ININFA   02677
INSTITUTO DE INVESTIGACIONES FARMACOLOGICAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
COCAINE ALTERS MOUSE MALE GERM CELLS EPIGENOME WITH DIRECT IMPACT HISTONES POST-TRANSLATIONAL MODIFICATIONS
Autor/es:
BISAGNO VERÓNICA; BETINA GONZALEZ; CANDELA R. GONZALEZ; VITULLO ALFREDO DANIEL; EDUARDO ROLDÁN
Reunión:
Simposio; Epigenetic Inheritance: Impact for Biology and Society; 2019
Resumen:
The mechanisms by which paternal experiences influence offspring are poorlyunderstood, but a reprogramming of testicular germ cells seems to be essential to THIS process. There is accumulating evidence that cocaine administration can trigger nongenetic inheritance through modifications of the male germ line, affecting development and behavior of the offspring. The influence of lifestyle and environmental factors on the epigenome of male germ cells appears to have a major impact if it takes place during the developmental phase when these cells are epigenetically reprogrammed. However, the mechanism by which cocaine alters testicular physiology and the epigenome has been poorly investigated. We have previously shown that cocaine administration induces testicular germ cell loss together with increases in ROS formation. Importantly, toxicity occurs in parallel to dysregulation of the testicular dopaminergic system: cocaine promoted increased tyrosine hydroxilase expression and dopamine receptors DRD1 and DRD2 downregulation (González et al. PLoS One 10: e0142713). Moreover, we found that chronic cocaine intake disrupts male germ cells epigenetic homeostasis, increasing global methylated cytosine (5-mC) levels in DNA andgerm cells and cauda epididymal sperm, increased acetylated histone 4 (H4ac) andecreased class I deacetylases HDAC1/2 protein levels (González et al. RBMO 20269-278). In the present study, we analyzed post-translational modifications (PTMs) of histones in isolated germ cells of adult male mice treated with cocaine (10 mg/kg) or vehicle, in an intermittent binge protocol (3 i.p. injections, 1 h apart, one day on/off for 13 days). We measured four specific PTMs on histone 3 (H3): H3K27ac, H3K9ac and H3K4me3, which are known to accumulate in active cis-regulatory elements like active and poised enhancers, and at the transcription-start sites (TSS) of active genes, and H3K9me3 as a mark of transcriptional repression. Immunolocalization studies show that H3K9ac, H3K27ac, H3K4me3 and H3K9me3 were mainly expressed in spermatogonia and early meiotic stages of spermatogenesis in vehicle- and cocaine-treated mice. Cocaine altered specific acetylation and methylation marks on histones, increasing H3K9ac and H3K9me3 and decreasing H3K4me3 and H3K27ac protein in isolated germ cells (p