Molecular mechanisms of environmental exposures and human disease.

A substantial proportion of disease risk for common complex disorders is attributable to environmental exposures and pollutants. An appreciation of how environmental pollutants act on our cells to produce deleterious health effects has led to advances in our understanding of the molecular mechanisms underlying the pathogenesis of chronic diseases, including cancer and cardiovascular, neurodegenerative and respiratory diseases. Here, we discuss emerging research on the interplay of environmental pollutants with the human genome and epigenome. We review evidence showing the environmental impact on gene expression through epigenetic modifications, including DNA methylation, histone modification and non-coding RNAs. We also highlight recent studies that evaluate recently discovered molecular processes through which the environment can exert its effects, including extracellular vesicles, the epitranscriptome and the mitochondrial genome. Finally, we discuss current challenges when studying the exposome - the cumulative measure of environmental influences over the lifespan - and its integration into future environmental health research.

AESurv: autoencoder survival analysis for accurate early prediction of coronary heart disease.

Coronary heart disease (CHD) is one of the leading causes of mortality and morbidity in the United States. Accurate time-to-event CHD prediction models with high-dimensional DNA methylation and clinical features may assist with early prediction and intervention strategies. We developed a state-of-the-art deep learning autoencoder survival analysis model (AESurv) to effectively analyze high-dimensional blood DNA methylation features and traditional clinical risk factors by learning low-dimensional representation of participants for time-to-event CHD prediction. We demonstrated the utility of our model in two cohort studies: the Strong Heart Study cohort (SHS), a prospective cohort studying cardiovascular disease and its risk factors among American Indians adults; the Women's Health Initiative (WHI), a prospective cohort study including randomized clinical trials and observational study to improve postmenopausal women's health with one of the main focuses on cardiovascular disease. Our AESurv model effectively learned participant representations in low-dimensional latent space and achieved better model performance (concordance index-C index of 0.864 ± 0.009 and time-to-event mean area under the receiver operating characteristic curve-AUROC of 0.905 ± 0.009) than other survival analysis models (Cox proportional hazard, Cox proportional hazard deep neural network survival analysis, random survival forest, and gradient boosting survival analysis models) in the SHS. We further validated the AESurv model in WHI and also achieved the best model performance. The AESurv model can be used for accurate CHD prediction and assist health care professionals and patients to perform early intervention strategies. We suggest using AESurv model for future time-to-event CHD prediction based on DNA methylation features.

Achieving Ideal and Environmentally Stable n-Type Charge Transport in Polymer Field-Effect Transistors.

Realizing ideal charge transport in field-effect transistors (FETs) of conjugated polymers is crucial for evaluating device performance, such as carrier mobility and practical applications of conjugated polymers. However, the current FETs using conjugated polymers as the active layers generally show certain non-ideal transport characteristics and poor stability. Here, ideal charge transport of n-type polymer FETs is achieved on flexible polyimide substrates by using an organic-inorganic hybrid double-layer dielectric. Deposited conjugated polymer films show highly ordered structures and low disorder, which are supported by grazing-incidence wide-angle X-ray scattering, near-edge X-ray absorption fine structure, and molecular dynamics simulations. Furthermore, the organic-inorganic hybrid double-layer dielectric provides low interfacial defects, leading to excellent charge transport in FETs with high electron mobility (1.49 ± 0.46 cm2 V-1 s-1) and ideal reliability factors (102 ± 7%). Fabricated polymer FETs show a self-encapsulation effect, resulting in high stability of the FET charge transport. The polymer FETs still work with high mobility above 1 cm2 V-1 s-1 after storage in air for more than 300 days. Compared with state-of-the-art conjugated polymer FETs, this work simultaneously achieves ideal charge transport and environmental stability in n-type polymer FETs, facilitating rapid device optimization of high-performance polymer electronics.

MicroRNA-431-5p inhibits angiogenesis, lymphangiogenesis, and lymph node metastasis by affecting TGF-ß1/SMAD2/3 signaling via ZEB1 in gastric cancer.

