c-Jun targets miR-451a to regulate HQ-induced inhibition of erythroid differentiation via the BATF/SETD5/ARHGEF3 axis.

Benzene, a widely used industrial chemical, has been clarified to cause hematotoxicity. Our previous study suggested that miR-451a may play a role in benzene-induced impairment of erythroid differentiation. However, the mechanism underlying remains unclear. In this study, we explored the role of miR-451a and its underlying mechanisms in hydroquinone (HQ)-induced suppression of erythroid differentiation in K562 cells. 0, 1.0, 2.5, 5.0, 10.0, and 50 µM HQ treatment of K562 cells resulted in a dose-dependent inhibition of erythroid differentiation, as well as the expression of miR-451a. Bioinformatics analysis was conducted to predict potential target genes of miR-451a and dual-luciferase reporter assays confirmed that miR-451a can directly bind to the 3'-UTR regions of BATF, SETD5, and ARHGEF3 mRNAs. We further demonstrated that over-expression or down-regulation of miR-451a altered the expression of BATF, SETD5, and ARHGEF3, and also modified erythroid differentiation. In addition, BATF, SETD5, and ARHGEF3 were verified to play a role in HQ-induced inhibition of erythroid differentiation in this study. Knockdown of SETD5 and ARHGEF3 reversed HQ-induced suppression of erythroid differentiation while knockdown of BATF had the opposite effect. On the other hand, we also identified c-Jun as a potential transcriptional regulator of miR-451a. Forced expression of c-Jun increased miR-451a expression and reversed the inhibition of erythroid differentiation induced by HQ, whereas knockdown of c-Jun had the opposite effect. And the binding site of c-Jun and miR-451a was verified by dual-luciferase reporter assay. Collectively, our findings indicate that miR-451a and its downstream targets BATF, SETD5, and ARHGEF3 are involved in HQ-induced erythroid differentiation disorder, and c-Jun regulates miR-451a as a transcriptional regulator in this process.

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.

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.

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.

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.

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.

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.

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.

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.

Hematological Effects and Benchmark Doses of Long-Term Co-Exposure to Benzene, Toluene, and Xylenes in a Follow-Up Study on Petrochemical Workers.

Benzene, toluene, and xylenes (BTX) commonly co-exist. Exposure to individual components and BTX-rich mixtures can induce hematological effects. However, the hematological effects of long-term exposure to BTX are still unclear, and respective reference levels based on empirical evidence should be developed. We conducted a follow-up study in BTX-exposed petrochemical workers. Long-term exposure levels were quantified by measuring cumulative exposure (CE). Generalized weighted quantile sum (WQS) regression models and Benchmark Dose (BMD) Software were used to evaluate their combined effects and calculate their BMDs, respectively. Many hematologic parameters were significantly decreased at the four-year follow-up (p < 0.05). We found positive associations of CE levels of benzene, toluene, and xylene with the decline in monocyte counts, lymphocyte counts, and hematocrit, respectively (ß > 0.010, Ptrend < 0.05). These associations were stronger in subjects with higher baseline parameters, males, drinkers, or overweight subjects (Pinteraction < 0.05). BTX had positive combined effects on the decline in monocyte counts, red-blood-cell counts, and hemoglobin concentrations (Ptrend for WQS indices < 0.05). The estimated BMDs for CE levels of benzene, toluene, and xylene were 2.138, 1.449, and 2.937 mg/m3 × year, respectively. Our study demonstrated the hematological effects of long-term BTX co-exposure and developed 8h-RELs of about 0.01 ppm based on their hematological effects.

Benzene Exposure Leads to Lipodystrophy and Alters Endocrine Activity In Vivo and In Vitro.

