The heterogeneity in associations between circulating fatty acids (FA) and mortality remained underexplored. Proteomics can profile the human physiological status. This study aimed to estimate interactions between FA and proteins in relation to mortality. We randomly divided 30,190 UK Biobank participants into train and test datasets. Multivariable Cox regression was utilized to assess the associations between FA and all-cause mortality and to explore proteome-wide interactions of FA in relation to mortality. Subgroup analyses were conducted to examine heterogeneity across varied protein levels. We also explored interactions between proteins and FA in relation to cause-specific mortality. We documented 3,345 deaths during 13.9 years of follow-up. MUFA-pct, Non-LA Omega-6 pct, Omega-6/Omega-3 ratio and SFA-pct were positively associated with all-cause mortality, while PUFA-pct, DHA-pct, LA-pct, and Omega-3-pct were negatively associated. We identified several robust interactions of proteins with MUFA-pct (n = 3), Omega-3-pct (n = 4), and Omega-6/Omega-3 ratio (n = 2). In subgroup analyses, individuals with high-level TNFRSF1B, MMP10, and CRHBP had higher all-cause mortality risks associated with MUFA-pct, while protective associations between Omega-3-pct and all-cause mortality were stronger among individuals with high-level TSPAN8, PLAU, ITGA5, and CEACAM1. Moreover, participants with high-level TSPAN8 and PLAU had higher risks of all-cause mortality with Omega-6/Omega-3 ratio. For cause-specific mortality, interaction and subgroup results were largely consistent with those of all-cause mortality. Our findings can provide new insights into heterogeneity in FA-mortality associations and highlight potential protein targets for personalized interventions across individuals with different physiological status.

ABSTRACT The heterogeneity in health effects of circulating proteins remained unclear. Previous studies have identified that glycoprotein acetyls (GlycA), a stable biomarker of inflammation, were associated with risks of mortality and chronic diseases. However, it remained unclear whether the health risks of proteins may differ across people with varied GlycA levels. Based on the multi‐omics profiling of the UK Biobank prospective cohort, we evaluated whether GlycA statistically modifies the protein–mortality associations. In the discovery dataset (n = 24,134), we observed that GlycA significantly modified the associations of ANG, CRHBP, CXCL16, and PRRT3 with all‐cause mortality, and these findings were replicated in the validation dataset (n = 6081). Subgroup analyses further indicated that associations between these proteins and mortality can be modulated by GlycA levels. Through exploratory analyses focused on chronic diseases and cause‐specific mortality, we identified that cross‐products of GlycA with these proteins can be associated with cancer mortality and heart failure. Together, the findings will expand our understanding of heterogeneity in protein‐health associations and highlight several potential therapeutic targets for interventions across people with varied inflammation status.

Exposure to heavy metals, namely cadmium, arsenic, lead, mercury, together with manganese, has been increasingly implicated in the prevalence and mortality of Alzheimer’s disease. To further clarify these associations, we conducted a comprehensive meta-analysis by systematically searching the Cochrane Library, PubMed, and Web of Science databases up to July 9, 2024. In total, 21 studies involving 2,867 participants were included for analyses using standardized mean differences, and 8 studies involving 288,737 participants were analyzed using odds ratios (ORs) or hazard ratios (HRs). Using a random-effects model with Stata 17.0, we found that cadmium levels in biological samples were higher in individuals with Alzheimer’s disease relative to those without the condition (SMD = 0.99, 95

