Metal exposure is linked to numerous pathological outcomes including cancer, cardiovascular disease, and diabetes. Over the past decades, we have made significant progress in our understanding of how ...metals are linked to disease, but there is still much to learn. In October 2022, experts studying the consequences of metal exposures met in Montréal, Québec, to discuss recent advances and knowledge gaps for future research. Here, we present a summary of presentations and discussions had at the meeting.
Arsenic as an immunotoxicant Giles, Braeden H.; Mann, Koren K.
Toxicology and applied pharmacology,
11/2022, Letnik:
454
Journal Article
Recenzirano
Arsenic is world-wide contaminant to which millions of people are exposed. The health consequences of arsenic exposure are varied, including cancer, cardiometabolic disease, and respiratory ...disorders. Arsenic is also toxic to the immune system, which may link many of the pathologies associated with arsenic exposure. The immune system can be classified into two interconnected arms: the innate and the adaptive immune responses. Herein, we discuss the effects of arsenic on key cell types within each of these arms, highlighting both in vitro and in vivo responses. These cells include macrophages, neutrophils, dendritic cells, and both B and T lymphocytes. Furthermore, we will explore data from human populations where altered immune status is implicated in disease and identify several data gaps where research is needed to complete our understanding of the immunotoxic effects of arsenic.
•Arsenic is immunotoxic to multiple different cell types within the immune system.•Immunotoxic effects link several different pathologies associated with arsenic exposure.•Immunotoxic effect of arsenic depend upon the type of arsenic, the dose tested, and the duration of exposure.
Exposure to environmental pollutants is linked to increased risk of cardiovascular disease. Beyond the extensive evidence for particulate air pollution, accumulating evidence supports that exposure ...to nonessential metals such as lead, cadmium, and arsenic is a significant contributor to cardiovascular disease worldwide. Humans are exposed to metals through air, water, soil, and food and extensive industrial and public use. Contaminant metals interfere with critical intracellular reactions and functions leading to oxidative stress and chronic inflammation that result in endothelial dysfunction, hypertension, epigenetic dysregulation, dyslipidemia, and changes in myocardial excitation and contractile function. Lead, cadmium, and arsenic have been linked to subclinical atherosclerosis, coronary artery stenosis, and calcification as well as to increased risk of ischemic heart disease and stroke, left ventricular hypertrophy and heart failure, and peripheral artery disease. Epidemiological studies show that exposure to lead, cadmium, or arsenic is associated with cardiovascular death mostly attributable to ischemic heart disease. Public health measures reducing metal exposure are associated with reductions in cardiovascular disease death. Populations of color and low socioeconomic means are more commonly exposed to metals and therefore at greater risk of metal-induced cardiovascular disease. Together with strengthening public health measures to prevent metal exposures, development of more sensitive and selective measurement modalities, clinical monitoring of metal exposures, and the development of metal chelation therapies could further diminish the burden of cardiovascular disease attributable to metal exposure.
Abstract
Cardiovascular disease remains the leading cause of death worldwide. In spite of cardiovascular prevention, there is residual risk not explicable by traditional risk factors. Metal ...contamination even at levels previously considered safe in humans may be a potential risk factor for atherosclerosis. This review examines evidence that 2 metals, lead, and cadmium, demonstrate sufficient toxicological and epidemiologic evidence to attribute causality for atherosclerotic disease. Basic science suggests that both metals have profound adverse effects on the human cardiovascular system, resulting in endothelial dysfunction, an increase in inflammatory markers, and reactive oxygen species, all of which are proatherosclerotic. Epidemiological studies have shown both metals to have an association with cardiovascular disease, such as peripheral arterial disease, ischemic heart disease, and cardiovascular mortality. This review also examines edetate disodium-based chelation as a possible pharmacotherapy to reduce metal burden in patients with a history of cardiovascular disease and thus potentially reduce cardiovascular events.
