Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis

International audienceBACKGROUND: Prostaglandins (PGs) play key roles in development and maintenance of homeostasis of the adult body. Despite these important roles, it remains unclear whether the PG pathway is a target for endocrine disruption. However, several known endocrine-disrupting compounds (EDCs) share a high degree of structural similarity with mild analgesics. OBJECTIVES AND METHODS: Using cell-based transfection and transduction experiments, mass spectrometry, and organotypic assays together with molecular modeling, we investigated whether inhibition of the PG pathway by known EDCs could be a novel point of endocrine disruption. RESULTS: We found that many known EDCs inhibit the PG pathway in a mouse Sertoli cell line and in human primary mast cells. The EDCs also reduced PG synthesis in ex vivo rat testis, and this reduction was correlated with a reduced testosterone production. The inhibition of PG synthesis occurred without involvement of canonical PG receptors or the peroxisome proliferator-activated receptors (PPARs), which have previously been described as targets of EDCs. Instead, our results suggest that the compounds may bind directly into the active site of the cyclooxygenase (COX) enzymes, thereby obstructing the conversion of arachidonic acid to PG precursors without interfering with the expression of the COX enzymes. A common feature of the PG inhibitory EDCs is the presence of aromatic groups that may stabilize binding in the hydrophobic active site of the COX enzymes. CONCLUSION: Our findings suggest a hitherto unknown mode of action by EDCs through inhibition of the PG pathway and suggest new avenues to investigate effects of EDCs on reproductive and immunological disorders that have become increasingly common in recent decades

Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat

International audienceBACKGROUND: More than half of pregnant women in the Western world report intake of mild analgesics, and some of these drugs have been associated with anti-androgenic effects in animal experiments. Intrauterine exposure to anti-androgens is suspected to contribute to the recent increase in male reproductive problems, and many of the anti-androgenic compounds are like the mild analgesics potent inhibitors of prostaglandin synthesis. Therefore, it appears imperative to further investigate the potential endocrine disrupting properties of mild analgesics. METHODS: In a prospective birth cohort study, 2297 Danish and Finnish pregnant women completed a questionnaire and 491 of the Danish mothers participated in a telephone interview, reporting on their use of mild analgesics during pregnancy. The testicular position of newborns was assessed by trained paediatricians. In rats, the impact of mild analgesics on anogenital distance (AGD) after intrauterine exposure was examined together with the effect on ex vivo gestational day 14.5 testes. RESULTS: In the Danish birth cohort, the use of mild analgesics was dose-dependently associated with congenital cryptorchidism. In particular, use during the second trimester increased the risk. This risk was further increased after the simultaneous use of different analgesics. The association was not found in the Finnish birth cohort. Intrauterine exposure of rats to paracetamol led to a reduction in the AGD and mild analgesics accordingly reduced testosterone production in ex vivo fetal rat testes. CONCLUSION: There was an association between the timing and the duration of mild analgesic use during pregnancy and the risk of cryptorchidism. These findings were supported by anti-androgenic effects in rat models leading to impaired masculinization. Our results suggest that intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders

Paracetamol (acetaminophen), aspirin (acetylsalicylic acid) and indomethacin are anti-androgenic in the rat foetal testis

International audienceMore than half the pregnant women in the Western world report taking mild analgesics. These pharmaceutical compounds have been associated with congenital cryptorchidism in humans, the best-known risk factor for low semen quality and testicular germ cell cancer. Furthermore, some of these mild analgesics exert potent anti-androgenic effects in the male rat and several endocrine-disrupting compounds, known to alter masculinization, have also been shown to be potent inhibitors of prostaglandin (PG) synthesis similar to mild analgesics. Using a 3-day ex vivo organotypic model system based on gestational day 14.5 rat testes, we herein show that testosterone production was inhibited by paracetamol, at doses of 0.1 μm to 100 μm. Similar results were obtained for aspirin (1-100 μm) and indomethacin (10 μm). The production of the other Leydig cell hormone, Insl3, was not disrupted by exposure to paracetamol. Investigations of the gross anatomy of the testis as well as Leydig cells number and rate of gonocyte apoptosis after the 3 days of ex vivo differentiation showed no significant effect of the analgesics tested compared with controls. These data indicate therefore that mild analgesics specifically inhibit testosterone production in rat foetal testes in vitro and that these compounds had no effect on gonocyte survival. Parallel determinations of prostaglandin D2 (PGD2) production indicated that the effects of paracetamol and aspirin on PGD2 and testosterone were not connected, whereas the effects of indomethacin were correlated. We conclude that mild analgesics exert direct and specific anti-androgenic effects in rat foetal testis in our experimental setup and that the mechanism of action is probably uncoupled from the inhibition of PG synthesis

Hearing rehabilitation and microbial shift after middle ear surgery with Vibrant Soundbridge in patients with chronic otitis media

