Screening Organic Components and Toxicogenic Structures from Regional Fine Particulate Matters Responsible for Myocardial Fibrosis in Male Mice.

Numerous studies indicate that fine particulate matters (PM2.5) and its organic components are urgent risk factors for cardiovascular diseases (CVDs). Combining toxicological experiments, effect-directed analyses, and nontarget identification, this study aims to explore whether PM2.5 exposure in coal-combustion areas induces myocardial fibrosis and how to identify the effective organic components and their toxic structures to support regional risk control. First, we constructed an animal model of real-world PM2.5 exposure during the heating season and found that the exposure impaired cardiac systolic function and caused myocardial fibrosis, with chemokine Ccl2-mediated inflammatory response being the key cause of collagen deposition. Then, using the molecular event as target coupled with two-stage chromatographic isolation and mass spectrometry analyses, we identified a total of 171 suspect organic compounds in the PM2.5 samples. Finally, using hierarchical characteristic fragment analysis, we predicted that 40 of them belonged to active compounds with 6 alert structures, including neopentane, butyldimethylamine, 4-ethylphenol, hexanal, decane, and dimethylaniline. These findings provide evidence for risk management and prevention of CVDs in polluted areas.

Fetal Origin of Abnormal Glucose Tolerance in Adult Offspring Induced by Maternal Bisphenol A Analogs Exposure.

With the widespread use of bisphenol A (BPA) analogs, their health risks have attracted attention. The effects of maternal BPA analogs exposure on glucose homeostasis in adult offspring and the underlying fetal origins require further exploration. Herein, we exposed pregnant mice to two types of BPA analogs─BPB and BPAF; we evaluated glucose homeostasis in adult offspring and maternal-fetal glucose transport by testing intraperitoneal glucose tolerance, determining glucose and glycogen contents, conducting positron emission tomography (PET)/computed tomography (CT), detecting expression of placental nutrient transport factors, and assessing placental barrier status. We observed that adult female offspring maternally exposed to BPB and BPAF exhibited low fasting blood glucose in adulthood, with even abnormal glucose tolerance in the BPAF group. This phenomenon can be traced back to the elevated fetal glucose induced by the increased efficiency of placenta glucose transport in late pregnancy. On the other hand, the expression of genes associated with vascular development and glucose transport was significantly altered in the placenta in the BPAF group, potentially contributing to enhanced fetal glucose. These findings provide preliminary insights into potential mechanisms underlying the disturbance of glucose metabolism in adult female offspring mice induced by maternal exposure to BPA analogs.

Multilevel Screening Strategy to Identify the Hydrophobic Organic Components of Ambient PM2.5 Associated with Hepatocellular Steatosis.

Hepatic steatosis is the first step in a series of events that drives hepatic disease and has been considerably associated with exposure to fine particulate matter (PM2.5). Although the chemical constituents of particles matter in the negative health effects, the specific components of PM2.5 that trigger hepatic steatosis remain unclear. New strategies prioritizing the identification of the key components with the highest potential to cause adverse effects among the numerous components of PM2.5 are needed. Herein, we established a high-resolution mass spectrometry (MS) data set comprising the hydrophobic organic components corresponding to 67 PM2.5 samples in total from Taiyuan and Guangzhou, two representative cities in North and South China, respectively. The lipid accumulation bioeffect profiles of the above samples were also obtained. Considerable hepatocyte lipid accumulation was observed in most PM2.5 extracts. Subsequently, 40 of 695 components were initially screened through machine learning-assisted data filtering based on an integrated bioassay with MS data. Next, nine compounds were further selected as candidates contributing to hepatocellular steatosis based on absorption, distribution, metabolism, and excretion evaluation and molecular dockingin silico. Finally, seven components were confirmed in vitro. This study provided a multilevel screening strategy for key active components in PM2.5 and provided insight into the hydrophobic PM2.5 components that induce hepatocellular steatosis.

Ambient fine particulate matter exposure induces reversible cardiac dysfunction and fibrosis in juvenile and older female mice.