Accumulating evidence suggests that lymphangiogenesis plays a crucial role in lymphatic metastasis, leading to tumor immune tolerance. However, the specific mechanism remains unclear. In this study, miR-431-5p was markedly downregulated in both gastric cancer (GC) tissues and plasma exosomes, and its expression were correlated negatively with LN metastasis and poor prognosis. Mechanistically, miR-431-5p weakens the TGF-ß1/SMAD2/3 signaling pathway by targeting ZEB1, thereby suppressing the secretion of VEGF-A and ANG2, which in turn hinders angiogenesis, lymphangiogenesis, and lymph node (LN) metastasis in GC. Experiments using a popliteal LN metastasis model in BALB/c nude mice demonstrated that miR-431-5p significantly reduced popliteal LN metastasis. Additionally, miR-431-5p enhances the efficacy of anti-PD1 treatment, particularly when combined with galunisertib, anti-PD1 treatment showing a synergistic effect in inhibiting GC progression in C57BL/6 mice. Collectively, these findings suggest that miR-431-5p may modulate the TGF-ß1/SMAD2/3 pathways by targeting ZEB1 to impede GC progression, angiogenesis, and lymphangiogenesis, making it a promising therapeutic target for GC management.

Myosteatosis predicts postoperative complications and long-term survival in robotic gastrectomy for gastric cancer: A propensity score analysis.

BACKGROUND: Robotic gastrectomy is increasingly utilized for gastric cancer, but high morbidity remains a concern. Myosteatosis or low skeletal muscle density reflecting fatty infiltration, associates with complications after other cancer surgeries but has not been evaluated for robotic gastrectomy. METHODS: This retrospective study analysed 381 patients undergoing robotic gastrectomy for gastric cancer from September 2019 to October 2022. Myosteatosis was quantified on preoperative computed tomography (CT) images at lumbar 3 (L3). Propensity score matching addressed potential confounding between myosteatosis and non-myosteatosis groups. Outcomes were postoperative complications, 30 days mortality, 30 days readmissions and survival. RESULTS: Myosteatosis was present in 33.6% of patients. Myosteatosis associated with increased overall (47.7% vs. 26.5%, p < 0.001) and severe complications (12.4% vs. 4.9%, p < 0.001). After matching, myosteatosis remained associated with increased overall complications, major complications, intensive care unit (ICU) transfer and readmission (all p < 0.05). Myosteatosis independently predicted overall [odds ratio (OR) = 2.86, 95% confidence interval (CI): 1.57-5.20, p = 0.001] and severe complications (OR = 4.81, 95% CI: 1.51-15.27, p = 0.008). Myosteatosis also associated with reduced overall (85.0% vs. 93.2%, p = 0.015) and disease-free survival (80.3% vs. 88.4%, p=0.029). On multivariate analysis, myosteatosis independently predicted poorer survival [hazard ratio (HR) = 2.83, 95% CI: 1.32-6.08, p=0.012] and disease-free survival (HR = 1.83, 95% CI: 1.01-3.30, p=0.032). CONCLUSION: Preoperative CT-defined myosteatosis independently predicts increased postoperative complications and reduced long-term survival after robotic gastrectomy for gastric cancer. Assessing myosteatosis on staging CT could optimize preoperative risk stratification.

GALNT6 promotes bladder cancer malignancy and immune escape by epithelial-mesenchymal transition and CD8+ T cells.

Bladder cancer (BC) ranks as the sixth cancer in males and the ninth most common cancer worldwide. Conventional treatment modalities, including surgery, radiation, chemotherapy, and immunotherapy, have limited efficacy in certain advanced instances. The involvement of GALNT6-mediated aberrant O-glycosylation modification in several malignancies and immune evasion is a subject of speculation. However, its significance in BC has not been investigated. Through the integration of bioinformatics analysis and laboratory experimentation, we have successfully clarified the role of GALNT6 in BC. Our investigation revealed that GALNT6 has significant expression in BC, and its high expression level correlates with advanced stage and high grade, leading to poor overall survival. Moreover, both in vitro and in vivo experiments demonstrate a strong correlation between elevated levels of GALNT6 and tumor growth, migration, and invasion. Furthermore, there is a negative correlation between elevated GALNT6 levels, the extent of CD8+ T cell infiltration in the tumor microenvironment, and the prognosis of patients. Functional experiments have shown that the increased expression of GALNT6 could enhance the malignant characteristics of cancer cells by activating the epithelial-mesenchymal transition (EMT) pathway. In brief, this study examined the impact of GALNT6-mediated abnormal O-glycosylation on the occurrence and progression of bladder cancer and its influence on immune evasion. It also explored the possible molecular mechanism underlying the interaction between tumor cells and immune cells, as well as the bidirectional signaling involved. These findings offer a novel theoretical foundation rooted in glycobiology for the clinical application of immunotherapy in BC.

