stress and psychiatric diseases. Regarding paternal transmission, it has been proposed that environmental factors like chronic stress, nutritional status, toxins and drugs of abuse trigger epigenetic mechanisms in the testicular germ line that can lead to variations in offspring?s development and behavior. Chronic psychostimulant intake also causes epigenetic changes and toxic consequences not only in dopaminergic brain areas but in peripheral organs as well, including the testis. The mechanisms by which the parental experience influences their offspring are poorly understood, but a reprogramming of testicular germ cells seems to be central to this process. In the present study, we measured epigenetic and functional markers in testis of adult mice treated with cocaine (Coc 10 mg/kg) compared to vehicle (Veh), in an intermittent binge protocol (3 i.p. injections, 1 h apart, one day on/off for 13 days). Mice were euthanized on day 14. We have previously shown that this Coc administration protocol induced testicular germ cell loss together with increased ROS species (González et al., PLoS One. 2015 doi: 10.1371/journal.pone.0142713). Importantly, toxicity occurred in parallel with testicular dopaminergic system dysregulation: Coc induced increased tyrosine hydroxilase expression and dopamine receptors Drd1 and Drd2 downregulation, similarly to Coc effects in CNS. In the present study, we found that Coc treatment caused a decreased in histone deacethylases HDAC1 and HDAC2 mRNA and protein expression and a concomitant increase in global histone 3 acetylation (H3ac), and no changes in global histone 4 acetylation (H4ac). We also found decreased Hdac3, Hdac8, Tet1 and Tet3, and increased Tet2 and Dnmt3a mRNA expression after Coc. We found no changes in Dnmt1 and Mecp2 among treatments. This data indicates that chronic Coc induce changes in markers associated with H3 acetylation and DNA methylation/hydroximetylation events in testicular cells. Our results further support that cocaine abuse can induce epigenetic changes in different cell types of the testis, that could lead to germ cells reprogramming affecting individuals from next generation.