BACKGROUND: Cardiovascular disease is the leading cause of mortality in the advanced world, and age is an important determinant of cardiac function. The purpose of the study is to determine whether the PM2.5-induced cardiac dysfunction is age-dependent and whether the adverse effects can be restored after PM2.5 exposure withdrawal. METHODS: Female C57BL/6 mice at different ages (4-week-old, 4-month-old, and 10-month-old) received oropharyngeal aspiration of 3 mg/kg b.w. PM2.5 every other day for 4 weeks. Then, 10-month-old and 4-week-old mice were exposed to PM2.5 for 4 weeks and withdrawal PM2.5 1 or 2 weeks. Heart rate and systolic blood pressure were measured using a tail-cuff system. Cardiac function was assessed by echocardiography. Left ventricles were processed for histology to assess myocardial fibrosis. ROS generation was detected by photocatalysis using 2',7'-dichlorodihydrofluorescein diacetate (DCFHDA). The expression of cardiac fibrosis markers (Col1a1, Col3a1) and possible signaling molecules, including NADPH oxidase 4 (NOX-4), transforming growth factor ß1 (TGFß1), and Smad3, were detected by qPCR and/ or Western blot. RESULTS: PM2.5 exposure induced cardiac diastolic dysfunction of mice, elevated the heart rate and blood pressure, developed cardiac systolic dysfunction of 10-month-old mice, and caused fibrosis in both 4-week-old and 10-month-old mice. PM2.5 exposure increased the expression of Col1a1, Col3a1, NOX-4, and TGFß1, activated Smad3, and generated more reactive oxygen species in the myocardium of 4-week-old and 10-month-old mice. The withdrawal from PM2.5 exposure restored blood pressure, heart rate, cardiac function, expression of collagens, and malonaldehyde (MDA) levels in hearts of both 10-month-old and 4-week-old mice. CONCLUSION: Juvenile and older mice are more sensitive to PM2.5 than adults and suffer from cardiac dysfunction. PM2.5 exposure reversibly elevated heart rate and blood pressure, induced cardiac systolic dysfunction of older mice, and reversibly induced fibrosis in juvenile and older mice. The mechanism by which PM2.5 exposure resulted in cardiac lesions might involve oxidative stress, NADPH oxidase, TGFß1, and Smad-dependent pathways.

Cadmium exposure on tissue-specific cadmium accumulation and alteration of hemoglobin expression in the 4th-instar larvae of Propsilocerus akamusi (Tokunaga) under laboratory conditions.

The expression of hemoglobin (Hb) genes has considerable potential as a biomarker for environmental monitoring in Chironomus. However, no sequence information is available regarding Hb genes in Propsilocerus akamusi (Tokunaga), thus the change in Hb mRNA gene expression caused by environmental pollutants remains unknown. In this study, we cloned two Hb gene fragments (PaHbV and PaHbVII) from P. akamusi, analyzed the expression patterns of the PaHbV and PaHbVII transcripts in different tissues using Real-Time quantitative PCR (RT-qPCR), and also measured the Cd levels in different tissues exposed to a sublethal concentration. The results showed significantly increased Cd concentrations and tissue-specific Cd distribution patterns in all of the tissues tested, including the hemolymph, during all time courses. A model describing the roles of specific tissues in Cd uptake and accumulation dynamics was also determined. The Malpighian tubules, gut, and epidermis were the primary sites of Cd accumulation, whereas the hemolymph was the temporary target organ of Cd accumulation, with the Cd being transferred to other internal tissues via the hemolymph. The relative mRNA expression profiles of PaHbV and PaHbVII indicated that their expression levels differed across the different tissues, indicating a tissue-specific response. Our results suggested a reverse effect between Hb expression and Cd accumulation during long-term Cd exposure in comparison with previous studies. The expressions of Hb genes in P. akamusi could be developed as biomarkers for assessing the general health conditions of freshwater ecosystems.

Effects of chlorpyrifos on glutathione S-transferase in migratory locust, Locusta migratoria.