Benzene is a ubiquitous pollutant and mainly accumulates in adipose tissue which has important roles in metabolic diseases. The latest studies reported that benzene exposure was associated with many metabolic disorders, while the effect of benzene exposure on adipose tissue remains unclear. We sought to investigate the effect using in vivo and in vitro experiments. Male adult C57BL/6J mice were exposed to benzene at 0, 1, 10 and 100 mg/kg body weight by intragastric gavage for 4 weeks. Mature adipocytes from 3T3-L1 cells were exposed to hydroquinone (HQ) at 0, 1, 5 and 25 µM for 24 hours. Besides the routine hematotoxicity, animal experiments also displayed significant body fat content decrease from 1 mg/kg. Interestingly, the circulating non-esterified fatty acid (NEFA) level increased from the lowest dose (ptrend < 0.05). Subsequent analysis indicated that body fat content decrease may be due to atrophy of white adipose tissue (WAT) upon benzene exposure. The average adipocyte area of WAT decreased significantly even from 1 mg/kg with no significant changes in total number of adipocytes. The percentages of small and large adipocytes in WAT began to significantly increase or decrease from 1 mg/kg (all p < 0.05), respectively. Critical genes involved in lipogenesis and lipolysis were dysregulated, which may account for the disruption of lipid homeostasis. The endocrine function of WAT was also disordered, manifested as significant decrease in adipokine levels, especially the leptin. In vitro cell experiments displayed similar findings in decreased fat content, dysregulated critical lipid metabolism genes, and disturbed endocrine function of adipocytes after HQ treatment. Pearson correlation analysis showed positive correlations between white blood cell (WBC) count with WAT fat content and plasma leptin level (r = 0.330, 0.344, both p < 0.05). This study shed light on the novel aspect that benzene exposure could induce lipodystrophy and disturb endocrine function of WAT, and the altered physiology of WAT might in turn affect benzene-induced hematotoxicity and metabolic disorders. The study provided new insight into understanding benzene-induced toxicity and the relationship between benzene and adipose tissue.

Risk assessment and dose-effect of co-exposure to benzene, toluene, ethylbenzene, xylene, and styrene (BTEXS) on pulmonary function: A cross-sectional study.

Inhalation is the most frequent route and the lung is the primary damaged organ for human exposure to benzene, toluene, ethylbenzene, xylene, and styrene (BTEXS). However, there is limited information on the risk and dose-effect of the BTEXS mixture on pulmonary function, particularly the overall effect. We conducted a cross-sectional study in a petrochemical plant in southern China. Spirometry and cumulative exposure dose (CED) of BTEXS were used to measure lung function and exposure levels for 635 workers in 2020, respectively. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were tested and interpreted as percentages to predicted values [FVC or FEV1% predicted], and FEV1 to FVC ratio [FEV1/FVC (%)]. We found the reduction in FVC% predicted and the risk of lung ventilation dysfunction (LVD) and its two subtypes (mixed and restrictive ventilation dysfunction, MVD, and MVD) were significantly associated with BTEXS individuals. In addition, pulmonary function damage associated with BTEXS was modified by the smoking status and age. Generalized weighted quantile sum (gWQS) regressions were used to estimate the overall dose-effect on lung function damage induced by the BTEXS mixture. Our results show wqs, an index of weighted quartiles for BTEXS, was potentially associated with the reduction in FVC and FEV1% predicted with the coefficients [95% confidence intervals (CI)] between -1.136 (-2.202, -0.070) and -1.230 (-2.265, -0.195). Odds ratios (ORs) and 95% CIs for the wqs index of LVD, MVD, and RVD were 1.362 (1.129, 1.594), 1.323 (1.084, 1.562), and 1.394 (1.096, 1.692), respectively. Furthermore, xylene, benzene, and toluene in the BTEXS mixture potentially contribute to the development of lung function impairment. Our novel findings demonstrated the dose-response relationships between pulmonary function impairment and the BTEXS mixture and disclosed the potential key pollutants in the BTEXS mixture.

Association between exposure to a mixture of benzene, toluene, ethylbenzene, xylene, and styrene (BTEXS) and small airways function: A cross-sectional study.

BACKGROUND: Lung is one of the primary target organs of benzene, toluene, ethylbenzene, xylene, and styrene (BTEXS). Small airways dysfunction (SAD) might be a sensitive indicator of early chronic respiratory disease. Here, we explored the relationships between exposure to BTEXS and small airways function, and identified the priority control pollutants in BTEXS mixtures. METHODS: 635 petrochemical workers were recruited. Standard spirometry testing was conducted by physicians. The cumulative exposure dose (CED) of BTEXS for each worker was estimated. The peak expiratory flow (PEF), forced expiratory flow between 25 and 75% of forced vital capacity (FEF25∼75%), and the expiratory flow rate found at 25%, 50%, and 75% of the remaining exhaled vital capacity (MEF25%, MEF50%, and MEF75%) were measured. SAD was also evaluated based on measured parameters. The associations between exposure to BTEXS individuals or mixtures and small airways function were evaluated using generalized linear regression models (GLMs) and quantile g-computation models (qgcomp). Meanwhile, the weights of each homolog in the association were estimated. RESULTS: The median CED of BTEXS are 9.624, 19.306, 24.479, 28.210, and 46.781 mg/m3·years, respectively. A unit increase in ln-transformed styrene CED was associated with a decrease in FEF25∼75% and MEF50% based on GLMs. One quartile increased in BTEXS mixtures (ln-transformed) was significantly associated with a 0.325-standard deviation (SD) [95% confidence interval (CI): -0.464, -0.185] decline in FEF25∼75%, a 0.529-SD (95%CI: -0.691, -0.366) decline in MEF25%, a 0.176-SD (95%CI: -0.335, -0.017) decline in MEF75%, and increase in the risk of abnormal of SAD [risk ratios (95%CI): 1.520 (95%CI: 1.143, 2.020)]. Benzene and styrene were the major chemicals in BTEXS for predicting the overall risk of SAD. CONCLUSION: Our novel findings demonstrate the significant association between exposure to BTEXS mixture and small airways function decline and the potential roles of key homologs (benzene and styrene) in SAD.

