(SC,RS)-Bromido-(N-{4-methyl-1-[(4-methyl-phenyl)sul-fan-yl]-pentan-2-yl}-N'-(pyridin-2-yl)imidazol-2-yl-idene)palladium(II) bromide.

The mol-ecule of the title NCNHCS pincer N-heterocyclic carbene palladium(II) complex, [PdBr(C21H25N3S)]Br, exhibits a slightly distorted square-planar coordination at the palladium(II) atom, with the five-membered chelate ring nearly planar. The six-membered chelate ring adopts an envelope conformation. Upon chelation, the sulfur atom becomes a stereogenic centre with an RS configuration induced by the chiral carbon of the precursor imidazolium salt. There are intra-molecular C-H⋯Br-Pd hydrogen bonds in the structure. The two inter-stitial Br atoms, as the counter-anion of the structure, are both located on crystallographic twofold axes and are connected to the complex cations via C-H⋯·Br hydrogen bonds.

Specific CpG sites methylation is associated with hematotoxicity in low-dose benzene-exposed workers.

Benzene is a broadly used industrial chemicals which causes various hematologic abnormalities in human. Altered DNA methylation has been proposed as epigenetic biomarkers in health risk evaluation of benzene exposure, yet the role of methylation at specific CpG sites in predicting hematological effects remains unclear. In this study, we recruited 120 low-level benzene-exposed and 101 control male workers from a petrochemical factory in Maoming City, Guangdong Province, China. Urinary S-phenylmercapturic acid (SPMA) in benzene-exposed workers was 3.40-fold higher than that in control workers (P < 0.001). Benzene-induced hematotoxicity was characterized by reduced white blood cells counts and nuclear division index (NDI), along with an increased DNA damage and urinary 8-hydroxy-2'-deoxyguanosine (all P < 0.05). Methylation levels of TRIM36, MGMT and RASSF1a genes in peripheral blood lymphocytes (PBLCs) were quantified by pyrosequencing. CpG site 6 of TRIM36, CpG site 2, 4, 6 of RASSF1a and CpG site 1, 3 of MGMT methylation were recognized as hot CpG sites due to a strong correlation with both internal exposure and hematological effects. Notably, integrating hot CpG sites methylation of multiple genes reveal a higher efficiency in prediction of integrative damage compared to individual genes at hot CpG sites. The negative dose-response relationship between the combined methylation of hot CpG sites in three genes and integrative damage enabled the classification of benzene-exposed individuals into high-risk or low-risk groups using the median cut-off value of the integrative index. Subsequently, a prediction model for integrative damage in benzene-exposed populations was built based on the methylation status of the identified hot CpG sites in the three genes. Taken together, these findings provide a novel insight into application prospect of specific CpG site methylation as epi-biomarkers for health risk assessment of environmental pollutants.

8-OHdG mediates the association of co-exposure to fifty-five typical endocrine-disrupting chemicals with renal function: a cross-section investigation in Southern Chinese adults.

Individual typical endocrine-disrupting chemicals (EDCs), including organophosphate triesters (OPEs), parabens, triclosan (TCS), bisphenols, benzophenones (BPs), phthalates (PAEs), and synthetic phenolic antioxidants (SPAs), are associated with renal dysfunction. However, the combined effects and underlying mechanisms of mixed EDC exposure on renal function remain unclear. Two hundred ninety-nine adult participants were enrolled in the cross-sectional survey conducted in Guangzhou, China. Urinary levels of 7 OPEs, 6 parabens, TCS, 14 bisphenols, 8 BPs, 15 PAEs, 4 SPAs, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were determined, and estimated glomerular filtration rate (eGFR) was served as the outcome index. We found elevated levels of diphenyl phosphate (DPP), bisphenol A (BPA), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-butyl phthalate (MBP) showed dose-responsive associations with eGFR decline, However, nonlinear associations were observed for bis(2-butoxyethyl) hydrogen phosphate (BBOEP), TCS, 4-hydroxybenzophenone (HBP), mono-n-pentyl phthalate (MnPP), and mono-benzyl phthalate (MBzP). The quantile-based g-computation model demonstrated that a quartile increase in the EDC mixture corresponded to a 0.383-SD decrease (95% CI - 0.658 ~ - 0.108, P = 0.007) in eGFR. Notably, BPA was identified as the primary contributor to this effect. Moreover, 8-OHdG mediated the eGFR decline associated with EDC mixtures with a mediation proportion of 25.49%. A sex-modified effect was also observed (P = 0.004), indicating that exposure to the mixture of EDC was linked to more pronounced renal dysfunction in females. Our novel findings suggest that exposure to a typical mixture of EDCs is associated with renal dysfunction in the general adult population of Southern China. Furthermore, 8-OHdG may play a role in the pathogenesis of EDC mixture-related renal dysfunction.