E‐cigarettes currently divide public opinion, with some considering them a useful tool for smoking cessation and while others are concerned with potentially adverse health consequences. However, it ...may take decades to fully understand the effects of e‐cigarette use in humans given their relative newness on the market. This highlights the need for comprehensive preclinical studies investigating the effects of e‐cigarette exposure on health outcomes. Here, we investigated the impact of chronic, low‐level JUUL aerosol exposure on multiple lung outcomes. JUUL is a brand of e‐cigarettes popular with youth and young adults. To replicate human exposures, 8‐ to 12‐week‐old male and female C57BL/6J mice were exposed to commercially available JUUL products (containing 59 mg/ml nicotine). Mice were exposed to room air, PG/VG, or JUUL daily for 4 weeks. After the exposure period, inflammatory markers were assessed via qRT‐PCR, multiplex cytokine assays, and differential cell count. Proteomic and transcriptomic analyses were also performed on samples isolated from the lavage of the lungs; this included unbiased analysis of proteins contained within extracellular vesicles (EVs). Mice exposed to JUUL aerosols for 4 weeks had significantly increased neutrophil and lymphocyte populations in the BAL and some changes in cytokine mRNA expression. However, BAL cytokines did not change. Proteomic and transcriptomic analysis revealed significant changes in numerous biological pathways including neutrophil degranulation, PPAR signaling, and xenobiotic metabolism. Thus, e‐cigarettes are not inert and can cause significant cellular and molecular changes in the lungs.
Environmental causes of cardiovascular diseases (CVDs) are global health issues. In particular, an association between metal exposure and CVDs has become evident but causal evidence still lacks. ...Therefore, this symposium at the Society of Toxicology 2022 annual meeting addressed epidemiological, clinical, pre-clinical animal model-derived and mechanism-based evidence by five presentations: 1) An epidemiologic study on potential CVD risks of individuals exposed occupationally and environmentally to heavy metals; 2) Both presentations of the second and third were clinical studies focusing on the potential link between heavy metals and pulmonary arterial hypertension (PAH), by presenting altered blood metal concentrations of both non-essential and essential metals in the patients with PAH and potential therapeutic approaches; 3) Arsenic-induced atherosclerosis via inflammatory cells in mouse model; 4) Pathogenic effects on the heart by adult chronic exposure to very low-dose cadmium via epigenetic mechanisms and whole life exposure to low dose cadmium via exacerbating high-fat-diet-lipotoxicity. This symposium has brought epidemiologists, therapeutic industry, physicians, and translational scientists together to discuss the health risks of occupational and environmental exposure to heavy metals through direct cardiotoxicity and indirect disruption of homeostatic mechanisms regulating essential metals, as well as lipid levels. The data summarized by the presenters infers a potential causal link between multiple metals and CVDs and defines differences and commonalities. Therefore, summary of these presentations may accelerate the development of efficient preventive and therapeutic strategies by facilitating collaborations among multidisciplinary investigators.
•CVD trends with environmental metal contamination continues increase globally•Potential link of non-essential metals to pulmonary arterial hypertension as one of CVDs•Three main clusters of macrophages independently involve in As-induced atherosclerosis•Exposure to low-dose cadmium may not directly induce, but increase HFD cardiotoxicity
The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma ...(LUAD) development, the most common histological type of lung cancer and a leading cause of cancer death worldwide. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2α), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2α causes the translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). Treatments with ISR inhibitors, including a memory-enhancing drug with limited toxicity, provides a suitable therapeutic option for KRAS-driven lung cancer insofar as they substantially reduce tumor growth and prolong mouse survival. Our data provide a rationale for the implementation of ISR-based regimens in LUAD treatment.
Flow cytometry is an essential tool for studying the tumor-immune microenvironment. It allows us to quickly quantify and identify multiple cell types in a heterogeneous sample. This chapter provides ...an overview of the flow cytometry instrumentation and a discussion of the appropriate considerations and steps in building a reproducible flow cytometry staining panel. We present an updated lymphoid tissue and solid tumor-infiltrating leucocyte flow cytometry staining protocol and an example of flow cytometry data analysis.
