This study investigated how exposure to per- and polyfluoroalkyl substances (PFAS) influence the levels of thyroid-stimulating hormone (TSH) and free thyroxine (fT4) and the risk of thyroid disease in euthyroid adults. A retrospective cohort study was conducted using data from 181 euthyroid Korean adults (59.4 ± 8.8 years, 33.1 % male) from the Korean Genome and Epidemiology Study. Serum concentrations of four PFAS (PFOA, PFOS, PFNA, and PFHxS) were measured using liquid chromatography-mass spectrometry, and a relative potency factor-based cumulative PFAS exposure (Cmix) was calculated. Linear regression and Bayesian Kernel Machine Regression (BKMR) were used to assess the associations between PFAS exposure and thyroid hormone levels. Cox regression analysis was conducted to assess the risk of thyroid disease during a 3.6 ± 1.3-year follow-up. Serum PFOS levels were negatively correlated with TSH, showing a reverse J-shaped dose-response relationship. PFOS and PFNA exhibited inverse J-shaped positive associations with fT4. Mixed PFAS exposure (lnCmix) significantly reduced TSH levels in females (adjusted linear regression coefficient -0.56, 95 % CI -1.03 ∼ -0.09, p = 0.021) but had no significant effect on fT4. In the BKMR analysis, PFOA, PFOS, and PFNA were identified as factors that influenced TSH levels, exhibiting a non-significant decreasing pattern of TSH upon mixed exposure. During follow-up, mixed PFAS exposure increased the risk of thyroid disease (adjusted HR 9.53, 95 % CI 1.29-70.6, p = 0.027). Mixed PFAS exposure decreases TSH levels, particularly in women, and increases the risk of thyroid disease. Further research is needed to assess the nonlinearity between exposure and outcomes, as well as to evaluate mixed exposures.

[2,3-diamino-N-(4-(benzo[d]thiazol-2-yl)phenyl)propanamide], named as ETN101, is a novel therapeutic agent for hepatocellular carcinoma. In vitro studies examined ETN101 metabolites in human, mouse, rat, dog, and monkey hepatocytes and identified the drug-metabolizing enzymes involved using cDNA-expressed human recombinant cytochrome P450s (CYPs), carboxylesterases (CESs), N-acetyltransferase (NAT) 1, and human liver cytosol. ETN101 showed similar metabolic stability across hepatocytes from five species, with particularly comparable stability in humans, rats, and monkeys. Its half-life was 75.0 min in humans, 68.9 in rats, 73.1 in monkeys, 120.4 in mice, and 112.7 in dogs. Thirty-four ETN101 metabolites, including the major metabolite M1, were identified using liquid chromatography–high-resolution mass spectrometry. ETN101 was primarily metabolized to M1 and CYP1A2 is exclusively responsible for M1 metabolism. Both NAT1 and NAT2 were responsible for the N-acetylation of M1 to M2. ETN101 remained stable in human CESs. In conclusion, this study provides comprehensive insights into the metabolic characteristics of ETN101, valuable for its toxicological and clinical development.

1. Feature-based molecular networking (FBMN), an advanced metabolomics tool leveraging MS/MS spectral similarity, was applied to update metabolite characterization of fenbendazole (FBZ), a veterinary antiparasitic agent with emerging anticancer potential in humans. Despite its therapeutic promise, FBZ's human metabolic pathways remain poorly understood.2. In this study, FBMN was utilised for the comprehensive in vitro profiling of FBZ metabolites across species, employing high-resolution liquid chromatography-mass spectrometry (LC-HRMS) with data-dependant MS² acquisition.3. Nine metabolites, including two novel sulfate-conjugated forms (M2 sulfate and M7 sulfate), were identified and structurally characterised through integrated FBMN analysis. Oxidative metabolites (M1-M4) were found to be more abundant in rat liver microsomes, whereas monkey hepatocytes exhibited higher levels of most metabolites. Notably, hydrolysed FBZ (M5) dominated human samples, accounting for the largest proportion in both liver microsomes and hepatocytes, suggesting species-specific enzymatic activity.4. The application of FBMN provided an enhanced, systematic approach for metabolite identification and inter-species comparison, revealing critical metabolic differences that support FBZ biotransformation. These findings offer novel insights into FBZ's metabolic pathways, supporting its safety and efficacy assessment for potential human therapeutic applications.

Jung YH, et al. J Clin Neurol. 2026 ;22:e33. https://doi.org/10.3988/jcn.2025.0556