The effects and potential mechanisms of essential metals on the associations of polycyclic aromatic hydrocarbons with blood cell-based inflammation markers.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are well-acknowledged pro-inflammatory chemicals, but their associations with blood cell-based inflammatory biomarkers need further investigation. Moreover, the effects and mechanisms of essential metals on PAH-related inflammation remain poorly understood. OBJECTS: To elucidate the associations of PAHs on inflammatory biomarkers, as well as the effects and mechanisms of essential metals on these associations. METHODS: A cross-sectional study was conducted on 1388 coke oven workers. We analyzed the modification effects of key essential metal(s) on PAHs-inflammatory biomarkers associations. To explore the possible mechanisms from an inflammation perspective, we performed a bioinformatic analysis on the genes of PAHs and essential metals obtained from the Comparative Toxicogenomics Database (CTD) and performed a mediation analysis. RESULTS: We observed associations of PAHs and essential metals with lymphocyte-to-monocyte ratio (LMR) (P < 0.05). PAH mixtures were inversely associated with LMR (ßQGC-index = -0.18, P < 0.001), with 1-hydroxypyrene (1-OH-Pyr) being the most prominent contributor (weight = 63.37%), whereas a positive association between essential metal mixtures and LMR was observed (ßQGC-index = 0.14, P < 0.001), with tin being the most significant contributor (weight = 51.61%). An inverse association of 1-OH-Pyr with LMR was weakened by increased tin exposure (P < 0.05). The CTD database showed that PAHs and tin compounds co-regulated 22 inflammation-associated genes, but they regulated most genes in opposite directions. Further identified the involvement of oxidative stress and mediation analysis showed that the mediation effect of 8-hydroxydeoxyguanosine (8-OHdG) on 1-OH-Pyr-LMR association presented heterogeneity between low and high tin tertile groups (I2 = 37.84%). CONCLUSION: 1-OH-Pyr and tin were significantly associated with LMR. Modification effects indicated that the inverse association of 1-OH-Pyr with LMR was mitigated with an increase in tin. The mediation effect of 8-OHdG on the inverse association of 1-OH-Pyr with LMR may be partially dependent on tin.

Empirical analysis of lead neurotoxicity mode of action and its application in health risk assessment.

The mode of action (MOA) framework is proposed to inform a biological link between chemical exposures and adverse health effects. Despite a significant increase in knowledge and awareness, the application of MOA in human health risk assessment (RA) remains limited. This study aims to discuss the adoption of MOA for health RA within a regulatory context, taking our previously proposed but not yet validated MOA for lead neurotoxicity as an example. We first conducted a quantitative weight of evidence (qWOE) assessment, which revealed that the MOA has a moderate confidence. Then, targeted bioassays were performed within an in vitro blood-brain barrier (BBB) model to quantitatively validate the scientific validity of key events (KEs) in terms of essentiality and concordance of empirical support (dose/temporal concordance), which increases confidence in utilizing the MOA for RA. Building upon the quantitative validation data, we further conducted benchmark dose (BMD) analysis to map dose-response relationships for the critical toxicity pathways, and the lower limit of BMD at a 5% response (BMDL5) was identified as the point of departure (POD) value for adverse health effects. Notably, perturbation of the Aryl Hydrocarbon Receptor (AHR) signaling pathway exhibited the lowest POD value, measured at 0.0062 µM. Considering bioavailability, we further calculated a provisional health-based guidance value (HBGV) for children's lead intake, determining it to be 2.56 µg/day. Finally, the health risk associated with the HBGV was assessed using the hazard quotient (HQ) approach, which indicated that the HBGV established in this study is a relative safe reference value for lead intake. In summary, our study described the procedure for utilizing MOA in health RA and set an example for MOA-based human health risk regulation.