Infertility is a global health concern, with asthenozoospermia (AZS) being a common male factor. Our previous research demonstrated that the semenogelin I-derived peptide SgI-52 (SgI-52) binds more rapidly and extensively to demembranated sperm and AZS sperm, significantly inhibiting sperm motility and impairing mitochondrial function. However, the specific molecular targets of SgI-52 on sperm and the mechanisms by which it modulates oxidative stress and sperm function remain unclear. This study therefore investigates the interactions of SgI-52 with sperm surface proteins and its impact on oxidative stress. Sperm proteins from AZS donors were extracted to identify SgI-52 targets using affinity chromatography and quantitative proteomics. The interaction with PRDX 6 was analyzed using AlphaFold 3 predictions and biolayer interferometry, and their localization on sperm membranes was determined by immunofluorescence and immunoelectron microscopy. Western blot measured SgI-52 in seminal plasma and PRDX 6 on sperm membranes. Functional assays evaluated the effects of SgI-52 on PRDX 6 enzymatic activity, oxidative stress levels, and mitochondrial membrane potential in sperm. SgI-52 bound to PRDX 6 and co-localized on sperm membranes. Both seminal plasma SgI-52 and membrane-associated PRDX 6 were higher in AZS donors than in normal donors. Functional assays showed that SgI-52 inhibited PRDX 6 activity, leading to increased ROS and MDA levels and mitochondrial dysfunction in sperm. In vitro study, we observed differential expression of SgI-52 and PRDX6 in normal and AZS samples and revealed their interaction, explaining the preferential binding of SgI-52 to compromised sperm. These findings suggest that SgI-52–derived peptides could serve as molecular probes for sperm quality evaluation and sperm selection in assisted reproductive technologies.

1,3-Diphenylguanidine (DPG) is a commonly used rubber vulcanization accelerator and a major component released from tire wear particles. Concerns have emerged regarding the widespread exposure and potential genotoxicity of DPG and its chlorinated derivative, 1,3-bis-(4-chlorophenyl) guanidine (BCPG). Here, we detected BCPG in the serum of pregnant women with mean concentration of 0.054ng/mL. We subsequently investigated the developmental toxicity of DPG and BCPG in embryonic zebrafish. Both DPG and BCPG exposure can cause lower survival rate, pericardial edema (fluid accumulation around the heart) and higher malformation rate of zebrafish embryos. Furthermore, in both DPG- and BCPG-exposed 96 hpf we observed a dose-dependent decrease in spontaneous movement and locomotion. Additionally, the expression levels of genes involved in cardiac and neurodevelopment pathways were significantly altered in DPG- or BCPG-treated zebrafish embryos. These findings highlight the developmental toxicity of DPG and BCPG, particularly during early life stages, and underscore the need for further investigation into their environmental and health impacts, especially in vulnerable populations such as pregnant women and children.

Perfluorooctane sulfonate (PFOS) is of great concern due to its accumulation in living organisms and reproductive toxicity. Although prior studies indicate that PFOS exposure causes female reproductive disorders, the underlying mechanism remains obscure. This study investigates the molecular mechanisms underlying PFOS‐induced female reproductive toxicity at human‐relevant exposure levels. These results demonstrate that PFOS exposure (0.2 and 20 µ M ) significantly reduces polar body extrusion (PBE) and delays germinal vesicle breakdown (GVBD) in oocytes. Additionally, PFOS exposure (1 mg kg −1 day −1 ) decreases the proportion of two‐cell embryos and reduces progesterone (P4) levels. Elevated O‐GlcNAcylation levels are observed in both ovaries and granulosa cells (GCs) under PFOS treatment. Proteomic profiling of protein O‐GlcNAcylation identifies that the O‐GlcNAcylation of forkhead box k1 (FOXK1) at threonine (Thr) 573 cite involved in ovarian steroidogenesis. Mechanistically, co‐immunoprecipitation (Co‐IP) combined with LC‐MS/MS analysis reveals a physical interaction between FOXK1 and pescadillo ribosomal biogenesis factor 1 (PES1). Increased O‐GlcNAcylation of FOXK1 at Thr573 inhibits the ubiquitination‐mediated degradation of PES1, leading to elevated PES1 expression. Furthermore, PES1 promotes aldo‐keto reductase family 1, member C18 (AKR1C18) to reduce P4 levels, ultimately disrupting oocyte maturation and early embryonic development. Overall, this study provides valuable insights into the role of protein post‐translational modifications in oocyte maturation and embryonic development under PFOS exposure.