Chlorpyrifos is a typical organophosphate pesticide and is among the most widely used worldwide. The objective of the present investigation was to assess the effect of chlorpyrifos exposure on glutathione S-transferase in Locusta migratoria. In the present study, chlorpyrifos (0.1, 0.2, and 0.4mgg(-1) body weight) was topically applied in the abdomen of locusts. The GST activity, mRNA levels of ten L. migratoria GSTs and protein levels of four representative GSTs were detected. The results showed that chlorpyrifos treatment caused significant decrease of 1,2-dichloro-4-nitrobenzene (DCNB) and p-nitro-benzyl chloride (p-NBC) activities, whereas 1-chloro-2,4-dinitrobenzene (CDNB) activity was not altered in locusts. The mRNA levels of seven L. migratoria GSTs, including LmGSTs2, LmGSTs3, LmGSTs4, LmGSTs5, LmGSTs6, LmGSTt1, and LmGSTu1, were decreased after chlorpyrifos exposure. The protein levels of LmGSTs5, LmGSTt1 and LmGSTu1 were significantly decreased at higher doses of chlorpyrifos. However, chlorpyrifos elevated the mRNA and protein expression of LmGSTd1. It indicated that LmGSTd1 might contribute to the resistance of locust to organophosphate pesticides such as chlorpyrifos, whereas the decrease in other GSTs might be an economic compensation by the insect to differentially regulate the expression of enzymes involved in the detoxification of insecticides on the expense of those that are not.

YTHDC2 mediated RNA m6A modification contributes to PM2.5-induced hepatic steatosis.

Exposure to fine particulate matter (PM2.5) is a significant risk factor for hepatic steatosis. The N6-methyladenosine (m6A) is implicated in metabolic disturbances triggered by exogenous environmental factors. However, the role of m6A in mediating PM2.5-induced hepatic steatosis remains unclear. Herein, male C57BL/6J mice were subjected to PM2.5 exposure throughout the entire heating season utilizing a real-ambient PM2.5 whole-body inhalation exposure system. Concurrently, HepG2 cell models exposed to PM2.5 were developed to delve the role of m6A methylation modification. Following PM2.5 exposure, significant hepatic lipid accumulation and elevated global m6A level were observed both in vitro and in vivo. The downregulation of YTHDC2, an m6A-binding protein, might contribute to this alteration. In vitro studies revealed that lipid-related genes CEPT1 and YWHAH might be targeted by m6A modification. YTHDC2 could bind to CDS region of them and increase their stability. Exposure to PM2.5 shortened mRNA lifespan and suppressed the expression of CEPT1 and YWHAH, which were reversed to baseline or higher level upon the enforced expression of YTHDC2. Consequently, our findings indicate that PM2.5 induces elevated m6A methylation modification of CEPT1 and YWHAH by downregulating YTHDC2, which in turn mediates the decrease in the mRNA stabilization and expression of these genes, ultimately resulting in hepatic steatosis.

Ozone induced multigenerational glucose and lipid metabolism disorders in Drosophila.

Ozone (O3), a persistent pollutant, poses a significant health threat. However, research on its multigenerational toxicity remains limited. Leveraging the Drosophila model with its short lifespan and advanced genetic tools, we explored the effects of O3 exposure across three generations of fruit flies. The findings revealed that O3 disrupted motility, body weight, stress resistance, and oxidative stress in three generations of flies, with varying effects observed among them. Transcriptome analysis highlighted the disruption of glucose metabolism-related pathways, encompassing gluconeogenesis/glycolysis, galactose metabolism, and carbon metabolism. Hub genes were identified, and RT-qPCR results indicated that O3 decreased their transcription levels. Comparative analysis of their human orthologs was conducted using Comparative Toxicogenomics Database (CTD) and DisGeNET databases. These genes are linked to various metabolic diseases, including diabetes, hypoglycemia, and obesity. The trehalose content was reduced in F0 generation flies but increased in F1-F2 generations after O3 exposure. While the trehalase and glucose levels were decreased across F0-F2 generations. TAG synthesis-related genes were significantly upregulated in F0 generation flies but downregulated in F1-F2 generations. The expression patterns of lipolysis-related genes varied among the three generations of flies. Food intake was increased in F0 generation flies but decreased in F1-F2 generations. Moreover, TAG content was significantly elevated in F0 generation flies by O3 exposure, while it was reduced in F2 generation flies. These differential effects of O3 across three generations of flies suggest a metabolic reprogramming aimed at mitigating the damage caused by O3 to flies. The study affirms the viability of employing the Drosophila model to investigate the mechanisms underlying O3-induced glucose and lipid metabolism disorders while emphasizing the importance of studying the long-term health effects of O3 exposure. Moreover, this research highlights the Drosophila model as a viable tool for investigating the multigenerational effects of pollutants, particularly atmospheric pollutants.

The Flow Stress Behavior and Physical-Based Constitutive Model for As-Quenched Al-Zn-Mg-Cu Alloy.