Combined systemic inflammatory immune index and prognostic nutrition index as chemosensitivity and prognostic markers for locally advanced gastric cancer receiving neoadjuvant chemotherapy: a retrospective study.

BACKGROUND: The prognosis nutritional index (PNI) and the systemic inflammatory immunological index (SII) are characteristic indicators of the nutritional state and the systemic inflammatory response, respectively. However, there is an unknown combined effect of these indicators in the clinic. Therefore, the practicality of using the SII-PNI score to predict prognosis and tumor response of locally advanced gastric cancer (LAGC) following chemotherapy was the main focus of this investigation. METHODS: We retrospectively analyzed 181 patients with LAGC who underwent curative resection after neoadjuvant chemotherapy in a prospective study (NCT01516944). We divided these patients into tumour regression grade(TRG) 3 and non-TRG3 groups based on tumor response (AJCC/CAP guidelines). The SII and PNI were assessed and confirmed the cut-off values before treatment. The SII-PNI values varied from 0 to 2, with 2 being the high SII (≥ 471.5) as well as low PNI (≤ 48.6), a high SII or low PNI is represented by a 1 and neither is represented by a 0, respectively. RESULTS: 51 and 130 samples had TRG3 and non-TRG3 tumor responses respectively. Patients with TRG3 had substantially higher SII-PNI scores than those without TRG3 (p < 0.0001). Patients with greater SII-PNI scores had a poorer prognosis (p < 0.0001). The SII-PNI score was found to be an independent predictor of both overall survival (HR = 4.982, 95%CI: 1.890-10.234, p = 0.001) and disease-free survival (HR = 4.763, 95%CI: 1.994-13.903, p = 0.001) in a multivariate analysis. CONCLUSION: The clinical potential and accuracy of low-cost stratification based on SII-PNI score in forecasting tumor response and prognosis in LAGC is satisfactory.

Metabolomic Effects of Folic Acid Supplementation in Adults: Evidence from the FACT Trial.

BACKGROUND: Folic acid (FA) is the oxidized form of folate found in supplements and FA-fortified foods. Most FA is reduced by dihydrofolate reductase to 5-methyltetrahydrofolate (5mTHF); the latter is the form of folate naturally found in foods. Ingestion of FA increases the plasma levels of both 5mTHF and unmetabolized FA (UMFA). Limited information is available on the downstream metabolic effects of FA supplementation, including potential effects associated with UMFA. OBJECTIVE: We aimed to assess the metabolic effects of FA-supplementation, and the associations of plasma 5mTHF and UMFA with the metabolome in FA-naïve Bangladeshi adults. METHODS: Sixty participants were selected from the Folic Acid and Creatine Trial; half received 800 µg FA/day for 12 weeks and half placebo. Plasma metabolome profiles were measured by high-resolution mass spectrometry, including 170 identified metabolites and 26,541 metabolic features. Penalized regression methods were used to assess the associations of targeted metabolites with FA-supplementation, plasma 5mTHF, and plasma UMFA. Pathway analyses were conducted using Mummichog. RESULTS: In penalized models of identified metabolites, FA-supplementation was associated with higher choline. Changes in 5mTHF concentrations were positively associated with metabolites involved in amino acid metabolism (5-hydroxyindoleacetic acid, acetylmethionine, creatinine, guanidinoacetate, hydroxyproline/n-acetylalanine) and 2 fatty acids (docosahexaenoic acid and linoleic acid). Changes in 5mTHF concentrations were negatively associated with acetylglutamate, acetyllysine, carnitine, propionyl carnitine, cinnamic acid, homogentisate, arachidonic acid, and nicotine. UMFA concentrations were associated with lower levels of arachidonic acid. Together, metabolites selected across all models were related to lipids, aromatic amino acid metabolism, and the urea cycle. Analyses of nontargeted metabolic features identified additional pathways associated with FA supplementation. CONCLUSION: In addition to the recapitulation of several expected metabolic changes associated with 5mTHF, we observed additional metabolites/pathways associated with FA-supplementation and UMFA. Further studies are needed to confirm these associations and assess their potential implications for human health. TRIAL REGISTRATION NUMBER: This trial was registered at https://clinicaltrials.gov as NCT01050556.