Recurrent miscarriage is a chronic and heterogeneous pregnancy disorder lacking effective treatment. Alterations at the maternal-fetal interface are commonly observed in recurrent miscarriage, with the loss of certain cell subpopulations believed to be a key cause. Through single-cell sequencing of recurrent miscarriage patients and healthy donors, we aim to identify aberrancy of cellular features in recurrent miscarriage tissues, providing new insights into the research. Natural killer cells, the most abundant immune cells in the decidua, are traditionally classified into dNK1, dNK2, and dNK3. In this study, we identified a new subset, dNK1/2, absent in recurrent miscarriage tissues. This subset was named because it expresses biomarkers of both dNK1 and dNK2. With further analysis, we discovered that dNK1/2 cells play roles in immunoregulation and cytokine secretion. On the villous side of the interface, a notable decrease of extravillous trophoblast cells was identified in recurrent miscarriage tissues. We clustered extravillous trophoblasts into EVT1 (absent in recurrent miscarriage) and EVT2 (retained in recurrent miscarriage). Pseudotime analysis revealed distinct differentiation paths, identifying CCNB1, HMGB1, and NPM1 as EVT1 biomarkers. Additionally, we found that EVT1 is involved in the regulation of cell death, while EVT2 exhibited more angiogenic activity. Cell communication analysis revealed that interaction between EVT1 and dNK1/2 mediates chemotaxis and endothelial cell regulation, crucial for spiral artery remodeling. The loss of this interaction may impair decidualization, which is associated with recurrent miscarriage. In summary, we propose that the loss of dNK1/2 and EVT1 cells is a significant pathological feature of recurrent miscarriage. SUMMARY SENTENCE:The communication between EVT1 and dNK1/2 mediated the chemotaxis of EVT1 and facilitated regulation of endothelial cell death, initiating spiral artery remodeling. The loss of this specific cellular interaction may result in impaired decidualization, leading to recurrent miscarriage.

Objective:To investigate the associations between eight serum per- and polyfluoroalkyl substances (PFASs) and regional fat depots, we analyzed the data from the National Health and Nutrition Examination Survey (NHANES) 2011-2018 cycles. Methods:Multiple linear regression models were developed to explore the associations between serum PFAS concentrations and six fat compositions along with a fat distribution score created by summing the concentrations of the six fat compositions. The associations between structurally grouped PFASs and fat distribution were assessed, and a prediction model was developed to estimate the ability of PFAS exposure to predict obesity risk. Results:Among females aged 39-59 years, trunk fat mass was positively associated with perfluorooctane sulfonate (PFOS). Higher concentrations of PFOS, perfluorohexane sulfonate (PFHxS), perfluorodecanoate (PFDeA), perfluorononanoate (PFNA), and n-perfluorooctanoate (n-PFOA) were linked to greater visceral adipose tissue in this group. In men, exposure to total perfluoroalkane sulfonates (PFSAs) and long-chain PFSAs was associated with reductions in abdominal fat, while higher abdominal fat in women aged 39-59 years was associated with short-chain PFSAs. The prediction model demonstrated high accuracy, with an area under the curve (AUC) of 0.9925 for predicting obesity risk. Conclusion:PFAS exposure is associated with regional fat distribution, with varying effects based on age, sex, and PFAS structure. The findings highlight the potential role of PFAS exposure in influencing fat depots and obesity risk, with significant implications for public health. The prediction model provides a highly accurate tool for assessing obesity risk related to PFAS exposure.

