Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells

Estrogen receptors display high levels of promiscuity in accommodating a wide range of ligand structures, but the functional consequence of changing receptor conformations in complex with distinct agonists is highly controversial. To determine variations in the transactivation capacity induced by different estrogenic agonists, we assessed global transcriptional profiles elicited by natural or synthetic xenoestrogens in comparison with the endogenous hormone 17β-estradiol. Human MCF7 and T47D carcinoma cells, representing the most frequently used model systems for tumorigenic responses in the mammary gland, were synchronized by hormone starvation during 48 h. Subsequently, a 24 h exposure was carried out with equipotent concentrations of the selected xenoestrogens or 17β-estradiol. Analysis of messenger RNA was performed on high-density oligonucleotide microarrays that display the sequences of 33 000 human transcripts, yielding a total of 181 gene products that are regulated upon estrogenic stimulation. Surprisingly, genistein (a phytoestrogen), bisphenol-A and polychlorinated biphenyl congener 54 (two synthetic xenoestrogens) produced highly congruent genomic fingerprints by regulating the same range of human genes. Also, the monotonous genomic signature observed in response to xenoestrogens is identical to the transcriptional effects induced by physiological concentrations of 17β-estradiol. This striking functional convergence indicates that the transcription machinery is largely insensitive to the particular structure of estrogen receptor agonists. The occurrence of such converging transcriptional programs reinforces the hypothesis that multiple xenoestrogenic contaminants, of natural or anthropogenic origin, may act in conjunction with the endogenous hormone to induce additive effects in target tissue

Global-genome Nucleotide Excision Repair Controlled by Ubiquitin/Sumo Modifiers

Global-genome nucleotide excision repair (GG-NER) prevents genome instability by excising a wide range of structurally unrelated DNA base adducts and crosslinks induced by chemical carcinogens, ultraviolet (UV) radiation or intracellular metabolic by-products. As a versatile damage sensor, xeroderma pigmentosum group C (XPC) protein initiates this generic defense reaction by locating the damage and recruiting the subunits of a large lesion demarcation complex that, in turn, triggers the excision of aberrant DNA by endonucleases. In the very special case of a DNA repair response to UV radiation, the function of this XPC initiator is tightly controlled by the dual action of cullin-type CRL4DDB2 and sumo-targeted RNF111 ubiquitin ligases. This twofold protein ubiquitination system promotes GG-NER reactions by spatially and temporally regulating the interaction of XPC protein with damaged DNA across the nucleosome landscape of chromatin. In the absence of either CRL4DDB2 or RNF111, the DNA excision repair of UV lesions is inefficient, indicating that these two ubiquitin ligases play a critical role in mitigating the adverse biological effects of UV light in the exposed skin

Catalytic diesel particulate filters reduce the in vitro estrogenic activity of diesel exhaust

An in vitro reporter gene assay based on human breast cancer T47D cells (ER-CALUX®) was applied to examine the ability of diesel exhaust to induce or inhibit estrogen receptor (ER)-mediated gene expression. Exhaust from a heavy-duty diesel engine was either treated by iron- or copper/iron-catalyzed diesel particulate filters (DPFs) or studied as unfiltered exhaust. Collected samples included particle-bound and semivolatile constituents of diesel exhaust. Our findings show that all of the samples contained compounds that were able to induce ER-mediated gene expression as well as compounds that suppressed the activity of the endogenous hormone 17β-estradiol (E2). Estrogenic activity prevailed over antiestrogenic activity. We found an overall ER-mediated activity of 1.63 ± 0.31ng E2 CALUX equivalents (E2-CEQs) per m3 of unfiltered exhaust. In filtered exhaust, we measured 0.74 ± 0.07 (iron-catalyzed DPF) and 0.55 ± 0.09ng E2-CEQ m−3 (copper/iron-catalyzed DPF), corresponding to reductions in estrogenic activity of 55 and 66%, respectively. Our study demonstrates that both catalytic DPFs lowered the ER-mediated endocrine-disrupting potential of diesel exhaus