Intraocular cetuximab: Safety and effect on axial elongation in young Guinea pigs with lens-induced myopization.

This study aimed to examine the intraocular tolerability of the epidermal growth factor receptor antibody cetuximab, when applied intravitreally, and its effect on axial elongation. Guinea pigs aged 2-3 weeks were subjected to bilateral plano glasses and bilateral lens-induced myopization (LIM) as a single procedure for group I (n = 8) and group II (n = 8), respectively. In the animals of group III (n = 8), group IV (n = 8), and group V (n = 8), the right eyes of the animals, in addition to LIM, received four weekly intravitreal injections of cetuximab (Erbitux®) in doses of 6.25 µg, 12.5 µg, and 25 µg, respectively. As controls, the left eyes, in addition to LIM, received corresponding intraocular injections of phosphate-buffered saline. The animals underwent regular ophthalmoscopic examinations and biometry for axial length measurements. With increasing doses of cetuximab, the inter-eye difference in axial elongation (at study end, left eyes minus right eyes) were significantly the smallest in group I (0.00 ± 0.02 mm) and group II (-0.01 ± 0.02 mm), they were larger in group III (0.04 ± 0.04 mm) and group IV (0.10 ± 0.03 mm), and they were the largest in group V (0.11 ± 0.01 mm). The inter-eye difference in axial elongation enlarged (P < 0.001) with the number of injections applied. Retinal thickness at the posterior pole (right eyes) was significantly thicker in group V than in group II (P < 0.01). The density of apoptotic cells (visualized by TUNEL-staining) did not vary significantly between any of the groups (all P > 0.05). The results suggest that intravitreal injections of cetuximab in young guinea pigs with LIM resulted in a reduction in axial elongation in a dose-dependent and number of treatment-dependent manner. Intraocular toxic effects, such as intraocular inflammation, retinal thinning, or an increased density of apoptotic cells in the retina, were not observed in association with the intravitreally applied cetuximab.

The scaffold of neutrophil extracellular traps promotes CCA progression and modulates angiogenesis via ITGAV/NFκB.

Neutrophil extracellular traps (NETs) have garnered attention for their dual role in host defense and tumor promotion. With their involvement documented across a spectrum of tumors, their influence on the progression of cholangiocarcinoma (CCA) is of paramount interest. We employed immunohistochemistry and immunofluorescence to detect NET deposition in CCA tissues. Through in vitro and in vivo investigation, including CCA organoid and transposon-based models in PAD4 KO mice, we explored the effects of NETs on cell proliferation and metastasis. Molecular insights were gained through RNA sequencing, enzyme linked immunosorbent assay, and chromatin immunoprecipitation. Elevated intratumoral NET deposition within CCA tissues was associated with poor survival. The influence of NETs on CCA proliferation, migration and invasion was primarily mediated by NET-DNA. RNA sequencing unveiled the activation of the NFκB signaling pathway due to NET-DNA stimulation. NET-DNA pull-down assay coupled with mass spectrometry revealed the interaction between NET-DNA and αV integrin (ITGAV), culmination in the activation of the NFκB pathway. Furthermore, NET-DNA directly upregulated the expression of VEGF-A in cancer cells. The study unequivocally establishes NETs as facilitators of CCA progression, orchestrating proliferation, metastasis, and angiogenesis through ITGAV/NFκB pathway activation. This novel insight positions NETs as prospective therapeutic targets for managing CCA patients. By implementing a variety of methodologies and drawing intricate connections between NETs, DNA interactions, and signaling pathways, this research expands our comprehension of the complex interplay between the immune system and cancer progression, offering promising avenues for intervention.

Tumor-Targeted CO Nanodelivery System Design and Therapy for Hepatocellular Carcinoma.

In recent years, carbon monoxide (CO) has garnered increased attention as a novel green therapy for hepatocellular carcinoma (HCC) treatment. However, the CO donor is still limited in clinical application due to its lack of targeted ability and unstable release rate. Here, self-assembled amphiphilic nanomicelles glucose-polyethylene glycol (PEG)-lipoic acid (LA)-Fe2(CO)6 (Glu-Fe2(CO)6) are first designed as a CO donor and synthesized via a chemical method, combining glucose with Fe2(CO)6 through PEG-LA. Some advantages of this tumor-targeted Glu-Fe2(CO)6 delivery system include (I) good water-solubility, (II) the glutathione responsive CO slow release, (III) the active tumor-targeted ability of glucose as targeted ligands, and (IV) outstanding efficacy of antitumor and safety of CO therapy of HCC both in vitro and in vivo. These findings suggest that Glu-Fe2(CO)6 nanomicelles hold promise for enhancing antitumor therapeutic capabilities, presenting a novel tumor-targeted delivery strategy in gas therapy for HCC treatment.

