Iopanoic acid 500mg tablets

Internal concentrations (ICs) are crucial for linking exposure to effects in the development of New Approach Methodologies. ICs of chemicals in aquatic organisms are primarily driven by hydrophobicity and modulated by biotransformation and efflux. Comparing the predicted baseline to observed toxicity enables the estimation of effect specificity, but biological processes can lead to overestimating ICs and bias the specificity assessment. To evaluate the prediction of a mass balance model (MBM) and the impact of biotransformation on ICs, experimental ICs of 63 chemicals in zebrafish embryos were compared to predictions with physicochemical properties as input parameters. Experimental ICs of 79% (50 of 63) of the chemicals deviated less than 10-fold from predictions, and the remaining 13 deviated up to a factor of 90. Using experimental ICs changed the classification for 19 chemicals, with ICs 5 to 90 times lower than predicted, showing the bias of specificity classification. Uptake kinetics of pirinixic acid, genistein, dexamethasone, ethoprophos, atorvastatin, and niflumic acid were studied over a 96 h exposure period, and transformation products (TPs) were elucidated using suspect- and nontarget screening with UPLC-HRMS. 35 TPs (5 to 8 TPs per compound) were tentatively identified and semiquantified based on peak areas, suggesting that biotransformation may partly account for the overpredictions of ICs.

Abstract licence: CC BY

Iodothyronine deiodinases (Dio) are selenocysteine-containing membrane enzymes that activate and inactivate the thyroid hormones (TH) through reductive iodide eliminations. The three deiodinase isoforms are homodimers sharing highly conserved amino acid sequences, but they differ in their regioselectivities for the deiodination reaction and regulatory features. We have now solved a crystal structure of the mouse deiodinase 2 (Dio2) catalytic domain. It reveals a high overall similarity to the deiodinase 3 structure, supporting the proposed common mechanism, but also Dio2-specific features, likely mediating its unique properties. Activity studies with an artificially enforced Dio dimer further confirm that dimerization is required for activity and requires both the catalytic core and the enzyme's N-terminus. Cross-linking studies reveal the catalytic core's dimerization interface, providing insights into the architecture of the complete, active Dio homodimer.

Abstract licence: CC BY

Active ingredients of pesticides or biocides and industrial chemicals can negatively affect environmental organisms, potentially endangering populations and ecosystems. European legislation mandates that chemical manufacturers provide data for the environmental risk assessment of substances to obtain registration. Endocrine disruptors, substances that interfere with the hormone system, are not granted marketing authorization due to their adverse effects. Current methods for identifying disruptors targeting the thyroid hormone system are costly and require many amphibians. Consequently, alternative methods compliant with the 3R principle (replacement, reduction, refinement) are essential to prioritize risk assessment using reliable biomarkers at non-protected life stages. Our study focused on detecting robust biomarkers for thyroid-disrupting mechanisms of action (MoA) by analyzing molecular signatures in zebrafish embryos induced by deiodinase inhibitor iopanoic acid and thyroid peroxidase inhibitor methimazole. We exposed freshly fertilized zebrafish eggs to these compounds, measuring lethality, hatching rate, swim bladder size and transcriptomic responses. Both compounds significantly reduced swim bladder size, aligning with prior findings. Transcriptome analysis revealed specific molecular fingerprints consistent with the MoA under investigation. This analysis confirmed regulation directions seen in other studies involving thyroid disruptors and allowed us to identify genes like tg, scl2a11b, guca1d, cthrc1a, si:ch211-226h7.5, soul5, nnt2, cox6a2 and mep1a as biomarker genes for thyroid disrupting MoA in zebrafish embryos as per OECD test guideline 236. Future screening methods based on our findings will enable precise identification of thyroid-related activity in chemicals, promoting the development of environmentally safer substances. Additionally, these biomarkers could potentially be incorporated into legally mandated chronic toxicity tests in fish, potentially replacing amphibian tests for thyroid disruption screening in the future.

Abstract licence: CC BY

Hyperthermia induced by phenethylamines, such as 3,4-methylenedioxymethamphetamine (MDMA), can lead to life-threatening complications and death. Activation of the sympathetic nervous system and subsequent release of norepinephrine and activation of uncoupling proteins have been demonstrated to be the key mediators of phenethylamine-induced hyperthermia (PIH). Recently, the gut microbiome was shown to also play a contributing role in PIH. Here, the hypothesis that bile acids (BAs) produced by the gut microbiome are essential to PIH was tested. Changes in the serum concentrations of unconjugated primary BAs cholic acid (CA) and chenodeoxycholic acid (CDCA) and secondary BA deoxycholic acid (DCA) were measured following MDMA (20 mg/kg, sc) treatment in antibiotic treated and control rats. MDMA-induced a significant hyperthermic response and reduced the serum concentrations of three BAs 60 min post-treatment. Pretreatment with antibiotics (vancomycin, bacitracin and neomycin) in the drinking water for five days resulted in the depletion of BAs and a hypothermic response to MDMA. Gut bacterial communities in the antibiotic-treated group were distinct from the MDMA or saline treatment groups, with decreased microbiome diversity and alteration in taxa. Metagenomic functions inferred using the bioinformatic tool PICRUSt2 on 16S rRNA gene sequences indicated that bacterial genes associated to BA metabolism are less abundant in the antibiotic-MDMA treated group. Overall, these findings suggest that gut bacterial produced BAs might play an important role in MDMA-induced hyperthermia.

Abstract licence: CC BY