Antigen-naive IgM-producing B cells are atheroprotective, whereas mature B cells producing class-switched antibodies promote atherosclerosis. Activation-induced cytidine deaminase (AID), which ...mediates class switch recombination (CSR), would thus be expected to foster atherosclerosis. Yet, AID also plays a major role in the establishment of B cell tolerance. We sought to define whether AID affects atherosclerotic plaque formation. We generated Ldlr
chimeras transplanted with bone marrow from Aicda
or wild-type (WT) mice, fed a HFD for 14 weeks. Decreased B cell maturation in Ldlr
Aicda
mice was demonstrated by 50% reduction in splenic and aortic BAFFR expression, a key signaling component of B2 cell maturation. This was associated with increased plasma IgM in Ldlr
Aicda
compared with Ldlr
WT animals. Importantly, Ldlr
Aicda
mice had reduced atherosclerotic lesion area (0.20 ± 0.03mm
) compared with Ldlr
WT (0.30 ± 0.04mm
, P < 0.05), although no differences in plaque composition were noted between groups. In addition, immunofluorescence analysis revealed increased splenic B and T cell areas independent of cell number. AID depletion directly inhibits atherosclerotic plaque formation.
Pyrethroid insecticides use for indoor residual spraying (IRS) in malaria-endemic areas results in high levels of exposure to local populations. Pyrethroids may cause asthma and respiratory allergies ...but no prior study has investigated this question in an IRS area.
We measured maternal urinary concentrations of pyrethroid metabolites (cis-DBCA, cis-DCCA, trans-DCCA, 3-PBA) in samples collected at delivery from 751 mothers participating in the Venda Health Examination of Mothers, Babies, and their Environment (VHEMBE), a birth cohort study based in Limpopo, South Africa. At 3.5-year and 5-year follow-up visits, caregivers of 647 and 620 children, respectively, were queried about children's respiratory allergy symptoms based on validated instruments. We applied marginal structural models for repeated outcomes to estimate associations between biomarker concentrations and asthma diagnosis as well as respiratory allergy symptoms at ages 3.5 and 5 years.
We found that a10-fold increase in maternal urinary cis-DCCA, trans-DCCA and 3-PBA concentrations were associated with more than a doubling in the risk of doctor-diagnosed asthma (cis-DCCA: RR = 2.1, 95% CI = 1.3, 3.3; trans-DCCA: RR = 2.1, 95% CI = 1.1, 3.9; 3-PBA: RR = 2.4, 95% CI = 1.0, 5.8) and an about 80% increase in the risk of wheezing or whistling in the chest (cis-DCCA: RR = 1.8, 95% CI = 1.1, 3.0; trans-DCCA: RR = 1.7, 95% CI = 1.1, 2.6; 3-PBA: RR = 1.8, 95% CI = 1.0, 3.3) and suspected asthma (cis-DCCA: RR = 1.8, 95% CI = 1.1, 3.1; trans-DCCA: RR = 1.8, 95% CI = 1.1, 2.8). We also observed that higher concentrations of cis-DBCA and 3-PBA were related to increases in the risks of dry cough at night (RR = 3.5, 95% CI = 1.3, 9.5) and seasonal rhinoconjunctivitis (RR = 2.0, 95% CI = 1.1, 3.9), respectively.
Maternal exposure to pyrethroids may increase the risk of asthma and other respiratory allergy symptoms among preschool children from an IRS area.
•Pyrethroids may cause respiratory allergies but human data is inconsistent.•No studies of pyrethroids and allergies have been conducted in IRS areas.•We determined pyrethroid metabolites in pregnancy and allergies at 3.5 and 5 years.•We applied marginal structural models, accounting for time-varying confounders.•Pyrethroids were related to asthma, wheezing, dry cough and rhinoconjunctivitis.
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