Trophectoderm biopsy is associated with lower risks of moderate to extreme prematurity and low birthweights: a national registry cohort study of singleton livebirths from frozen-thawed blastocyst transfers.

BACKGROUND: Trophectoderm biopsy has become the mainstay assisted reproductive technique performed for preimplantation genetic testing, accounting for 43.8% of embryo transfer cycles in the United States in 2019 alone. Despite its prevalence, data on the obstetric and perinatal outcomes post-trophectoderm biopsy remains sparse and mixed. OBJECTIVE: This study aimed to examine the risks of adverse perinatal outcomes in birthweights and prematurity after transfers of the vitrified-thawed blastocyst with trophectoderm biopsy for preimplantation genetic testing. STUDY DESIGN: This was a retrospective observational cohort study of 45,712 singleton livebirths resulting from autologous vitrified-thawed blastocyst transfer cycles with or without trophectoderm biopsy for preimplantation genetic testing, reported by participating member clinics to the Society for Assisted Reproductive Technology national registry between 2014 and 2017. Adverse perinatal outcomes of preterm births and low birthweights were analyzed. Multivariable regression analyses were performed to control for covariates. Comparing the trophectoderm biopsy (n=21,584) and no trophectoderm biopsy (n=24,128) groups, adjusted odds ratios were calculated for the outcomes of small-for-gestational-age, large-for-gestational-age, low birthweight <2500 g, very low birthweight <1500 g, extremely low birthweight <1000 g, late preterm births <37 weeks, moderate preterm births <34 weeks, and extremely preterm births <28 weeks. RESULTS: Women in the trophectoderm biopsy group were older and more likely to have prior pregnancies, deliveries, and a history of spontaneous abortions. Tobacco use, diminished ovarian reserve, and recurrent pregnancy loss were also more prevalent in the trophectoderm biopsy group. Trophectoderm biopsy was not associated with small-for-gestational-age (adjusted odds ratio, 0.97; 95% confidence interval, 0.85-1.12; P=.72) or large-for-gestational-age newborns (adjusted odds ratio, 1.10; 95% confidence interval, 0.99-1.22; P=.09). Risks of preterm births <37 weeks gestation were similar between the biopsy and nonbiopsy groups (adjusted odds ratio, 0.93; 95% confidence interval, 0.85-1.02; P=.11). Trophectoderm biopsy was associated with a significantly lower risk of low birthweight <2500 g (adjusted odds ratio, 0.80; 95% confidence interval, 0.70-0.92; P<.001), very low birthweight <1500 g (adjusted odds ratio, 0.62; 95% confidence interval, 0.46-0.83; P<.001), extremely low birthweight <1000 g (adjusted odds ratio, 0.48; 95% confidence interval, 0.31-0.74; P<.001), moderate preterm birth <34 weeks (adjusted odds ratio, 0.76; 95% confidence interval, 0.64-0.91; P=.003), and extreme preterm birth <28 weeks (adjusted odds ratio, 0.63; 95% confidence interval, 0.43-0.92; P=.02). CONCLUSION: Trophectoderm biopsy is not associated with increased risks of small-for-gestational-age, large-for-gestational-age, or late preterm birth. Risks of low birthweight, very low birthweight, and extremely low birthweight from moderate and extreme preterm births are lower after trophectoderm biopsy, possibly by selecting against confined placental mosaicism or inducing placental epigenetic changes, the mechanisms of which warrant further investigation.

Lysosomal K+ channel TMEM175 promotes apoptosis and aggravates symptoms of Parkinson's disease.