Co-exposure of petrochemical workers to noise and mixture of benzene, toluene, ethylbenzene, xylene, and styrene: Impact on mild renal impairment and interaction.

Epidemiological evidence concerning effects of simultaneous exposure to noise and benzene, toluene, ethylbenzene, xylene, and styrene (BTEXS) on renal function remains uncertain. In 2020, a cross-sectional study was conducted among 1160 petrochemical workers in southern China to investigate effects of their co-exposure on estimated glomerular filtration rate (eGFR) and mild renal impairment (MRI). Noise levels were assessed using cumulative noise exposure (CNE). Urinary biomarkers for BTEXS were quantified. We found the majority of workers had exposure levels to noise and BTEXS below China's occupational exposure limits. CNE, trans, trans-muconic acid (tt-MA), and the sum of mandelic acid and phenylglyoxylic acid (PGMA) were linearly associated with decreased eGFR and increased MRI risk. We observed U-shaped associations for both N-acetyl-S-phenyl-L-cysteine (SPMA) and o-methylhippuric acid (2-MHA) with MRI. In further assessing the joint effect of BTEXS (ß, -0.164 [95% CI, -0.296 to -0.033]) per quartile increase in all BTEXS metabolites on eGFR using quantile g-computation models, we found SPMA, tt-MA, 2-MHA, and PGMA played pivotal roles. Additionally, the risk of MRI associated with tt-MA was more pronounced in workers with lower CNE levels (P = 0.004). Multiplicative interaction analysis revealed antagonisms of CNE and PGMA on MRI risk (P = 0.034). Thus, our findings reveal negative dose-effect associations between noise and BTEXS mixture exposure and renal function in petrochemical workers. With the exception of toluene, benzene, xylene, ethylbenzene, and styrene are all concerning pollutants for renal dysfunction. Effects of benzene, ethylbenzene, and styrene exposure on renal dysfunction were more pronounced in workers with lower CNE.

MOF-Derived Bimetallic Selenide CoNiSe2 Nanododecahedrons Encapsulated in Porous Carbon Matrix as Advanced Anodes for Lithium-Ion Batteries.

Transition metal selenides have received considerable attention as promising candidates for lithium-ion battery (LIB) anode materials due to their high theoretical capacity and safety characteristics. However, their commercial viability is hampered by insufficient conductivity and volumetric fluctuations during cycling. To address these issues, we have utilized bimetallic metal-organic frameworks to fabricate CoNiSe2/C nanodecahedral composites with a high specific surface area, abundant pore structures, and a surface-coated layer of the carbon-based matrix. The optimized material, CoNiSe2/C-700, exhibited impressive Li+ storage performance with an initial discharge specific capacity of 2125.5 mA h g-1 at 0.1 A g-1 and a Coulombic efficiency of 98% over cycles. Even after 1000 cycles at 1.0 A g-1, a reversible discharge specific capacity of 549.9 mA h g-1 was achieved. The research highlights the synergistic effect of bimetallic selenides, well-defined nanodecahedral structures, stable carbon networks, and the formation of smaller particles during initial cycling, all of which contribute to improved electronic performance, reduced volume change, increased Li+ storage active sites, and shorter Li+ diffusion paths. In addition, the pseudocapacitance behavior contributes significantly to the high energy storage of Li+. These features facilitate rapid charge transfer and help maintain a stable solid-electrolyte interphase layer, which ultimately leads to an excellent electrochemical performance. This work provides a viable approach for fabricating bimetallic selenides as anode materials for high-performance LIBs through architectural engineering and compositional tailoring.