Although heat-treatable Al-Zn-Mg-Cu alloys are widely used in aerospace industries, distortion and cracks exist due to the residual stress during quenching. Understanding the flow stress behavior and numerically modeling the process is the key to predicting the residual stress. This paper investigated the flow stress behavior of the as-quenched 7050 alloy at strain rates from 0.1 s-1 to 1 s-1, temperatures between 423 K and 723 K, and cooling rates from 0.1 K/s to 10 K/s. The experimental results showed that the strain rate, cooling rate, and temperature have effects on the flow stress value, except for the cooling rates at a temperature of 423 K or 723 K. The kinetics model was used to obtain the precipitate features, i.e., precipitate size and volume fraction. Then, a physical constitutive model based on the evolution of immobile dislocation, solutes, and precipitates was developed. The predicted flow stresses showed good agreement with the experimental data. The findings of this work expand the knowledge on the as-quenched flow behavior of Al-Zn-Mg-Cu alloys, improving the prediction accuracy of residual stress by FEM.

Overview of PM2.5 and health outcomes: Focusing on components, sources, and pollutant mixture co-exposure.

PM2.5 varies in source and composition over time and space as a complicated mixture. Consequently, the health effects caused by PM2.5 varies significantly over time and generally exhibit significant regional variations. According to numerous studies, a notable relationship exists between PM2.5 and the occurrence of many diseases, such as respiratory, cardiovascular, and nervous system diseases, as well as cancer. Therefore, a comprehensive understanding of the effect of PM2.5 on human health is critical. The toxic effects of various PM2.5 components, as well as the overall toxicity of PM2.5 are discussed in this review to provide a foundation for precise PM2.5 emission control. Furthermore, this review summarizes the synergistic effect of PM2.5 and other pollutants, which can be used to draft effective policies.

Circadian rhythm disturbances involved in ozone-induced glucose metabolism disorder in mouse liver.

Ozone (O3) is a key environmental factor for developing diabetes. Nevertheless, the underlying mechanisms remain unclear. This study aimed to investigate alterations of glycometabolism in mice after O3 exposure and the role of circadian rhythms in this process. C57BL/6 male mice were randomly assigned to O3 (0.5 ppm) or filtered air for four weeks (4 h/day). Then, hepatic tissues of mice were collected at 4 h intervals within 24 h after O3 exposure to test. The results showed that hepatic circadian rhythm genes oscillated abnormally, mainly at zeitgeber time (ZT)8 and ZT20 after O3 exposure. Furthermore, detection of glycometabolism (metabolites, enzymes, and genes) revealed that O3 caused change in the daily oscillations of glycometabolism. The serum glucose content decreased at ZT4 and ZT20, while hepatic glucose enhanced at ZT16 and ZT24(0). Both G6pc and Pck1, which are associated with hepatic gluconeogenesis, significantly increased at ZT20. O3 exposure disrupted glycometabolism by increasing gluconeogenesis and decreasing glycolysis in mice liver. Finally, correlation analysis showed that the association between Bmal1 and O3-induced disruption of glycometabolism was the strongest. The findings emphasized the interaction between adverse outcomes of circadian rhythms and glycometabolism following O3 exposure.

Biochemical evidence of PM2.5 critical components for inducing myocardial fibrosis in vivo and in vitro.

PM2.5 constituents are tightly linked to the initiation of many cardiovascular diseases (CVDs). Little is known, however, about the events which critical components of PM2.5 can induce the initiating events in CVDs. C57BL/6 female mice were exposed to PM2.5 (3 mg/kg b.w.) from four different cities (Taiyuan, Beijing, Hangzhou, and Guangzhou) by oropharyngeal aspiration every other day. PM2.5 from Taiyuan increased the diastolic function of the hearts and induced myocardial fibrosis with increased areas of interstitial fibrosis through the NOX4/TGF-ß1/Smad 3/Col1a1 pathways. Pb, Cr, Mn, Zn, and most of the polycyclic aromatic hydrocarbons (PAHs) were positively associated with the related indicators of cardiac diastolic function and myocardial fibrosis by using Pearson correlation (R2 = 0.9085-0.9897). To determine the critical components in PM2.5 that can induce the occurrence of myocardial fibrosis, BEAS-2b cells were treated with one or more of five candidate components with/without Guangzhou PM2.5, and then the conditioned medium of BEAS-2b was used to culture AC16 cells. The results showed that Zn + Pb + Mn + BaP with PM2.5 from Guangzhou exposure significantly increased reactive oxygen species production of BEAS-2b cells and induced a dramatic increase of myocardial fiber-related gene expression (Col1a1 and TGF-ß) in AC16 cells. It indicated that the different mass concentrations of Zn, Pb, Mn, and ΣPAHs in PM2.5 might be the critical factors that modulated myocardial fibrosis induction by targeted. Our study provided a novel avenue for further elucidation of molecular mechanisms of PM2.5 components-induced myocardial fibrosis.