Assessment of intestinal injury of hexavalent chromium using a modified in vitro gastrointestinal digestion model.

Intestinal injury assessment of hexavalent chromium (Cr-VI) in humans is crucial for quantifying assessment of adverse health risk posed by the intake of Cr (VI)-contaminated water. To overcome the deficiency in simulating human gastric reduction and intestinal absorption, we modified the constituents of simulated gastric fluid in in vitro digestion method by adding reductants glutathione (18 µM) and ascorbic acid (180 µM), which incorporated with human intestinal epithelial model to construct an in vitro gastrointestinal digestion (IVGD) model for intestinal injury assessment. Cr-VI bioaccessibility results from IVGD model showed that weak gastric acidity significantly increased the intestinal accessible Cr-VI dose by 22.41-38.43 folds. The time-course intestinal absorption indicated prolongation of intestinal exposure destroyed the intestinal epithelium, and 24 h after Cr-VI treatment was a good time point to perform intestinal absorption and toxicity assessment. A series of cell-based bioassays provided initial warning of adverse effect, suggesting that epithelial integrity exhibited greatest sensitivity to Cr-VI exposure and might be used as a sensitive marker for the toxicity assessment of oral exposure to Cr-VI. Notably, this study provides a feasible strategy for delineation of Cr-VI biotransformation and intestinal injury following ingestion exposure, which contributes to address the toxicity data gap of low-dose exposure in humans and puts forward a reference for intestinal toxicity assessment of other chemicals.

Characteristics and management of children with Clostridioides difficile infection at a tertiary pediatric hospital in China

ABSTRACT Background: Clostridiodes difficile infection (CDI) is one of the most common causes of antibiotic-associated diarrhea in children. Conventional antibiotics and emerging fecal micro-biota transplantation (FMT) are used to treat CDI. Methods: Children with CDI admitted to the Shanghai Children's Hospital, from September 2014 to September 2020, were retrospectively included to this observational study. Pediatric patients were assigned as initial CDI and recurrent CDI (RCDI), and symptoms, comorbid-ities, imaging findings, laboratory tests, and treatments were systematically recorded and analyzed. Results: Of 109 pediatric patients with CDI, 58 were boys (53.2%), and the median age was 5 years (range, 2-9 years). The main clinical symptoms of CDI children were diarrhea (109/109, 100%), hematochezia (55/109, 50.46%), abdominal pain (40/109, 36.70%); fever, pseudomembrane, vomit, and bloating were observed in 39 (35.78%), 33 (30.28%), and 24 (22.02%) patients, respectively. For the primary therapy with conventional antibiotics, 68 patients received metronidazole, and 41 patients received vancomycin. RCDI occurred in 48.53% (33/68) of those initially treated with metronidazole compared with 46.33% (19/41) of those initially treated with vancomycin (p=0.825). The total resolution rate of FMT for RCDI children was significantly higher than with vancomycin treatment (28/29, 96.55% vs 11/23, 47.83%, p < 0.001). There were no serious adverse events (SAEs) reported after two months of FMT. Conclusions: The major manifestations of children with CDI were diarrhea, hematochezia, and abdominal pain. The cure rate of FMT for pediatric RCDI is superior to vancomycin treatment.

Construction of Mode of Action for Cadmium-Induced Renal Tubular Dysfunction Based on a Toxicity Pathway-Oriented Approach.