Antimicrobial Resistance of Clostridioides difficile in Children from a Tertiary Pediatric Hospital in Shanghai, China.

Background: Our previous study reported a high rate of recurrence in children with Clostridioides difficile (C. difficile) infection (CDI) after conventional antibiotic therapy. Here, we aimed to explore whether metronidazole and vancomycin resistant C. difficile isolates are circulating in pediatric CDI. Methods: Antimicrobial susceptibility testing (AST) using the agar dilution method according to the Clinical and Laboratory Standard Institute (CLSI) were performed on C. difficile isolates collected from children with CDI between 2019 and 2022 at the Shanghai Children's Hospital. Whole-genome sequencing (WGS) was performed on all C. difficile isolates, and the presence of antibiotic resistance genes (ARGs) were identified using Resfinder and the Comprehensive Antibiotic Resistance Database (CARD). The presence of plasmid pCD-METRO was detected using SRST2 (v0.2.0) against 8 pCD-METRO coding sequences. Results: A total of 50 C. difficile isolates were collected from stools of CDI children. The overall resistance rate on all isolates was 30.00% for metronidazole, 6.00% for vancomycin, 0% for rifaximin, 2.00% for rifampin, 24.00% for meropenem, 100.00% for ceftriaxone and clindamycin, 86.00% for erythromycin, 30.0% for levofloxacin, and 50.0% for tetracycline. Multidrug-resistant (MDR) was presented in 44 isolates (88.00%). Sixteen reported potential ARGs relating with resistance to antibiotic classes of aminoglycoside (AAC(6')-Ie-APH(2")-Ia, aad(6), ANT(6)-Ib, APH(2")-If, APH(3')-IIIa), lincosamide-clindamycin-erythromycin (ErmB, ErmQ), fluoroquinolones (CdeA), glycopeptides (vanRG), nucleoside (SAT-4), tetracycline (tetM, tetA(P), tetB(P), tetO), and trimethoprim (dfrF) were identified. However, the pCD-METRO plasmid and vanA/B were not detected in any isolates. Conclusion: C. difficile isolates from children with reduced susceptibility to metronidazole and vancomycin are emerging in pediatric CDI in China. The lack of pCD-METRO plasmid and vanA/B associated with reduced antibiotic susceptibility suggests there are additional mechanisms of resistance.

Visible-Light-Induced Cascade Cyclization of 1-Acryloyl-2-cyanoindole: Access of Difluoroalkylated Pyrrolo[1,2-a]indolediones.

An effective method for accessing diverse difluoroalkylated pyrrolo[1,2-a]indolediones via visible-light-induced PhI(OAc)2-promoted cascade difluoroalkylation/cyclization reaction under mild conditions has been established. This method is noteworthy for its use of DMSO-H2O as a green medium at room temperature and avoidance of photocatalysts. The reactions are straightforward to execute and convenient to expand on, provide good to excellent yields, and have good functional group tolerance.

Selectfluor-mediated tandem cyclization of enaminones with diselenides toward the synthesis of 3-selenylated chromones.

A practical and metal-free approach for the regioselective selenation of chromones employing Selectfluor reagent under mild conditions is described. The developed method is suitable for a wide substrate scope and affords 3-selenylated chromones in good to excellent yield with high selectivity. An ionic mechanism is proposed for this transformation. Furthermore, the application of potassium thiocyanate with enaminones for the synthesis of thiocyano chromones in this transformation is also successful.

Visible-Light-Induced Intramolecular Tandem Cyclization of Unactivated Indoloalkynes for the Synthesis of Sulfonylated and Selenylated Indolo[1,2-a]quinolines.