Effects of differential regional PM2.5 induced hepatic steatosis and underlying mechanism.

Emerging evidence suggests that exposure to PM2.5 is associated with a high risk of nonalcoholic fatty liver disease (NAFLD). NAFLD is typically characterised by hepatic steatosis. However, the underlying mechanisms and critical components of PM2.5-induced hepatic steatosis remain to be elucidated. In this study, ten-month-old C57BL/6 female mice were exposed to PM2.5 from four cities in China (Taiyuan, Beijing, Hangzhou, and Guangzhou) via oropharyngeal aspiration every other day for four weeks. After the exposure period, hepatic lipid accumulation was evaluated by biochemical and histopathological analyses. The expression levels of genes related to lipid metabolism and metabolomic profiles were assessed in the mouse liver. The association between biomarkers of hepatic steatosis (hepatic Oil Red O staining area and serum and liver triglyceride contents) and typical components of PM2.5 was identified using Pearson correlation analysis. Oil Red O staining and biochemical results indicated that PM2.5 from four cities significantly induced hepatic lipid accumulation. The most severe hepatic steatosis was observed after Guangzhou PM2.5 exposure. Moreover, Guangzhou PM2.5-induced the most significant changes in gene expression associated with lipid metabolism, including increased hepatic fatty acid uptake and lipid droplet formation and decreased fatty acid synthesis and lipoprotein secretion. Contemporaneously, exposure to Guangzhou PM2.5 significantly perturbed hepatic lipid metabolism. According to metabolomic analysis, disturbed hepatic lipid metabolism was primarily concentrated in linoleic acid, α-linoleic acid, and arachidonic acid metabolism. Finally, correlation analysis revealed that copper (Cu) and other inorganic components, as well as the majority of polycyclic aromatic hydrocarbons (PAHs), were related to changes in biomarkers of hepatic steatosis. These findings showed that PM2.5 exposure caused hepatic steatosis in aged mice, which could be related to the critical chemical components of PM2.5. This study provides critical information regarding the components of PM2.5, which cause hepatic steatosis.

Structural and catalytic role of two conserved tyrosines in Delta-class glutathione S-transferase from Locusta migratoria.

Glutathione S-transferases (GSTs) are an important family of detoxifying enzymes and play a key role in pesticide resistance in the insect. Tyrosine is essential for its detoxification function. In the present study, two conserved tyrosine residues are located at positions 108 and 116 in H-site of LmGSTD1. To elucidate how the two residues participate in the catalytic process and keeping structural stability, four mutants, Y108A, Y108E, Y116A, and Y116E, were generated. It was found that the four mutants affected the specific activity of LmGSTD1 in various degrees, depending on the types of substrate and reaction mechanism. Steady-state kinetics assay revealed that Y108E and Y116E had a significant influence on GSH-binding ability, which indicates the two tyrosine residues of H-site contribute to topology rearrangement of G-site. Both Y116A and Y116E exhibited lower CDNB-binding affinity, suggesting that Y116 takes part in hydrophobic substrate binding. The thermostability assay, intrinsic, and 8-anilino-1-naphthalenesulfonic acid (ANS) florescence results showed that the two tyrosine residues were involved in regulation of active-site conformation. Finally, homology modeling provided evidence that the two tyrosines in H-site participate in hydrophobic substrate binding. Furthermore, Y108 is closer to the S atom of S-hexylglutathione. In conclusion, the two tyrosines in LmGSTD1 are important residues in both the catalytic process and protein stability.

Suppression of NADPH oxidase 4 inhibits PM2.5-induced cardiac fibrosis through ROS-P38 MAPK pathway.

