Ractopamine, a synthetic β-adrenoreceptor agonist, is used as an animal feed additive to increase food conversion efficiency and accelerate lean mass accretion in farmed animals. The U.S. Food and Drug Administration claimed that ingesting products containing ractopamine residues at legal dosages might not cause short-term harm to human health. However, the effect of ractopamine on chronic inflammatory diseases and atherosclerosis is unclear. Therefore, we investigated the effects of ractopamine on atherosclerosis and its action mechanism in apolipoprotein E-null (apoe⁻/⁻) mice and human endothelial cells (ECs) and macrophages. Daily treatment with ractopamine for four weeks increased the body weight and the weight of brown adipose tissues and gastrocnemius muscles. However, it decreased the weight of white adipose tissues in apoe⁻/⁻ mice. Additionally, ractopamine exacerbated hyperlipidemia and systemic inflammation, deregulated aortic cholesterol metabolism and inflammation, and accelerated atherosclerosis. In ECs, ractopamine treatment induced endothelial dysfunction and increased monocyte adhesion and transmigration across ECs. In macrophages, ractopamine dysregulated cholesterol metabolism by increasing oxidized low-density lipoprotein (oxLDL) internalization and decreasing reverse cholesterol transporters, increasing oxLDL-induced lipid accumulation. Collectively, our findings revealed that ractopamine induces EC dysfunction and deregulated cholesterol metabolism of macrophages, which ultimately accelerates atherosclerosis progression.

Polychlorinated biphenyls (PCBs) are notorious environmental pollutants. For their hydrophobic and lipophilic capability, they are wildly spread to environment to threat human health thus attracts more attention. In this study, we observed increasing numbers of CD163 positive (CD163⁺) macrophages in aortic valve of ApoE⁻/⁻ mice after 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ) treatment, the metabolite of polychlorinated biphenyl. In addition, in vitro studies identified that PCB29-pQ exposure significantly provoked the shifting of RAW264.7 macrophages and bone marrow derived monocytes (BMDMs) to CD163⁺ macrophages. Upon PCB29-pQ administration, CD163 and CD206 levels were enhanced in RAW264.7 cells as well as in BMDMs. However, the concentration of iron and total cholesterol (TC) were reduced due to the boosting of ferroportin (Fpn) and ATP binding cassette transporter, subfamily A, member 1 (ABCA1) which are efflux transporters of iron and cholesterol individually. Further investigation on mechanism indicated that PCB29-pQ exposure induced reactive oxygen species (ROS), which may result in activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a protein responsible for macrophage polarization. After that, we blocked Nrf2 through Nrf2 shRNA and ROS scavenger NAC, which significantly reversed the shifting of macrophage to CD163⁺ sub-population. These results confirmed the importance of Nrf2 in inducing macrophage polarization. In short, our study uncovered that PCB29-pQ could promote macrophage/monocyte polarization to CD163⁺ macrophage which would be a potential incentive to accelerate atherosclerosis through Nrf2 signaling pathway.

In this study, we explore whether altered global histone modifications respond to low-level benzene exposure as well as their association with the hematotoxicity. We recruited 147 low-level benzene-exposed workers and 122 control workers from a petrochemical factory in Maoming City, Guangdong Province, China. The internal exposure marker level, urinary S-phenylmercapturic acid (SPMA), in benzene-exposed workers was 1.81-fold higher than that of the controls (P < 0.001). ELISA method was established to examine the specific histone modifications in human peripheral blood lymphocytes (PBLCs) of workers. A decrease in the counts of white blood cells (WBC), neutrophils, lymphocytes, and monocytes appeared in the benzene-exposed group (all P < 0.05) compared to the control group. Global trimethylated histone 3 lysine 4 (H3K4me3) modification was enhanced in the benzene-exposed group (P < 0.05) and was positively associated with the concentration of urinary SPMA (β = 0.103, P = 0.045) and the extent of DNA damage (% Tail DNA: β = 0.181, P = 0.022), but was negatively associated with the leukocyte count (WBC: β = −0.038, P = 0.023). The in vitro study revealed that H3K4me3 mark was enriched in the promoters of several DNA damage responsive (DDR) genes including CRY1, ERCC2, and TP53 in primary human lymphocytes treated with hydroquinone. Particularly, H3K4me3 modification was positively correlated with the expression of CRY1 in the PBLCs of benzene-exposed workers. These observations indicate that H3K4me3 modification might mediate the transcriptional regulation of DDR genes in response to low-dose benzene exposure.