A convenient and efficient visible-light-induced method has been developed for the construction of sulfonated and selenylated indolo[1,2-a]quinolines through sulfonyl or selenyl radical-initiated tandem cyclization of unactivated alkynes with sodium sulfinates or diaryl diselenides under mild conditions. This protocol, which simply utilizes visible light as the safe and eco-friendly energy source and an inexpensive and nontoxic organic dye as a photocatalyst without the aid of an external photocatalyst, provides various sulfonyl- and selenyl-containing indolo[1,2-a]quinolines in moderate to good yields.

Moderate body lipid accumulation in mice attenuated benzene-induced hematotoxicity via acceleration of benzene metabolism and clearance.

Recent population and animal studies have revealed a correlation between fat content and the severity of benzene-induced hematologic toxicity. However, the precise impact of lipid deposition on benzene-induced hematotoxicity and the underlying mechanisms remain unclear. In this study, we established a mouse model with moderate lipid accumulation by subjecting the mice to an 8-week high-fat diet (45% kcal from fat, HFD), followed by 28-day inhalation of benzene at doses of 0, 1, 10, and 100 ppm. The results showed that benzene exposure caused a dose-dependent reduction of peripheral white blood cell (WBC) counts in both diet groups. Notably, this reduction was less pronounced in the HFD-fed mice, suggesting that moderate lipid accumulation mitigates benzene-related hematotoxicity. To investigate the molecular basis for this effect, we performed bioinformatics analysis of high-throughput transcriptome sequencing data, which revealed that moderate lipid deposition alters mouse metabolism and stress tolerance towards xenobiotics. Consistently, the expression of key metabolic enzymes, such as Cyp2e1 and Gsta1, were upregulated in the HFD-fed mice upon benzene exposure. Furthermore, we utilized a real-time exhaled breath detection technique to monitor exhaled benzene metabolites, and the results indicated that moderate lipid deposition enhanced metabolic activation and increased the elimination of benzene metabolites. Collectively, these findings demonstrate that moderate lipid deposition confers reduced susceptibility to benzene-induced hematotoxicity in mice, at least in part, by accelerating benzene metabolism and clearance.

Mucin2 regulated by Ho1/p38/IL-10 axis plays a protective role in polystyrene nanoplastics-mediated intestinal toxicity.

Micro/nano-plastics (MPs/NPs) are a newly discovered environmental pollutant that can be ingested by humans through food and drinking water. In this study we evaluated the impact of MPs/NPs on the intestinal barrier and its mechanism. Doses of MPs/NPs were used to treat Caco-2/HT29-MTX in-vitro model and in-vivo model. In in-vitro model, 20 nm polystyrene nanoplastics (PS-NPs) had higher cytotoxicity than larger particles (200 nm and 2000 nm), and led to the increase of the permeability along with the decreased expression of tight junction proteins. Intriguingly, 20 nm PS-NPs elevated the expression of MUC2 simultaneously. Further studies revealed that PS-NPs increased the expression of HO1 through ROS generation, and then activated p38 to elevate IL-10 secretion in Caco-2 cell. The IL-10 secreted by Caco-2 cell promoted the expression of MUC2 in HT29-MTX cell through STAT1/3. Elevated MUC2 expression alleviates the cytotoxicity of PS-NPs. Besides, increased intestinal permeability and up-regulation of MUC2 through Ho1/p38/IL-10 pathway was also observed in 20 nm PS-NPs treated mouse model. In conclusion, PS-NPs can induce the intestinal toxicity and result in the increased adaptive expression of MUC2 to resist this adverse effect. People with inadequate mucin expression need to pay more attention to the toxicity of PS-NPs. This study provided a valuable insight for clarifying the mechanism and potential risk of intestinal toxicity induced by nanoplastics.

METTL3-mediated m6A mRNA modification was involved in cadmium-induced liver injury.