Fine particulate matter (PM2.5) has been consistently linked to cardiovascular diseases, and cardiac fibrosis plays a crucial role in the occurrence and development of heart diseases. It is reported that NOX4-dependent redox signaling are responsible for TGFß-mediated profibrotic responses. The current study was designed to explore the possible mechanisms of cardiac fibrosis by PM2.5 both in vitro and in vivo. Female C57BL/6 mice received PM2.5 (3 mg/kg b.w.) exposure with/without NOX4 inhibitor (apocynin, 25 mg/kg b.w.) or ROS scavenger (NALC, 50 mg/kg b.w.), every other day, for 4 weeks. H9C2 cells were incubated with PM2.5 (3 µg/mL) with/without 5 mM NALC, TGFß inhibitor (SB431542, 10 µM), or siRNA-NOX4 for 24 h. The results demonstrated that PM2.5 induced evident collagen deposition and elevated expression of fibrosis biomarkers (Col1a1 & Col3a1). Significant systemic inflammatory response and cardiac oxidative stress were triggered by PM2.5. PM2.5 increased the protein expression of TGFß1, NOX4, and P38 MAPK. Notably, the increased effects of PM2.5 could be suppressed by SB431542, siRNA-NOX4 in vitro or apocynin in vivo, and NALC. The reverse verification experiments further supported the involvement of the TGFß/NOX4/ROS/P38 MAPK signaling pathway in the myocardial fibrosis induced by PM2.5. In summary, the current study provided evidence that PM2.5 challenge led to cardiac fibrosis through oxidative stress, systemic inflammation, and subsequent TGFß/NOX4/ROS/P38 MAPK pathway and may offer new therapeutic targets in cardiac fibrosis.

Activation of δ-opioid Receptors in Anterior Cingulate Cortex Alleviates Affective Pain in Rats.

The negative emotions caused by persistent pain, called affective pain, are known to seriously affect human physical and mental health. The anterior cingulate cortex (ACC), especially the rostral ACC (rACC) plays a key role in the development of this affective pain. N-methyl-d-aspartate (NMDA) receptors, which are widely distributed in the ACC, are involved in the regulation of emotional behavior. It is well known that activation of opioid receptors can relieve pain, but whether it can alleviate affective pain is not clear. In the present study, conditioned place avoidance (CPA) responses induced by complete Freund's adjuvant (CFA) were used to represent the affective pain of place aversion. The behavioral measurements were synchronously combined with multichannel electrophysiological recordings of the discharge frequency of rACC pyramidal neurons to explore whether affective pain could be alleviated by the synthetic opioid [D-Ala2, D-Leu5]-Enkefalin (DADLE), an agonist of δ-opioid receptors. To further investigate this treatment as a mechanism for the relief of affective pain in CFA-treated animals, we used whole-cell patch recordings in slice preparations of the rACC region to determine the dose-dependent effects of DADLE on NMDA receptor-mediated currents. Then, western blot was used to determine levels of phosphorylated NMDA receptor subunits GluN1, GluN2 and GluN3 as affected by the δ-opioid receptor activation. The results showed that activation of δ-opioid receptors down-regulates the phosphorylation of NMDA receptor subunits, thereby inhibiting NMDA currents, decreasing the discharge frequency of rACC pyramidal neurons, and reversing the CPA response. Thus, δ-opioid receptor activation in the rACC region can alleviate affective pain.

Comparative studies on regional variations in PM2.5 in the induction of myocardial hypertrophy in mice.