Although it is recognized that cadmium (Cd) causes renal tubular dysfunction, the mechanism of Cd-induced nephrotoxicity is not yet fully understood. Mode of action (MOA) is a developing tool for chemical risk assessment. To establish the mechanistic MOA of Cd-induced renal tubular dysfunction, the Comparative Toxicogenomics Database (CTD) was used to obtain genomics data of Cd-induced nephrotoxicity, and Ingenuity® Pathway Analysis (IPA) software was applied for bioinformatics analysis. Based on the perturbed toxicity pathways during the process of Cd-induced nephrotoxicity, we established the MOA of Cd-induced renal tubular dysfunction and assessed its confidence with the tailored Bradford Hill criteria. Bioinformatics analysis showed that oxidative stress, DNA damage, cell cycle arrest, and cell death were the probable key events (KEs). Assessment of the overall MOA of Cd-induced renal tubular dysfunction indicated a moderate confidence, and there are still some evidence gaps to be filled by rational experimental designs.

Microbial and metabolic features associated with outcome of infliximab therapy in pediatric Crohn's disease.

Gut microbial dysbiosis and altered metabonomics have been implicated in the pathogenesis of Crohn's disease (CD). The aim of our study was to characterize the gut microbiome structure and metabolic activities in pediatric CD patients with different clinical outcomes after infliximab (IFX) therapy. Fecal samples were collected from 20 healthy children and 29 newly diagnosed pediatric CD patients. 16S rRNA/ITS2 gene sequencing and targeted metabolomics analysis were applied to profile the gut bacterial microbiome, mycobiome, and metabolome, respectively. Pediatric CD patients exhibited lower relative abundances of short-chain fatty acids (SCFAs)-producing bacteria including Faecalibacterium, Clostridium clusters IV and XIVb, Roseburia, and Ruminococcus, which were correlated with reduced fecal levels of SCFAs. Decreased unconjugated bile acids (BAs) pool size and a lower unconjugated/conjugated BAs ratio were associated with reduced relative abundances of Bifidobacterium and Clostridium clusters IV and XIVb which contain bile salt hydrolases (BSH) genes. IFX treatment enriched the BSH-producing bacteria in CD subjects, which may explain a decreased level of conjugated BAs and an increase in unconjugated BAs as well as the unconjugated/conjugated BAs ratio. Furthermore, a sustained response (SR) of IFX therapy was associated with higher abundances of Methylobacterium, Sphingomonas, Staphylococcus, and Streptococcus, and higher fecal concentrations of amino acids, including L-aspartic acid, linoleic acid, and L-lactic acid at baseline. Our study suggests that the effects of IFX might be partially mediated by enriching bacteria taxa that producing SCFAs and BSH thereby inhibiting inflammation and restoring the BA metabolism. Some fecal bacteria and metabolites may be predictive of outcomes of IFX therapy for pediatric CD patients.

Perturbation of Specific Signaling Pathways Is Involved in Initiation of Mouse Liver Fibrosis.

BACKGROUND AND AIMS: To identify the regulatory role of protein phosphatase 2A (PP2A) in the development of liver disease, we generated a mouse model with hepatocyte-specific deletion of Ppp2r1a gene (encoding PP2A Aα subunit). APPROACH AND RESULTS: Homozygote (HO) mice and matched wild-type littermates were investigated at 3, 6, 9, 12, 15, and 18 months of age. Pathological examination showed that PP2A Aα deficiency in hepatocytes resulted in progressive liver fibrosis phenotype from 9 months of age. No hepatocyte death was observed in HO mice. However, perturbation of pathways including epidermal growth factor receptor 1 (EGFR1), amino acid metabolism, and translation factors as well as leptin and adiponectin led to pronounced hepatic fibrosis. In vitro studies demonstrated the involvement of specific B subunit complexes in the regulation of EGFR1 signaling pathway and cross talk between defected hepatocytes and stimulation of interstitial hyperplasia. It is noteworthy that HO mice failed to develop hepatocellular carcinoma for as long as 22 months of age. We further demonstrate that PP2A Aß-containing holoenzymes played a critical role in preventing hepatocyte apoptosis and antagonizing tumorigenesis through specific pathways on Aα loss. Furthermore, PP2A Aα and Aß were functionally distinct, and the Aß isoform failed to substitute for Aα in the development of inflammation and liver fibrosis. CONCLUSIONS: These observations identify pathways that contribute to the pathogenesis of liver fibrosis and provide putative therapeutic targets for its treatment.