Cadmium is an environmental pollutant that has extensive deleterious effects. However, the mechanisms underlying the hepatotoxicity induced by long-term exposure to cadmium remained undefined. In the present study, we explored the role of m6A methylation in the development of cadmium-induced liver disease. We showed a dynamic change of RNA methylation in liver tissue from mice administrated with cadmium chloride (CdCl2) for 3, 6 and 9 months, respectively. Particularly, the METTL3 expression was declined in a time-dependent manner, associated with the degree of liver injury, indicating the involvement of METTL3 in hepatotoxicity induced by CdCl2. Moreover, we established a mouse model with liver-specific over-expression of Mettl3 and administrated these mice with CdCl2 for 6 months. Notably, METTL3 highly expressed in hepatocytes attenuated CdCl2-induced steatosis and liver fibrosis in mice. In vitro assay also showed METTL3 overexpression ameliorated the CdCl2-induced cytotoxicity and activation of primary hepatic stellate cells. Furthermore, transcriptome analysis identified 268 differentially expressed genes both in mice liver tissue treated with CdCl2 for 3 months and 9 months. Among them, 115 genes were predicted to be regulated by METTL3 determined by m6A2Target database. Further analysis revealed the perturbation of metabolic pathway, glycerophospholipid metabolism, ErbB signaling pathway, Hippo signaling pathway, and choline metabolism in cancer, and circadian rhythm, led to hepatotoxicity induced by CdCl2. Collectively, our findings reveal new insight into the crucial role of epigenetic modifications in hepatic diseases caused by long-term exposure to cadmium.

Altered gut microbiota and microbial metabolism in children with hepatic glycogen storage disease: a case-control study.

Background: Accumulating evidence has demonstrated that gut microbiota dysbiosis correlated with altered metabolism are implicated in liver metabolic diseases. However, data on pediatric hepatic glycogen storage disease (GSD) are limited. Here, we aimed to investigate the features of the gut microbiota and metabolites in hepatic GSD children from China. Methods: Totals of 22 hepatic GSD patients and 16 age- and gender-matched healthy children were enrolled from the Shanghai Children's Hospital, China. Pediatric GSD patients were confirmed as having hepatic GSD via genetic diagnosis and/or liver biopsy pathology. The control group comprised children without any history of chronic diseases or clinically relevant GSD or symptoms of any other metabolic diseases. The baseline characteristics of the two groups were gender- and age-matched matched using chi-squared test and the Mann-Whitney U test, respectively. The gut microbiota, bile acids (BAs), and short chain fatty acids (SCFAs) were determined from the feces using 16S ribosomal RNA (rRNA) gene sequencing, ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), and gas chromatography-mass spectrometry (GC-MS), respectively. Results: The alpha diversity of fecal microbiome was significantly lower in hepatic GSD patients [observed species richness (Sobs): P=0.011; abundance-based coverage estimator (ACE): P=0.011; Chao: P=0.011; Shannon: P<0.001], and their microbial community was more distanced from that of the control [principal coordinate analysis (PCoA) on genus level, unweighted UniFrac: P=0.011]. Relative abundances of phyla Firmicutes (P=0.030) and Bacteroidetes (P=0.029), families Lachnospiraceae (P=0.012), Ruminococcaceae (P=0.008), and Peptostreptococcaceare (P=0.031), genera Blautia (P=0.017), Eubacterium_hallii_group (P=0.032), and Faecalibacterium (P=0.017) were decreased, whereas phyla Actinobacteria (P=0.033), Proteobacteria (P=0.049), families Bifidobacteriaceae (P=0.030), Lactobacillaceae (P=0.034), and Veillonellaceae (P=0.033), genera Lactobacillus (P=0.011), Enterobater (P=0.034), and Veillonella (P=0.014) were increased in hepatic GSD. Altered microbial metabolisms were characterized by increased abundances of primary BAs (P=0.009) and decreased concentrations of SCFAs in hepatic GSD children. Furthermore, the altered bacterial genera were correlated with the changes of both fecal BAs and SCFAs. Conclusions: The hepatic GSD patients in this study presented with gut microbiota dysbiosis which correlated with altered BAs metabolism and fecal SCFAs changes. Further studies are needed to investigate the driver of these changes mediated by either the genetic defect, disease status, or diet therapy.