Lysosomes are degradative organelles and play vital roles in a variety of cellular processes. Ion channels on the lysosomal membrane are key regulators of lysosomal function. TMEM175 has been identified as a lysosomal potassium channel, but its modulation and physiological functions remain unclear. Here, we show that the apoptotic regulator Bcl-2 binds to and inhibits TMEM175 activity. Accordingly, Bcl-2 inhibitors activate the channel in a caspase-independent way. Increased TMEM175 function inhibits mitophagy, disrupts mitochondrial homeostasis, and increases production of reactive oxygen species (ROS). ROS further activates TMEM175 and thus forms a positive feedback loop to augment apoptosis. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), knockout (KO) of TMEM175 mitigated motor impairment and dopaminergic (DA) neuron loss, suggesting that TMEM175-mediated apoptosis plays an important role in Parkinson's disease (PD). Overall, our study reveals that TMEM175 is an important regulatory site in the apoptotic signaling pathway and a potential therapeutic target for Parkinson's disease (PD).

Interleukin-19 enhances eosinophil infiltration through upregulation of epithelium-derived RANTES expression via the ERK/NF-κB signalling pathway in patients with eosinophilic CRSwNP.

BACKGROUD: The recurrence rate of chronic rhinosinusitis with nasal polyps (CRSwNP) is positively correlated with eosinophil infiltration. Increased interleukin (IL)-19 and eosinophil chemokine RANTES levels have been reported in patients with CRSwNP. This study aimed to clarify the role of IL-19 in mediating RANTES expression and eosinophilic infiltration in eosinophilic CRSwNP (Eos CRSwNP). METHODS: Nasal tissue samples were obtained from patients with CRSwNP and controls. The expression of IL-19, its receptors, ECP, and RANTES in tissues was investigated. Primary human nasal epithelial cells (HNECs) and nasal polyp tissue blocks were cultured, then stimulated by IL-19; ERK phosphorylation, NF-κB pathway activation, RANTES level, eosinophils migration and infiltration were detected using RT-qPCR, ELISA, western blotting, HE, immunohistochemistry, immunofluorescence staining, confocal microscopy, and transwell migration assay. RESULTS: The expression of IL-19 and its receptors (IL-20R1/IL-20R2), eosinophil cationic protein, and RANTES in nasal tissues from patients with Eos CRSwNP was significantly increased compared to that in non-Eos CRSwNP and control subjects. IL-19 co-localized with RANTES in nasal tissues and significantly elevated RANTES expression in HNECs. IL-19-blocking antibody and siRNA knockdown of IL-20R1 ameliorated the effect of IL-19 on RANTES secretion in HNECs. Moreover, IL-19-induced RANTES upregulation was associated with the activation of the ERK and NF-κB pathways. NF-κB activation was mediated by the ERK pathway in IL-19-treated HNECs, and IL-19 enhanced eosinophil infiltration in nasal polyp tissue blocks. CONCLUSIONS: Our findings indicate that IL-19 promotes RANTES expression via the ERK/NF-κB pathway in HNECs and is implicated in eosinophil infiltration in patients with Eos CRSwNP.

Foliar Application of Nanoparticles Reduced Cadmium Content in Wheat (Triticum aestivum L.) Grains via Long-Distance "Leaf-Root-Microorganism" Regulation.

Foliar application of beneficial nanoparticles (NPs) exhibits potential in reducing cadmium (Cd) uptake in crops, necessitating a systematic understanding of their leaf-root-microorganism process for sustainable development of efficient nano-enabled agrochemicals. Herein, wheat grown in Cd-contaminated soil (5.23 mg/kg) was sprayed with different rates of four commonly used NPs, including nano selenium (SeNPs)/silica (SiO2NPs)/zinc oxide/manganese dioxide. SeNPs and SiO2NPs most effectively reduced the Cd concentration in wheat grains. Compared to the control, Cd concentration in grains was significantly decreased by 35.0 and 33.3% by applying 0.96 mg/plant SeNPs and 2.4 mg/plant SiO2NPs, and the grain yield was significantly increased by 33.9% with SeNPs application. Down-regulated gene expression of Cd transport proteins (TaNramp5 and TaLCT1) and up-regulated gene expression of vacuolar Cd fixation proteins (TaHMA3 and TaTM20) were observed with foliar SeNPs and SiO2NPs use. SeNPs increased the levels of leaf antioxidant metabolites. Additionally, foliar spray of SeNPs resulted in lower abundances of rhizosphere organic acids and reduced Cd bioavailability in rhizosphere soil, and soil microorganisms related to carbon and nitrogen (Solirubrobacter and Pedomicrobium) were promoted. Our findings underscore the potential of the foliar application of SeNPs and SiO2NPs as a plant and rhizosphere soil metabolism-regulating approach to reduce Cd accumulation in wheat grains.