Bromochloroacetamide (BCAcAm), an inevitable byproduct of the water treatment disinfection process, is widely detected in drinking water. Previous toxicological and in silico results suggested that developmental effects are associated with analogous chemical exposure; however, the key molecular events and underlying mechanisms remain unclear, especially in the early stages of aquatic organisms. In the present study, a zebrafish larval model was used to comprehensively assess the developmental toxicity of BCAcAm via transcriptional, metabolic, biochemical and morphological tests. Integration analyses of RNA sequencing and untargeted metabolomic data revealed crucial biological processes related to drug metabolism, cardiac muscle contraction and oxidative phosphorylation, which started from the initial stage, and ferroptosis progressed to the advanced stage in validated cardiac defects. Biochemical assays further verified ATP depletion, ROS and MDA accumulation, and hyperactivation of detoxification (increased GST activity) and the antioxidative system (increased GSH and GSSG levels). Transcriptionally, BCAcAm led to gpx4 downregulation, iron homeostasis perturbation (upregulated tfr and tf and downregulated fth) and lipid peroxidation (elevated alox12 and lpcat3), suggesting the involvement of ferroptosis. Moreover, the application of Fer-1 (a ferroptosis inhibitor) reversed BCAcAm-induced mitochondrial dysfunction and subsequent cardiotoxicity. In addition, the BMD and IBRv2 indices were derived from molecules across various biological levels. The general ranking of the different biomarkers in terms of better responsiveness and sensitivity performance is as follows: transcriptomics > metabolomics > biochemical assays. In the present study, an approach to detecting chemical-induced adverse outcomes and deciphering the underlying mechanisms through high-throughput data analysis is applied. This study provides valuable insights into the responsiveness and sensitivity of biomarkers, which may be instrumental for evaluating the ecological and health risks associated with newly emerged contaminants.

BACKGROUND:Bisphenol S (BPS) is a substitute for bisphenol A in various commercial products and is increasingly used globally due to restrictions on bisphenol A usage. Consequently, there are increasing public health concerns that substantial effects mediated by synthetic chemicals may impact human health. Recently, epidemiology studies reported associations between bisphenol exposure and nonalcoholic fatty liver disease [metabolic dysfunction-associated steatotic liver disease (MASLD)]. However, the causal relationship and the molecular mechanisms affecting hepatocellular functions are still unknown. OBJECTIVES:Our study aimed to understand the molecular mechanism by which BPS exposure caused hepatic lipid deposition. METHODS:C57BL/6J mice were exposed to BPS for 3 months, and its effects were assessed by histology. RNA sequencing (RNA-seq), assay for transposase-accessible chromatin with high-throughout sequencing (ATAC-seq), and cleavage under targets and tagmentation (CUT&Tag) were used to investigate mechanistic details. ATF3 liver-specific knockout mice and cells were used to validate its functions in BPS-induced hepatotoxicity. RESULTS:Here, mice that were chronically exposed to BPS showed significant lipid deposition in the liver and dyslipidemia and were predisposed to MASLD, accompanied with a reprogrammed liver transcriptional network and chromatin accessibility that was enriched for the Atf3 binding motif. Comparing to the control group, we identified numerous differential Atf3 binding sites associated with signaling pathways integral to lipid catabolism and synthesis in the BPS exposure group, resulting in a drastic surge in lipid accumulation. Moreover, knocking out Atf3 in vitro and in vivo significantly attenuates BPS-induced hepatic lipid accumulation via the regulation of chromatin accessibility and gene expression. Besides, inhibiting JunB also eliminates BPS-induced Atf3 upregulation and lipid accumulation. CONCLUSION:Our study reveals a novel mechanism, through which BPS upregulates JunB and Atf3 to impair hepatic lipid metabolism, and provides new insights into the hepatotoxicity of BPS. https://doi.org/10.1289/EHP17057.

Evidence for associations of housing disadvantages with cardiovascular disease (CVD) is scarce. This study aimed to assess the association of housing disadvantages with CVD among middle-aged and older populations in China. We conducted analyses by data from China Health and Retirement Longitudinal Study, 2011–2018. CVD events were ascertained by self-reported data. A total of 9,843 individuals were included in stroke sub-cohort, and 8,752 individuals were included in heart disease sub-cohort. Cox regression was used to estimate hazard ratio (95