Recently, health damage to children exposed to synthetic polyurethane (PU) running tracks has aroused social panic in China. Some possible toxic volatiles may be responsible for these damages. However, the exact cause remains unclear. We have detected a low concentration of sulfur dioxide (SO₂; 1.80–3.30 mg/m³) on the surface of the PU running track. Surprisingly, we found that SO₂ was generated from the PU running track, and even such a low concentration of SO₂ could induce severe lung inflammation with hemorrhage, inflammatory cell infiltration, and inflammatory factor secretion in mice after 2-week exposure. Prolonged exposure (5 weeks) to the SO₂ caused chronic pulmonary inflammation and pulmonary fibrosis in the mice. Peripheral hemogram results showed that platelet concentration increased significantly in the SO₂ group compared to that in the control group, and the proportion of blood neutrophils and monocytes among total leukocytes was more imbalanced in the SO₂ group (16.6%) than in the control group (8.0%). Further histopathology results of sternal marrow demonstrated that hematopoietic hyperplasia was severely suppressed with increased reticular stroma and adipocytes under SO₂ exposure. These data indicate that a low concentration of SO₂ generated spontaneously from PU running track outdoors as a secondary product is still harmful to health, as it impairs the respiratory system, hematopoiesis, and immunologic function. This indicates that the low-concentration SO₂ could be a major cause of diseases induced by air pollution, such as chronic obstructive pulmonary disease.

Ammonium persulfate (AP) causes occupational asthma (OA) and diesel exhaust particles (DEP) exacerbate asthma; however, the role of DEP in asthma due to chemical agents has not been assessed to date. Therefore, the present work aims to study the immunomodulatory effects of DEP in a mouse model of chemical asthma. BALB/c ByJ mice were randomly divided into four experimental groups. On days 1 and 8, mice were dermally sensitized with AP or saline. On days 15, 18 and 21, they received intranasal instillations of AP or saline. Two experimental groups received DEP on every of the three challenges. Airway hyperresponsiveness (AHR), lung mechanics, pulmonary inflammation in bronchoalveolar lavage, leukocyte numbers in total lung tissue, oxidative stress and optical projection tomography (OPT) studies were assessed. The AP-sensitized and challenged group showed asthma-like responses, such as airway hyperresponsiveness, increased levels of eosinophils and NKs and lower numbers of monocytes and CD11b-Ly6C- dendritic cells (DCs). Mice exposed to DEP alone showed increased levels of neutrophils and NKs, reduced numbers of monocytes and alveolar macrophages, and increased levels of CD11b + Ly6C- DCs. The AP sensitized and AP + DEP challenged group also showed asthma-like symptoms such as AHR, as well as increased numbers of eosinophils, neutrophils, CD11b + Ly6C- DCs and decreased levels of total and alveolar macrophages and tolerogenic DCs. Particle deposition was visualised using OPT. In the DEP group the particles were distributed relatively evenly, while in the AP + DEP group they were seen mainly in the large conducting airways. The results show that DEP exposure activates the innate immune response and, together with AP, exacerbates asthma immune hallmarks. This mouse model provides the first evidence of the capacity of DEPs to increase CD11b + Ly6C- (Th2-related) DCs. This study also demonstrates, for the first time, a differential deposition pattern of DEP in lungs depending on asthma status.

The level of di-(2-ethylhexyl) phthalate (DEHP) is elevated in chronic kidney disease patients undergoing dialysis. However, statins are unable to reduce the cardiovascular events in chronic dialysis patients. In this study, we investigated the effects of DEHP on statin-conferred pleiotropic effects and the underlying molecular mechanism in peritoneal dialysis (PD) patients and endothelial cells (ECs). In PD patients with serum DEHP level ≥0.0687 μg/mL, statin treatment was not associated with lower risk of cardiovascular disease. In ECs, exposure to DEHP abrogated the simvastatin-induced NO bioavailability and EC-related functions. Additionally, DEHP abolished the anti-inflammatory effect of simvastatin on the tumor necrosis factor α-induced upregulation of adhesion molecules and monocyte adhesion to ECs. Mechanistically, DEHP blunted the activation of transient receptor potential vanilloid type 1 (TRPV1), which is required for NO production by simvastatin in ECs. Notably, DEHP increased the activity and expression of protein phosphatase 2B (PP2B), a negative regulator of TRPV1 activity. The effect of DEHP on PP2B activation was mediated by the activation of the NADPH oxidase/reactive oxygen species (NOX−ROS) pathway. Inhibition of PP2B activity by pharmacological antagonists prevented the inhibitory effects of DEHP on simvastatin-induced Ca²⁺ influx, NO bioavailability, and EC migration, proliferation, tube formation, and anti-inflammatory action. Collectively, DEHP activates the NOX−ROS−PP2B pathway, which in turns inhibits TRPV1/Ca²⁺-dependent signaling and abrogates the statin-conferred pleiotropic protection in ECs.