Associations of co-exposure to polycyclic aromatic hydrocarbons and metals with hyperuricemia risk in Chinese coke oven workers: Mediating roles of oxidative damage.

Ubiquitous polycyclic aromatic hydrocarbons (PAHs) and metals could induce hyperuricemia and oxidative damage individually, while their co-exposure effects on hyperuricemia risk and the potential roles of oxidative damage in these health outcomes remain poorly understood. We conducted a cross-sectional study in 1379 coke oven workers. We evaluated the levels of PAH-metal exposure and oxidative damage by urinary monohydroxy-PAHs, plasma benzo [a]pyrene-7,8-diol-9,10-epoxide-albumin (BPDE-Alb) adducts, urinary metals, urinary 8-iso-prostaglandin-F2α, and urinary 8-hydroxydeoxyguanosine (8-OH-dG). The subjects were classified into cases of hyperuricemia and controls by the levels of blood uric acid. We found that the sum of multiple hydroxyphenanthrene (ΣOH-Phe) was robustly associated with the increase in hyperuricemia risk, while rubidium and strontium had robust protective associations with hyperuricemia risk (Ptrend<0.05). The risk association of ΣOH-Phe was weaker in workers with high levels of rubidium and strontium [P for modifying effect (PME) < 0.030]. The protective association of strontium was more pronounced in workers with higher ΣOH-Phe (PME = 0.014). We also found that 8-OH-dG was a risk factor for hyperuricemia (Ptrend = 0.006) and mediated 10.13% of the elevated hyperuricemia risk associated with ΣOH-Phe. Our findings suggested that individual PAHs and metals, as well as their co-exposure, may influence hyperuricemia risk among coke oven workers, with oxidative DNA damage playing a potential mediating role in their associations.

Health risk assessment of cadmium exposure by integration of an in silico physiologically based toxicokinetic model and in vitro tests.

Cadmium (Cd) is a common environmental pollutant that can damage multiple organs, including the kidney. To prevent renal effects, international authorities have set health-based guidance values of Cd from epidemiological studies. To explore the health risk of Cd exposure and whether human equivalent doses (HEDs) derived from in vitro tests match the current guidance values, we integrated renal tubular epithelial cell-based assays with a physiologically based toxicokinetic model combined with the Monte Carlo method. For females, the HEDs (µg/kg/week) derived from KE2 (DNA damage), KE3 (cell cycle arrest), and KE4 (apoptosis) were 0.20 (2.5th-97.5th percentiles: 0.09-0.48), 0.52 (0.24-1.26), and 2.73 (1.27-6.57), respectively; for males the respective HEDs were 0.23 (0.10-0.49), 0.60 (0.27-1.30), and 3.11 (1.39-6.78). Among them, HEDKE4 (female) was close to the tolerable weekly intake (2.5 µg/kg/week) set by the European Food Safety Authority. The margin of exposure (MOE) derived from HEDKE4 (female) indicated that risks of renal toxicity for populations living in cadmium-contaminated regions should be of concern. This study provided a new approach methodology (NAM) for environmental chemical risk assessment using in silico and in vitro methods.

Effects of coexposure to noise and mixture of toluene, ethylbenzene, xylene, and styrene (TEXS) on hearing loss in petrochemical workers of southern China.