Perfluorohexane sulfonic acid (PFHxS) is extensively used in waterproof coatings and fire-fighting foams, and several studies have found it to be a potential health hazard, but there is still unknown about its effects on spermatogenesis. Our results showed that PFHxS-treated mice have significant reproductive toxicity, including a decrease in sperm count and motility, and the levels of sex hormones (P < 0.05). Concurrently, structural abnormalities are observed in sperm, affecting ≈60-75% of those in the PFHxS-treated group. Additionally, it is found that the structure of the blood-testis barrier (BTB) is damaged after PFHxS treatment, leading to higher expression levels of inflammatory cytokines in the microenvironment for spermatogenesis. Moreover, the expression of proteins associated with mitochondrial biogenesis, including PTEN-induced kinase 1 (PINK1) and NADPH oxidase 4 (NOX4), is dysregulated in the testes after PFHxS treatment. Based on metabolome data, the differential metabolite 3-hydroxybutanoic acid is identified in the PFHxS-treated group, which can regulate the histone Kac levels, especially H3K4ac and H3K9ac. In summary, the results of this study suggest that in the testes of PFHxS-treated mice, inflammatory factors disrupt the mitochondrial function and metabolic profiles and hinder the progress of gene transcription through histone Kac, ultimately causing sperm dysfunction.

BACKGROUND:The widespread use of bisphenol A (BPA) has led to universal exposure among the population, raising concerns about its health effects. Epidemiological studies have linked environmentally relevant levels of BPA exposure to obesity. OBJECTIVES:We aimed to uncover the complex mechanisms by which oral exposure during pregnancy with BPA affects the offspring. METHODS:We conducted a two-stage mouse study. In stage 1, we gavaged dams with BPA at 0.05, 0.5, and 5mg/kg per day during pregnancy, and we tracked the offspring's weight and diet to 12 wk of age. In stage 2, exosomes from BPA-exposed dams and offspring were injected into pregnant mice and 3-wk-old males, respectively, and the mice were observed up to 12 wk. We then sequenced exosomal microRNAs (miRNAs) in male offspring whose dams had been exposed to BPA during pregnancy and checked their expression in adipose, liver, and serum samples at weeks 3, 6, 9, and 12. Finally, we explored the functions of exosomes and exosomal miRNAs secreted by adipose-derived mesenchymal stem cells, and we investigated whether the exosomes and miRNAs they secreted could affect glucose uptake, triglyceride synthesis, and the expression of genes related to glucose and lipid metabolism in alpha mouse liver 12 cells. RESULTS:Gavage of 0.05mg/kg per day of BPA during pregnancy in dams led to obesity in male offspring mice, and injection of exosomes from male offspring with BPA exposure during pregnancy also induced similar outcomes in the next generation of male pups. Exosomal miRNA sequencing identified differentially expressed miRNAs associated with BPA-induced obesity in male offspring, revealing sustained high expression of miRNAs in adipose tissue and a gradual increase in the liver and serum over time. Further mechanistic studies showed that exosomes derived from BPA-treated adipose-derived stem cells reduced the expression of peroxisome proliferator-activated receptor-gamma and fibroblast growth factor 21, leading to impaired insulin signaling and lipid metabolism in hepatocytes. Overexpression of miR-124-3p in hepatocytes mimicked these effects; in contrast, knockdown of miR-124-3p or inhibition of exosome secretion reversed them. DISCUSSION:The present study corroborates the regulatory function of adipose-derived exosomal miRNAs in obesity in male offspring mice resulting from BPA exposure during pregnancy. Exosomal miRNA may be a key and novel molecular biomarker in the adverse effects of chemical exposure during pregnancy. https://doi.org/10.1289/EHP14888.