Activated Carbon Application Simultaneously Alleviates Paddy Soil Arsenic Mobilization and Carbon Emission by Decreasing Porewater Dissolved Organic Matter.

Flooding of paddy fields during the rice growing season enhances arsenic (As) mobilization and greenhouse gas (e.g., methane) emissions. In this study, an adsorbent for dissolved organic matter (DOM), namely, activated carbon (AC), was applied to an arsenic-contaminated paddy soil. The capacity for simultaneously alleviating soil carbon emissions and As accumulation in rice grains was explored. Soil microcosm incubations and 2-year pot experimental results indicated that AC amendment significantly decreased porewater DOM, Fe(III) reduction/Fe2+ release, and As release. More importantly, soil carbon dioxide and methane emissions were mitigated in anoxic microcosm incubations. Porewater DOM of pot experiments mainly consisted of humic-like fluorophores with a molecular structure of lignins and tannins, which could mediate microbial reduction of Fe(III) (oxyhydr)oxides. Soil microcosm incubation experiments cospiking with a carbon source and AC further consolidated that DOM electron shuttling and microbial carbon source functions were crucial for soil Fe(III) reduction, thus driving paddy soil As release and carbon emission. Additionally, the application of AC alleviated rice grain dimethylarsenate accumulation over 2 years. Our results highlight the importance of microbial extracellular electron transfer in driving paddy soil anaerobic respiration and decreasing porewater DOM in simultaneously remediating As contamination and mitigating methane emission in paddy fields.

Exposome Profiling of Environmental Pollutants in Seminal Plasma and Novel Associations with Semen Parameters.

Indicators of male fertility are in decline globally, but the underlying causes, including the role of environmental exposures, are unclear. This study aimed to examine organic chemical pollutants in seminal plasma, including both known priority environmental chemicals and less studied chemicals, to identify uncharacterized male reproductive environmental toxicants. Semen samples were collected from 100 individuals and assessed for sperm concentration, percent motility, and total motile sperm. Targeted and nontargeted organic pollutant exposures were measured from seminal plasma using gas chromatography, which showed widespread detection of organic pollutants in seminal plasma across all exposure classes. We used principal component pursuit (PCP) on our targeted panel and derived one component (driven by etriadizole) associated with total motile sperm (p < 0.001) and concentration (p = 0.03). This was confirmed by the exposome-wide association models using individual chemicals, where etriadizole was negatively associated with total motile sperm (FDR q = 0.01) and concentration (q = 0.07). Using PCP on 814 nontargeted spectral peaks identified a component that was associated with total motile sperm (p = 0.001). Bayesian kernel machine regression identified one principal driver of this association, which was analytically confirmed to be N-nitrosodiethylamine. These findings are promising and consistent with experimental evidence showing that etridiazole and N-nitrosodiethylamine may be reproductive toxicants.

The association between toenail metals and extracellular MicroRNAs (ex-miRNAs) among the participants of the Normative Aging study (NAS).

BACKGROUND: Mechanistic studies of the effects of environmental risk factors have been exploring the potential role of microRNA(miRNAs) as a possible pathway to clinical disease. In this study we examine whether levels of toenail metals are associated with changes in extracellular miRNA(ex-miRNA) expression. METHODS: We used data derived from the Normative Aging Study from 1996 to 2014 to conduct our analyses. We looked at associations between measured toenail metals: arsenic, cadmium, lead, manganese, and mercury and 282 ex-miRNAs in this population using canonical correlation analyses (CCAs) and longitudinal median regression. We adjusted for covariates such as age, education, body mass index, drinking and smoking behaviors, diabetes, and where available, seafood consumption. The p-values obtained from regression analyses were corrected for multiple comparisons. Ex-miRNAs identified to be associated with toenail metal levels were further examined using pathway analyses. RESULTS: Our dataset included 937 observations from 589 men with an average age of 72.9 years at baseline. Both our correlation and regression analyses identified lead and cadmium as exposures most strongly associated with ex-miRNA expression. Numerous ex-miRNAs were identified as being associated with toenail metal levels. miR-27b-3p, in particular, was found to have high correlation with the first canonical dimension in the CCA and was significantly associated with cadmium in the regression analysis. Pathway analyses revealed messenger RNA (mRNA) targets for the ex-miRNAs that were associated with a number of clinical disorders including cancer, cardiovascular disease, and neurological disorders, etc. CONCLUSION: Toenail metals were associated with changes in ex-miRNA levels in both correlational and regression analyses. The ex-miRNAs identified can be linked to a variety of clinical disorders. Further studies are required to validate these findings.