Many harmful factors existing simultaneously with noise are reported to induce hearing impairment, such as organic solvents. However, the existing hearing safety limits and current risk assessment for hearing loss rely on single noise exposure. It is urgent to clarify the combined effect of noise and other harmful factors on hearing loss. Petrochemical workers are always exposed to noise and organic solvents, mainly benzene, toluene, ethylbenzene, xylene, and styrene (BTEXS), while the combined effect of their coexposure on hearing remains unclear. Herein we conducted a cross-sectional survey, measuring pure-tone audiometry of 1496 petrochemical workers in southern China. Participants exposed to BTEXS were 569, 524, 156, 452, and 177 respectively. Individual cumulative noise exposure (CNE) levels and BTEXS exposure were assessed. The average CNE was 93.27 ± 4.92 dB(A)·years, and the concentrations of BTEXS were far below the occupational exposure limits of China. Logistic regression analyses showed that CNE was consistently positively associated with hearing loss (HL) and high-frequency hearing loss (HFHL) but not related to speech-frequency hearing loss (SFHL). Compared with participants in the lowest quartile of CNE, those in the highest quartile showed an OR of 5.229 (95% CI: 3.179, 8.598) for HFHL. Two-pollutant model analysis indicated that TEXS exposure was positively associated with HL (OR 1.679, 95%CI 1.086, 2.597), SFHL (OR 2.440, 95%CI 1.255, 4.744), and HFHL (OR 1.475, 95%CI 1.077, 2.020). However, no interactions were observed between CNE and TEXS coexposure on hearing loss. In our study, covariates including smoking and drinking status, body mass index (BMI), ear protection and personal protective equipment, and use of earphone/headphone were adjusted. In conclusion, coexposure to noise and low-level TEXS could induce more severe damage on hearing function than exposure to each alone, especially SFHL. Therefore, petrochemical workers simultaneously exposed to noise and TEXS, even at low-level, should be included in hearing protection programs.

Case Report: Eosinophilic gastritis with pyloric stenosis in immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare X-linked recessive immunodeficiency caused by mutations in the forkhead box protein 3 (FOXP3) gene. IPEX is characterized by the onset of intractable diarrhea, type 1 diabetes mellitus (T1DM), and eczema in the early stages of life. The typical clinic triad for IPEX is not always seen. Here, we report a 15-year-old male patient with atypical IPEX syndrome complicated with severe eosinophilic gastritis (EG) and pyloric stenosis. The patient had noticeable eczema during the first year of life and had a history of food allergies. At the age of 3 years, the patient was diagnosed with EG, Helicobacter pylori (HP) infection, pyloric stenosis with recurrent vomiting, and failure to thrive. The patient did not respond to long-term symptomatic treatments in the following years, including methylprednisolone, proton pump inhibitors (PPI), L-glutamine and sodium gualenate granules, anti-HP therapy, and balloon dilation. At the age of 12 years, the patient received surgical interventions, including a laparoscopic jejunostomy feeding tube placement, gastrojejunal anastomosis bypass, and jejunal-jejunal end-to-side anastomosis. Intractable diarrhea and T1DM were not present in the patient. At the age of 14 years, the patient was diagnosed with IPEX syndrome due to a c.748-750del (p.Lys250del) mutation in the leucine zipper domain of the FOXP3 protein. The patient underwent matched sibling peripheral blood hematopoietic stem cell transplantation (HSCT) and showed good evolution after 3 months of HSCT. In summary, this case report provides information of unusual gastrointestinal findings in IPEX syndrome and highlights the need for increased awareness and early diagnosis of IPEX syndrome, which is vital for improving the patient's outcome.

Transition-metal-free radical difluorobenzylation/cyclization of unactivated alkenes: access to ArCF2-substituted ring-fused quinazolinones.

A mild and efficient transition-metal-free radical difluorobenzylation/cyclization of unactivated alkenes toward the synthesis of difluorobenzylated polycyclic quinazolinone derivatives with easily accessible α,α-difluoroarylacetic acids has been developed. This transformation has the advantages of wide functional group compatibility, a broad substrate scope, and operational simplicity. This methodology provided a highly attractive access to pharmaceutically valuable ArCF2-containing polycyclic quinazolinones.