Introduction and Objective: The apolipoprotein E (APOE)ε4 genotypes were typically associated with metabolic dysfunction. The health effects of APOEε4 genotypes on diabetes remained unclear. We aimed to expand the understanding of associations between APOEε4 genotypes and diabetes based on proteome-wide protein-gene interaction. Methods: APOEε4 genotypes (i.e., non-carrier, APOEε3/ε4, and APOEε4/ε4 as ordinal variables) were determined by two variants (rs429358-C and rs7412-T). We estimated the proteome-wide interaction with APOEε4 status and corresponding variants in relation to incident diabetes based on a prospective cohort (European ancestry, n=38,618, 1385 incident cases). We further evaluated the associations between proteins and incident diabetes by varied APOEε4 status. Results: No significant association between APOEε4 variants and diabetes risk was found (All P>0.05). Among the 2911 proteins, we identified that apolipoprotein F (APOF) and paraoxonase 3 (PON3) as candidate proteins interacted with APOEε4 genotypes (HRint for APOF=1.52, P=3.2E-72, HRint for PON3=0.87, P=2.4E-7) on diabetes after Bonferroni correction. Among people carried with APOEε3/ε4 and ε4/ε4, associations of APOF with diabetes were weaker, and PON3 had stronger protective associations with diabetes. We found that both the APOF and PON3 significantly interacted with rs429358-C and rs7412-T, with similar effect sizes. In addition, we identified that complement factor P (CFP) interacted with rs7412-T (HRint=1.28, P=2.2E-6, and carriers had higher diabetes risk (HR=1.46, P=4.8E-14) than non-carriers (HR=1.15, P=2.1E-19). Conclusion: Our study provided evidence that APOEε4 genotypes may modulate the diabetes risk associated with APOF, PON3, and CFP. Future studies are necessary for validating the findings and exploring the underlying mechanisms. C. Tao: None. X. Wang: None. Z. Li: None. Z. Qiao: None. Y. Yuan: None. H. Qian: None. Q. Xu: None. Y. Fan: None. C. Lu: None. This work was supported by the National Key Research and Development Program of China (No. 2023YFC2705700), and the National Natural Science Foundation of China (No. 82271691).

Inappropriate apparent temperature (AT) is a major global threat to human health. Although the association between temperature and health has been studied extensively, limited evidence regarding emergency ambulance calls (EACs) is available. Daily emergency department visit records, meteorological data, and air pollutant data were obtained from 1 January 2014 to 31 December 2019. A distributed lag non-linear model was applied to examine the interaction between AT and lagged effects. The analysis was stratified according to disease aetiology, sex, and age. The proportion of EACs attributable to AT was calculated as an indicator of associated burden. A non-linear U-shaped relationship was observed between AT and non-accidental, cardiovascular, and circulatory EACs, with the lowest risk AT occurring at 22.54 °C, 17.12 °C, and 12.74 °C, respectively. High AT effects manifested immediately, whereas low AT effects were delayed. Stratified analysis indicated that males and individuals aged ≥65 years demonstrated heightened sensitivity to both extreme heat (97.5th percentile, 35.98 °C) and cold (2.5th percentile, −1.27 °C), whereas females displayed greater vulnerability to extreme heat [relative risks = 1.16, 95% confidence intervals (CI): 1.04–1.29]. The attributable fraction (AF) for non-accidental EACs in Wuxi was 6.88% (95% CI: 4.09–9.26%), with higher AFs observed for cardiovascular (10.37%) and respiratory (4.94%) emergencies. Moderate thermal variations substantially affected the EACs more than extreme AT conditions. These findings underscore the necessity of implementing early warning mechanisms targeting thermal extremes and developing temperature-regulated public facilities to safeguard vulnerable groups, particularly older citizens, during extreme temperature events.

Bisphenol F (BPF), a substitute for bisphenol A (BPA), is ubiquitous existed in various environmental media. Exposure to BPF may promote non-alcoholic fatty liver disease (NAFLD), while the potential mechanism is still unknown. In current study, we used in vitro and in vivo model to evaluate its hepatotoxicity and molecular mechanism. Using multi-omics approach, we found that BPF exposure led to changes in hepatic transcriptome, metabolome and chromatin accessible regions that were enriched for binding sites of transcription factors in bZIP family. These alterations were enriched with pathways integral to the endoplasmic reticulum stress and NAFLD. These findings suggested that BPF exposure might reprogram the chromatin accessibility and enhancer landscape in the liver, with downstream effects on genes associated with endoplasmic reticulum stress and lipid metabolism, which relied on bZIP family transcription factors. Overall, our study describes comprehensive molecular alterations in hepatocytes after BPF exposure and provides new insights into the understanding of the hepatoxicity of BPF.

