Contribution à l'identification du danger contaminant alimentaire (le 3-monochloropropane-1,2-diol en termes de génotoxicité, cancérogenèse et effets sur l'organogenèse testiculaire chez le rat)

Ce travail porte sur un contaminant alimentaire cancérogène, le 3-monochloropropane-1,2-diol (3-MCPD). Nous avons montré que le 3-MCPD traverse la barrière placentaire chez le rat mais n'a pas d'effet sur la formation ou la différentiation des gonades mâles des fœtus exposés in utero. L'absence d'effets génotoxiques du 3-MCPD dans les organes cibles de la cancérogenèse (rein, testicules) a été montrée dans le test des comètes. Malgré un effet mitogène observé dans le foie, le 3-MCPD est dépourvu d'activité promotrice dans un modèle d'hépatocancérogenèse à moyen terme chez le rat. Les modifications des taux sériques des hormones gonadotropes et sexuelles que nous avons observées pourraient expliquer les tumeurs des cellules de Leydig et des glandes mammaires induites chez les rats mâles par le 3-MCPD. En conclusion, l'effet cancérogène du 3-MCPD pourrait s'expliquer par des mécanismes épigénétiques liés à un déséquilibre hormonal. L'effet mitogène du 3-MCPD doit être confirmé.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

The role of poly(ADP-ribosyl)ation in epigenetic events

Epigenetic refers to a range of heritable chromatin modifications including DNA methylation, histone modifications, remodeling of nucleosomes and higher order chromatin modifications. In the framework of chromatin remodeling activities, the poly(ADP-ribosyl)ation of nuclear proteins catalyzed by PARPs, particularly PARP-1 and PARP-2, plays a fundamental role and as such have the potential to orchestrate various chromatin-based biological tasks including transcription, DNA repair and differentiation. In this review, we propose a short overview of the more recent experimental data that shed light on the role of poly(ADP-ribosyl)ation in the translation of the histone code. We will essentially focus on the different mechanisms by which PARP activity regulates the global chromatin environment and how this affects cellular pathways

Poly(ADP-ribose) polymerase 1 (PARP1) associates with E3 ubiquitin-protein ligase UHRF1 and modulates UHRF1 biological functions

Poly(ADP-ribose) polymerase 1 (PARP1, also known as ARTD1) is an abundant nuclear enzyme that plays important roles in DNA repair, gene transcription, and differentiation through the modulation of chromatin structure and function. In this work we identify a physical and functional poly(ADP-ribose)-mediated interaction of PARP1 with the E3 ubiquitin ligase UHRF1 (also known as NP95, ICBP90) that influences two UHRF1-regulated cellular processes. On the one hand, we uncovered a cooperative interplay between PARP1 and UHRF1 in the accumulation of the heterochromatin repressive mark H4K20me3. The absence of PARP1 led to reduced accumulation of H4K20me3 onto pericentric heterochromatin that coincided with abnormally enhanced transcription. The loss of H4K20me3 was rescued by the additional depletion of UHRF1. In contrast, although PARP1 also seemed to facilitate the association of UHRF1 with DNMT1, its absence did not impair the loading of DNMT1 onto heterochromatin or the methylation of pericentric regions, possibly owing to a compensating interaction of DNMT1 with PCNA. On the other hand, we showed that PARP1 controls the UHRF1-mediated ubiquitination of DNMT1 to timely regulate its abundance during S and G2 phase. Together, this report identifies PARP1 as a novel modulator of two UHRF1-regulated heterochromatin-associated events: the accumulation of H4K20me3 and the clearance of DNMT1

Functional interplay between Parp-1 and SirT1 in genome integrity and chromatin-based processes

Poly(ADP-ribose) polymerase-1 (Parp-1) and the protein deacetylase SirT1 are two of the most effective NAD(+)-consuming enzymes in the cell with key functions in genome integrity and chromatin-based pathways. Here, we examined the in vivo crosstalk between both proteins. We observed that the double disruption of both genes in mice tends to increase late post-natal lethality before weaning consistent with important roles of both proteins in genome integrity during mouse development. We identified increased spontaneous telomeric abnormalities associated with decreased cell growth in the absence of either SirT1 or SirT1 and Parp-1 in mouse cells. In contrast, the additional disruption of Parp-1 rescued the abnormal pericentric heterochromatin, the nucleolar disorganization and the mitotic defects observed in SirT1-deficient cells. Together, these findings are in favor of key functions of both proteins in cellular response to DNA damage and in the modulation of histone modifications associated with constitutive heterochromatin integrity

The mammalian-specific Tex19.1 gene plays an essential role in spermatogenesis and placenta-supported development

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Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P < 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)