Exposure to fine particulate matter (PM2.5) has been indicated to be related to an increased risk of cardiovascular diseases (CVDs) in sensitive people. However, the underlying mechanisms of PM2.5-induced CVDs are poorly understood. In the present study, PM2.5 samples were collected during winter from four cities (Taiyuan, Beijing, Hangzhou, and Guangzhou) in China. Ten-month-old C57BL/6 female mice were exposed to PM2.5 suspension at a dosage of 3 mg·kg-1 (b. w.) every other day for 4 weeks by oropharyngeal aspiration. PM2.5 from Taiyuan increased the blood pressure and the thicknesses of the left ventricular anterior and posterior walls, decreased the ratio of nucleus to cytoplasm in cardiomyocytes and reduced the systolic function of the heart in mice. Further investigation revealed that PM2.5 from Taiyuan induced lung inflammatory cytokines with up-regulated expressions of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). The mRNA expression levels of myocardial hypertrophy markers atrial natriuretic peptide and the ß isoform of myosin heavy chain (ANP and ß-MHC), matrix metalloproteinase 2 (MMP2), MMP9, and inflammatory cytokines TNF-α and IL-6 in the myocardium were significantly increased after exposure to PM2.5 of Taiyuan. Furthermore, PM2.5 from Taiyuan activated the IL-6/JAK2/STAT3/ß-MHC signaling pathway in the myocardium. The correlation between the PM2.5 components and myocardial hypertrophy markers suggested that Zinc (Zn) and acenaphthene (AC) are related to the changes in ANP and ß-MHC at the transcriptional level, respectively. The above results indicated that PM2.5 exposure induced myocardial hypertrophy in older mice, which might be related to the critical contributions of Zn and AC in PM2.5. The present study provides new insights into the mechanism of myocardial hypertrophy after PM2.5 exposure.

Association of exposure to ambient air pollution with ovarian reserve among women in Shanxi province of north China.

Air pollution has been an important risk factor for female reproductive health. However, epidemiological evidence of ambient air pollution on the predictor for ovarian reserve (antral follicle count, AFC) is deficient. We aim to comprehensively evaluate the association of long-term exposure to ambient air pollution with AFC among women of reproductive age in Shanxi of north China. 600 women with spontaneous menstrual cycle, not using controlled ovarian stimulation, were enrolled in the retrospective study. Two distinct periods of antral follicle development were designed as exposure windows. Generalized linear model was employed to estimate the change of AFC associated with exposure of atmospheric pollutants (SO2, NO2, PM10, PM2.5, CO and O3). Stratification analysis based on age (<30, ≥30 years), university degree (yes, no), years of exposure (2013-2016, 2017-2019) and duration of infertility (<2, 2-5, >5 years) along with two pollutants model were employed to further illustrate the association. We found every 10 µg/m3 increase in SO2 concentration level during the entire development stage of antral follicle was associated with a -0.01 change in AFC (95% confidence interval: -0.016, -0.002) adjusting for the confounders including age, BMI, parity and infertility diagnosis factors. The significant association of increased SO2 level with decreased AFC was particularly observed during the early transition from primary follicle to preantral follicle stage by 10 µg/m3 increase in SO2 exposure level with a -0.01 change (95% CI: -0.015, -0.002) in AFC. The negative association was pronounced among women aged ≥30 years old, and also significant in two pollutants model after adjusting the confounders. No significant associations between other air pollutants and AFC were observed. Our finding suggests that long-term exposure to air pollutant SO2 is associated with lower AFC, raising our concern that atmospheric SO2 exposure may have potential adverse impact on women ovarian reserve.

Expression of oncogenes and tumor suppressor genes in lungs of rats exposed to sulfur dioxide and benzo(a)pyrene.

Concurrent exposure to SO(2) and benzo(a)pyrene (B(a)P) resulted in an increased incidence of lung tumors in rodents compared to exposure to B(a)P alone. A synergistic effect on the expression of c-fos and c-jun between SO(2) and B(a)P was observed in lungs after SO(2) and B(a)P exposure. However, tumorigenesis occurs by multiple events that may involve the activation of more than one oncogene, as well as the functional loss of the tumor suppressor gene. In order to further investigate the interactions between SO(2) and B(a)P, male Wistar rats were exposed via intratracheal instillation of B(a)P (3 mg) or SO(2) (56 mg/m(3)) inhalation, alone or together. The mRNA and protein levels of oncogenes (c-myc and H-ras) and tumor suppressor genes (p53, p16, and Rb) were analyzed in lungs by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot, respectively. The results showed that all treatments increased mRNA and protein expression levels of c-myc, H-ras, and p53, and reduced expression levels of p16 and Rb. In general, the combination of SO(2) and B(a)P was more effective in influencing these expression levels than either agent alone, except for H-ras expression. These findings indicate that multiple cell cycle regulatory proteins play key roles in the toxicity of SO(2) and B(a)P. It might involve the activation of c-fos, c-jun, c-myc, and p53. And the p16-Rb pathway might also participate in the progress. Elucidating the expression patterns of those factors after SO(2) and B(a)P exposure may be critical to understanding the mechanisms of SO(2) cocarcinogenesis and helpful for therapeutic intervention.