Background. Extracellular vesicles (EVs) are membrane-bound vesicles containing various proteins, lipids, and nucleic acids. EVs are found in many body fluids, such as blood and urine. The release of EVs can facilitate intercellular communication through fusion with the plasma membrane or endocytosis into the recipient cell or through internalization of the contents. Recent studies have reported that EVs isolated from human endometrial epithelial cells (EECs) promote sperm fertilization ability. EVs from uterine flushing fluid more closely resemble the physiological condition of the uterus. However, it is unclear whether EVs derived directly from uterine flushing fluid have the same effect on sperm. This study aimed to research the effect of EVs from uterine flushing fluid on sperm. Methods. EVs were isolated from the uterine flushing fluid. The presence of EVs was confirmed by nanoparticle tracking analysis (NTA), Western blot, and transmission electron microscopy (TEM). EVs were incubated with human sperm for 2 h and 4 h. The effects of EVs on sperm were evaluated by analyzing acrosome reaction, sperm motility, and reactive oxygen species (ROS). Results. The EVs fractions isolated from the uterine fluid were observed in cup-shaped vesicles of different sizes by TEM. All isolated vesicles contained similar numbers of vesicles in the expected size range (30-200 nm) by NTA. CD9 and CD63 were detected in EVs by western blot. Comparing the motility of the two groups incubated sperm motility significantly differed at 4 h. The acrosome reactions were promoted by incubating with EVs significantly. ROS were increased in sperm incubated with EVs. Conclusion. Our results showed EVs present in the uterine fluid. Acrosome reactions and ROS levels increased in human sperm incubated with EVs. EVs from uterine fluid can promote the capacitation of human sperm. The increased capacitation after sperm interaction with EVs suggests a possible physiological effect during the transit of the uterus.

Effect modification of integrated neighborhood environment on associations of air pollution with mortality remained unclear. We analyzed data from UK biobank prospective study (n = 421,650, median 12.5 years followup) to examine disparities of mortality risk associated with air pollution among varied neighborhood settings. Fine particulate matter (PM2.5), PM10 and nitrogen dioxide (NO2) were measured and assigned to each participants' address. Diverse ecological and societal settings of neighborhoods were integrated with principal component analysis and categorized into disadvantaged, intermediate and advantaged levels. We estimated mortality risk associated with air pollution across diverse neighborhoods using Cox regression. We calculated community -level proportions of mortality attributable to air pollutants. There was evidence of higher all -cause and respiratory disease mortality risk associated with PM 2.5 and NO 2 among those in disadvantaged neighborhoods. In disadvantaged communities, air pollutants explained larger proportions of deaths and such disparities persisted over past decades. Across 2010 -2021, reducing PM 2.5 and NO 2 to 10 mu g/m 3 (World Health Organization limits) would save 87,000 (52,000-120,000) and 91,000 (37,000-145,000) deaths of populations aged >= 40 years, with 150 000 deaths occurred in disadvantaged neighborhood settings. These findings suggested that disadvantaged neighborhoods can exacerbate mortality risk associated with air pollution.

Particulate matter (PM) exposure may be associated with male semen quality. Besides, PM exposure induces up and down levels of trace metals in tissues or organs. The levels of trace metals in semen are critical for adverse male semen quality. This study aims to evaluate the concentrations of seminal-level trace metals in fertile men and assess its associations with PM exposure and to explore the mediation role of trace metals in seminal plasma plays in the relationship between PM exposure and semen quality. Total 1225 fertile men who participated in a cohort study from 2014 to 2016 were finally recruited. Multivariate linear regression was applied to explore associations between each two of PM exposure, trace metals and semen parameters. 1-year PM2.5 and PM10 exposure levels were positively associated with arsenic (As), mercury (Hg), lanthanum (La), praseodymium (Pr), neodymium (Nd) but negatively associated with vanadium (V), magnesium (Mg), strontium (Sr), barium (Ba) in semen. It was also found that most of the elements were associated with total sperm number, followed by sperm concentration. Redundancy analysis (RDA) also determined several strong positive correlations or negative correlations between 1-year PM exposure and trace metals. Mediation analysis found that trace metals had a potentially compensatory or synergetic indirect effect on the total effect of the association between 1-year PM exposure and semen quality. The retrospective cohort study provides long-term PM exposure that may cause abnormal semen quality by affecting seminal plasma element levels.