Lead (Pb) and polycyclic aromatic hydrocarbon (PAH) exposure is positively associated with cardiovascular disease (CVD), and the possible potential mechanism may be caused by damage to the endothelium by modulation of inflammatory processes. No comprehensive research shows co-exposure of Pb and PAH on cardiovascular endothelial inflammation in electronic waste (e-waste) exposed populations. Given this, the aim of this study is to provide evidence for a relationship between Pb and PAH co-exposure and cardiovascular endothelial inflammation, in an e-waste-exposed population, to delineate the link between a potential mechanism for CVD and environmental exposure. We recruited 203 preschool children (3–7 years) were enrolled from Guiyu (e-waste-exposed group, n = 105) and Haojiang (reference group, n = 98). Blood Pb levels and urinary PAH metabolites were measured. Percentages of T cells, CD4⁺ T cells and CD8⁺ T cells, complete blood counts, endothelial inflammation biomarker (serum S100A8/A9), and other inflammatory biomarkers [serum interleukin (IL)-6, IL-12p70, gamma interferon-inducible protein 10 (IP-10)] levels were evaluated. Blood Pb, total urinary hydroxylated PAH (ΣOHPAH), total hydroxynaphthalene (ΣOHNap) and total hydroxyfluorene (ΣOHFlu) levels, S100A8/A9, IL-6, IL-12p70 and IP-10 concentrations, absolute counts of monocytes, neutrophils, and leukocytes, as well as CD4⁺ T cell percentages were significantly higher in exposed children. Elevated blood Pb, urinary 2-hydroxynaphthalene (2-OHNap) and ΣOHFlu levels were associated with higher levels of IL-6, IL-12p70, IP-10, CD4⁺ T cell percentages, neutrophil and monocyte counts. Mediator models indicated that neutrophils exert the significant mediation effect on the relationship between blood Pb levels and S100A8/A9. IL-6 exerts a significant mediation effect on the relationship between blood Pb levels and IP-10, as well as the relationship between urinary ΣOHFlu levels and IP-10. Our results indicate that children with elevated exposure levels of Pb and PAHs have exacerbated vascular endothelial inflammation, which may indicate future CVD risk in e-waste recycling areas.

The short-term alteration of peripheral cytokines may be an early adverse health effect of PM₂.₅ exposure and may be further associated with cardiovascular disease. We conducted a randomized, double-blind crossover trial using true or sham air filtration among 54 healthy college students in Beijing to investigate the potential benefits of short-term indoor air filtration and the adverse health effects of time-weighted personal PM₂.₅ exposure through inflammatory cytokines. The participants randomly received true or sham air filtration intervention for a week, and the treatment was changed after a two-week washout period. Peripheral blood samples were collected after each intervention period to measure 38 inflammatory cytokines. A linear mixed-effects model was applied to estimate the impacts of air purification or a 10 μg/m³ PM₂.₅ exposure increase on cytokines. Lag effects of PM₂.₅ exposure were analyzed using single-day and moving average lag models. Air filtration reduced indoor and time-weighted average personal PM₂.₅ concentrations by 69.0% (from 33.6 to 10.4 μg/m³) and 40.3% (from 40.6 to 24.3 μg/m³), respectively. We observed a significant association of PM₂.₅ exposure with growth-regulated alpha protein (GRO-α) of −11.3% (95%CI: 17.0%, −5.4%). In the lag models, significant associations between personal PM₂.₅ exposure and interleukin-1 receptor antagonist (IL-1Ra), monocyte chemotactic protein (MCP-1), and eotaxin were obtained at lag0, while associations with cytokines including vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), fibroblast growth factor-2 (FGF-2), granulocyte colony-stimulating factor (G-CSF), macrophage inflammatory protein-1β (MIP-1β), IL-4, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) were noted at relatively long lagged exposure windows (lag5-lag6). No significant alteration in cytokines was observed under true air filtration intervention. Our study indicates the effectiveness of air filtration on indoor PM₂.₅ reduction. PM₂.₅ exposure may decrease GRO-α levels and change different cytokine levels time-varyingly. Further study is still needed to explore the mechanisms of PM₂.₅ exposure on the inflammatory response.