Per- and polyfluoroalkyl substances, polychlorinated biphenyls, organochlorine pesticides, and polybrominated diphenyl ethers and dysregulation of MicroRNA expression in humans and animals-A systematic review.

BACKGROUND: Persistent organic pollutants (POPs) are chemicals characterized by their environmental persistence. Evidence suggests that exposure to POPs, which is ubiquitous, is associated with microRNA (miRNA) dysregulation. miRNA are key regulators in many physiological processes. It is thus of public health concern to understand the relationships between POPs and miRNA as related to health outcomes. OBJECTIVES: This systematic review evaluated the relationship between widely recognized, intentionally manufactured, POPs, including per- and polyfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and organochlorine pesticides (dichlorodiphenyltrichloroethane [DDT], dichlorodiphenyldichloroethylene [DDE], hexachlorobenzene [HCB]), with miRNA expression in both human and animal studies. METHODS: We used PubMed and Embase to systematically search the literature up to September 29th, 2023. Search results for human and animal studies were included if they incorporated at least one POP of interest in relation to at least one miRNA. Data were synthesized to determine the direction and significance of associations between POPs and miRNA. We utilized ingenuity pathway analysis to review disease pathways for miRNA that were associated with POPs. RESULTS: Our search identified 38 eligible studies: 9 in humans and 29 in model organisms. PFAS were associated with decreased expression of miR-19, miR-193b, and miR-92b, as well as increased expression of miR-128, miR-199a-3p, and miR-26b across species. PCBs were associated with increased expression of miR-15a, miR-1537, miR-21, miR-22-3p, miR-223, miR-30b, and miR-34a, as well as decreased expression of miR-130a and let-7b in both humans and animals. Pathway analysis for POP-associated miRNA identified pathways related to carcinogenesis. DISCUSSION: This is the first systematic review of the association of POPs with miRNA in humans and model organisms. Large-scale prospective human studies are warranted to examine the role of miRNA as mediators between POPs and health outcomes.

Exposure to per- and polyfluoroalkyl substances and alterations in plasma microRNA profiles in children.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that persist in the environment and can accumulate in humans, leading to adverse health effects. MicroRNAs (miRNAs) are emerging biomarkers that can advance the understanding of the mechanisms of PFAS effects on human health. However, little is known about the associations between PFAS exposures and miRNA alterations in humans. OBJECTIVE: To investigate associations between PFAS concentrations and miRNA levels in children. METHODS: Data from two distinct cohorts were utilized: 176 participants (average age 17.1 years; 75.6% female) from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort in the United States, and 64 participants (average age 6.5 years, 39.1% female) from the Rhea study, a mother-child cohort in Greece. PFAS concentrations and miRNA levels were assessed in plasma samples from both studies. Associations between individual PFAS and plasma miRNA levels were examined after adjusting for covariates. Additionally, the cumulative effects of PFAS mixtures were evaluated using an exposure burden score. Ingenuity Pathways Analysis was employed to identify potential disease functions of PFAS-associated miRNAs. RESULTS: Plasma PFAS concentrations were associated with alterations in 475 miRNAs in the Teen-LABs study and 5 miRNAs in the Rhea study (FDR p < 0.1). Specifically, plasma PFAS concentrations were consistently associated with decreased levels of miR-148b-3p and miR-29a-3p in both cohorts. Pathway analysis indicated that PFAS-related miRNAs were linked to numerous chronic disease pathways, including cardiovascular diseases, inflammatory conditions, and carcinogenesis. CONCLUSION: Through miRNA screenings in two independent cohorts, this study identified both known and novel miRNAs associated with PFAS exposure in children. Pathway analysis revealed the involvement of these miRNAs in several cancer and inflammation-related pathways. Further studies are warranted to enhance our understanding of the relationships between PFAS exposure and disease risks, with miRNA emerging as potential biomarkers and/or mediators in these complex pathways.