IntroductionPatients with otitis media (OM) encounter significant functional hearing impairment with conductive, or a combined hearing loss and long-term sequelae involving impaired speech/language development in children, reduced academic achievement and irreversible disorders of middle and inner ear requiring a long time therapy and/or multiple surgeries. In its persistent chronic form, Otitis media (COM) can often only be treated by undergoing ear surgery for hearing restoration. The persistent inflammatory reaction plays a major role, often caused by multi-resistant pathogens in the ear. Herein, we present outcomes of patients implanted with currently the only FDA approved active Middle Ear Implant Vibrant Soundbridge (VSB), suffering from persistent COM.MethodsThe study enrolled 42 patients, treated by performing middle ear (ME) surgery to different extents and implanted with the VSB to various structures in the ME. Included were 17 children and 25 adults that had recurrent and/or persisting OM and significant hearing loss. Preoperative and postoperative patients' audiometric data were evaluated and the benefit with VSB assessed using the Glasgow Benefit Inventory for adults and pediatric cohorts. The microbial spectrum of pathogens was assessed before and after surgery, exploring the colonization of the otopathogens, as well as the intestinal microbiome from individually burdened patients.ResultsThe mean functional gain is 29.7 dB HL (range from 10 to 56.2 dB HL) with a significant improvement in speech intelligibility in quiet. Following VSB implantation, no significant differences in coupling were observed at low complication rates. Postoperatively patients showed significantly increased benefit with VSB compared to the untreated situation, including less otorrhea, pain, medical visits, and medication intake, with no recurrent OM and significant bacterial shift in otopathogens. The analysis of the intestinal microbiome displayed a high abundance of bacterial strains that might be linked to chronic and persistent inflammation.ConclusionsFunctional ear surgery including rehabilitation with a VSB in patients suffering from COM present to be safe and effective. The successful acceptance accompanied by the improved audiological performance resulted in significant benefit with VSB, with a shift in the ear pathogens and altered microbiome and thus is a great opportunity to be treated

Survey on the need for an e-learning-platform for ENT residents

Objective Interactive e-learning-platforms may replace the classical textbook in the future. Such media have the possible advantage of including video and audio files in a more comprehensive way, but ENT-specific platforms do not currently exist. So far, the actual needs and wishes of ENT residents are unclear and may be affected by the so called digital revolution. Material and methods An online survey was carried out addressing all ENT residents in Germany known to the German society of oto-rhino-laryngology, head and neck surgery. A 17-items survey was developed by ENT doctors receiving and providing training and distributed by e-mail. The survey was available to answer in April and May 2019. Results A total of 150 out of 671 ENT specialists and residents took part in the study. Of these, 80 % were residents and 20 % were ENT specialists. 63-80 % of the respondents already use online media in general at work, in preparation for the ENT specialist examination, for training purposes and for support as a clinician. 92-95 % of the participants indicated the willingness to use an interactive platform for their ENT specialist examination preparation and further training. On average, e-learning media are used by the responders to prepare for the ENT specialist examination or in clinical everyday life and for further training 108 or 130 min/week. The desire for surgical instruction videos is also very high. Conclusion There is a high demand for a structured e-learning-platform especially for ENT. An interactive e-learning-platform would ensure, supplement and support qualified education and training

Dynamic Microscopic Optical Coherence Tomography as a New Diagnostic Tool for Otitis Media

Hypothesis: Otitis media (OM) can be successfully visualized and diagnosed by dynamic microscopic optical coherence tomography (dmOCT). Background: OM is one of the most common infectious diseases and, according to the WHO, one of the leading health problems with high mortality in developing countries. Despite intensive research, the only definitive treatment of therapy-refractory OM for decades has been the surgical removal of inflamed tissue. Thereby, the intra-operative diagnosis is limited to the surgeon’s visual impression. Supportive imaging modalities have been little explored and have not found their way into clinical application. Finding imaging techniques capable of identifying inflamed tissue intraoperatively, therefore, is of significant clinical relevance. Methods: This work investigated a modified version of optical coherence tomography with a microscopic resolution (mOCT) regarding its ability to differentiate between healthy and inflamed tissue. Despite its high resolution, the differentiation of single cells with mOCT is often impossible. A new form of mOCT termed dynamic mOCT (dmOCT) achieves cellular contrast using micro-movements within cells based on their metabolism. It was used in this study to establish correlative measurements with histology. Results: Using dmOCT, images with microscopic resolution were acquired on ex vivo tissue samples of chronic otitis media and cholesteatoma. Imaging with dmOCT allowed the visualization of specific and characteristic cellular and subcellular structures in the cross-sectional images, which can be identified only to a limited extent in native mOCT. Conclusion: We demonstrated for the first time a new marker-free visualization in otitis media based on intracellular motion using dmOCT