Individuals with metabolic disorders exhibit enhanced susceptibility to the cardiovascular health effects of particulate air pollution, but the underlying mechanisms are not yet understood. We aim to assess whether changes in proinflammatory lipid signals are associated with fine particulate matter (PM₂.₅) exposure in individuals with and without prediabetes. A longitudinal panel study was conducted in Beijing, China, and included 120 participants followed up over 589 clinical visits from August 2013 to February 2015. We measured 12 lipids derived from arachidonic acid pathways in blood samples of the participants via targeted lipidomic analyses. Ambient PM₂.₅ concentrations were continuously monitored at a station for associations with the lipids. Among the 120 participants, 110 (mean [SD] age at recruitment, 56.5 [4.2] years; 31 prediabetics) who visited the clinic at least twice over the follow-up period were assigned exposure values of the outdoor residential PM₂.₅ concentrations during the 1–14 days preceding each clinical visit. With an interquartile range increase in the 1-day-lag PM₂.₅ exposure (64.0 μg/m³), the prediabetic group had consistently greater increases in the concentration of arachidonate metabolites derived from the cytochrome P450 (CYP450) pathway (5,6-DHET, 15.8% [95% CI, 3.5–29.7%]; 8,9-DHET, 9.7% [95% CI, 0.6–19.6%]; 11,12-DHET, 8.3% [95% CI, 1.9–15.1%]; 14,15-DHET, 7.4% [95% CI, 0.9–14.4%]; and 20-HETE, 8.9% [95% CI, 1.0–17.5%]), compared with the healthy group. Among CYP450-derived lipids, 14,15-DHET and 20-HETE significantly mediated 8% and 8% of the PM₂.₅-associated increase in white blood cells, 10% and 13% of that in neutrophils, and 20% and 23% of that in monocytes, respectively, in the prediabetic group. In conclusion, proinflammatory lipid signals from CYP450 pathways triggered the health effects of particulate air pollution in individuals with prediabetes, suggesting that targeting lipid metabolism has therapeutic potential to attenuate or prevent the cardiovascular effects of air pollution in susceptible populations.

Exposure to metal nanoparticles causes both pulmonary and systemic effects. Nanoparticles can enter the circulation and act directly or indirectly on blood cells, such as monocytes. Monocytes/macrophages are among the first cells to home to inflammatory sites and play a key role in the immune response. Here we investigated the effects of nickel nanoparticles (Nano-Ni), partially [O]-passivated Nano-Ni (Nano-Ni-P), and carbon-coated Nano-Ni (Nano-Ni-C) on MMP-2 and MMP-9 production in mouse primary monocytes both in vitro and in vivo and explored the potential mechanisms involved. The dose- and time-response studies showed that exposure of primary monocytes from wild-type (WT) mice to 30 μg/mL of Nano-Ni for 24 h caused significant MMP-2 and MMP-9 production; therefore, these dose and time point were chosen for the following in vitro studies. Nano-Ni and Nano-Ni-P caused miR-21 upregulation, as well as MMP-2, MMP-9, TIMP-1 and TIMP-2 upregulation in monocytes from WT, but not miR-21 knock-out (KO), mice, indicating the important role of miR-21 in Nano-Ni-induced MMPs and TIMPs upregulation. However, Nano-Ni-C did not cause these effects, suggesting surface modification of Nano-Ni, such as carbon coating, alleviates Nano-Ni-induced miR-21 and MMPs upregulation. These results were further confirmed by in vivo studies by intratracheal instillation of nickel nanoparticles into WT and miR-21 KO mice. Finally, our results demonstrated that exposure of primary monocytes from WT mice to Nano-Ni and Nano-Ni-P caused downregulation of RECK, a direct miR-21 target, suggesting the involvement of miR-21/RECK pathway in Nano-Ni-induced MMP-2 and MMP-9 production.