Online-Informationssystem für die Phytotherapie bei Tieren

Die Phytotherapie gewinnt auch in der Veterinärmedizin zunehmend an Beliebtheit. Um das therapeutische Potenzial der Arzneipflanzen auszuschöpfen und deren sicheren Einsatz zu gewährleisten, bedarf es aber besonderer Kenntnisse der wirksamen Pflanzenteile beziehungsweise Zubereitungen. Unsachgemässe Anwendungen und Überdosierungen von Arzneipflanzen können toxisch sein. Deshalb haben wir mit www.phytoarznei.ch eine Entscheidungshilfe geschaffen, die online einen raschen Zugriff auf das aktuelle Wissen zu Arzneipflanzen und deren Gebrauch bei Tieren erlaubt. Dieses ­Informationssystem basiert auf der verfügbaren Fach­literatur, die nach kritischer Auswertung in eine strukturierte Datenbank eingebracht wurde. Für jede Arz­neipflanze beziehungsweise pflanzliche Droge sind therapeutische Indikationen, Anwendungsarten, organoleptische Eigenschaften, Inhaltsstoffe, pharmakologische Wirkungen, Dosierungen, Behandlungsdauer, Toxizität, gesetzliche Vorschriften bei Nutztieren sowie Dopingrelevanz aufgeführt. Zwei Suchprogramme gewährleisten einen benutzerfreundlichen Zugang, entweder durch die Eingabe des Pflanzennamens, des Drogennamens bzw. der Inhaltsstoffe der Pflanze in einem Suchfeld oder durch die Auswahl der gewünschten Tierspezies sowie therapeutischen Anwendung aus entsprechenden Dropdown-Listen. Diese Datenbank zu Arzneipflanzen ist mit der Giftpflanzendatenbank der Universität Zürich und, falls entsprechende Fertigpräparate vorliegen, mit dem Schweizerischen Tierarzneimittelkompendium sowie einem Verzeichnis von Veterinärprodukten verknüpft

Regulation of Nucleotide Excision Repair by UV-DDB: Prioritization of Damage Recognition to Internucleosomal DNA

This study reveals the molecular mechanism by which the nucleotide excision repair protein DDB2 prioritises excision of UV-induced DNA lesions in the nucleosome landscape

ASH1L-MRG15 methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair

To recognize DNA adducts, nucleotide excision repair (NER) deploys the XPC sensor, which detects damage-induced helical distortions, followed by engagement of TFIIH for lesion verification. Accessory players ensure that this factor handover takes place in chromatin where DNA is tightly wrapped around histones. Here, we describe how the histone methyltransferase ASH1L, once activated by MRG15, helps XPC and TFIIH to navigate through chromatin and induce global-genome NER hotspots. Upon UV irradiation, ASH1L adds H3K4me3 all over the genome (except in active gene promoters), thus priming chromatin for XPC relocations from native to damaged DNA. The ASH1L-MRG15 complex further recruits the histone chaperone FACT to DNA lesions. In the absence of ASH1L, MRG15 or FACT, XPC is misplaced and persists on damaged DNA without being able to deliver the lesions to TFIIH. We conclude that ASH1L-MRG15 makes damage verifiable by the NER machinery through the sequential deposition of H3K4me3 and FACT

To incise or not and where: SET-domain methyltransferases know

The concept of the histone code posits that histone modifications regulate gene functions once interpreted by epigenetic readers. A well-studied case is trimethylation of lysine 4 of histone H3 (H3K4me3), which is enriched at gene promoters. However, H3K4me3 marks are not needed for the expression of most genes, suggesting extra roles, such as influencing the 3D genome architecture. Here, we highlight an intriguing analogy between the H3K4me3-dependent induction of double-strand breaks in several recombination events and the impact of this same mark on DNA incisions for the repair of bulky lesions. We propose that Su(var)3–9, Enhancer-of-zeste and Trithorax (SET)-domain methyltransferases generate H3K4me3 to guide nucleases into chromatin spaces, the favorable accessibility of which ensures that DNA break intermediates are readily processed, thereby safeguarding genome stability

Effect of antimicrobial stewardship on antimicrobial prescriptions for selected diseases of dogs in Switzerland.

BACKGROUND Antimicrobial stewardship programs (ASPs) are important tools to foster prudent antimicrobial use. OBJECTIVE To evaluate antimicrobial prescriptions by Swiss veterinarians before and after introduction of the online ASP AntibioticScout.ch in December 2016. ANIMALS Dogs presented to 2 university hospitals and 14 private practices in 2016 or 2018 for acute diarrhea (AD; n = 779), urinary tract infection (UTI; n = 505), respiratory tract infection (RTI; n = 580), or wound infection (WI; n = 341). METHODS Retrospective study. Prescriptions of antimicrobials in 2016 and 2018 were compared and their appropriateness assessed by a justification score. RESULTS The proportion of dogs prescribed antimicrobials decreased significantly between 2016 and 2018 (74% vs 59%; P < .001). The proportion of prescriptions in complete agreement with guidelines increased significantly (48% vs 60%; P < .001) and those in complete disagreement significantly decreased (38% vs 24%; P < .001) during this time. Antimicrobial prescriptions for dogs with AD were significantly correlated with the presence of hemorrhagic diarrhea in both years, but a significantly lower proportion of dogs with hemorrhagic diarrhea were unnecessarily prescribed antimicrobials in 2018 (65% vs 36%; P < .001). In private practices, in 2018 a bacterial etiology of UTI was confirmed in 16% of dogs. Prescriptions for fluoroquinolones significantly decreased (29% vs 14%; P = .002). Prescriptions for antimicrobials decreased significantly in private practices for RTI (54% vs 31%; P < .001). CONCLUSION Antimicrobials were used more prudently for the examined indications in 2018 compared to 2016. The study highlights the continued need for ASPs in veterinary medicine