Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy.

Asbestos causes malignant transformation of primary human mesothelial cells (HM), leading to mesothelioma. The mechanisms of asbestos carcinogenesis remain enigmatic, as exposure to asbestos induces HM death. However, some asbestos-exposed HM escape cell death, accumulate DNA damage, and may become transformed. We previously demonstrated that, upon asbestos exposure, HM and reactive macrophages releases the high mobility group box 1 (HMGB1) protein that becomes detectable in the tissues near asbestos deposits where HMGB1 triggers chronic inflammation. HMGB1 is also detectable in the sera of asbestos-exposed individuals and mice. Searching for additional biomarkers, we found higher levels of the autophagy marker ATG5 in sera from asbestos-exposed individuals compared to unexposed controls. As we investigated the mechanisms underlying this finding, we discovered that the release of HMGB1 upon asbestos exposure promoted autophagy, allowing a higher fraction of HM to survive asbestos exposure. HMGB1 silencing inhibited autophagy and increased asbestos-induced HM death, thereby decreasing asbestos-induced HM transformation. We demonstrate that autophagy was induced by the cytoplasmic and extracellular fractions of HMGB1 via the engagement of the RAGE receptor and Beclin 1 pathway, while nuclear HMGB1 did not participate in this process. We validated our findings in a novel unique mesothelial conditional HMGB1-knockout (HMGB1-cKO) mouse model. Compared to HMGB1 wild-type mice, mesothelial cells from HMGB1-cKO mice showed significantly reduced autophagy and increased cell death. Autophagy inhibitors chloroquine and desmethylclomipramine increased cell death and reduced asbestos-driven foci formation. In summary, HMGB1 released upon asbestos exposure induces autophagy, promoting HM survival and malignant transformation.

Investigating palygorskite's role in the development of mesothelioma in southern Nevada: Insights into fiber-induced carcinogenicity.

Similar to asbestos fibers, nonregulated mineral fibers can cause malignant mesothelioma (MM). Recently, increased proportions of women and young individuals with MM were identified in southern Nevada, suggesting that environmental exposure to carcinogenic fibers was causing the development of MM. Palygorskite, a fibrous silicate mineral with a history of possible carcinogenicity, is abundant in southern Nevada. In this study, our aim was to determine whether palygorskite was contributing to the development of MM in southern Nevada. While palygorskite, in vitro, displayed some cytotoxicity toward primary human mesothelial (HM) cells and reduced their viability, the effects were roughly half of those observed when using similar amounts of crocidolite asbestos. No Balb/c (0/19) or MexTAg (0/18) mice injected with palygorskite developed MM, while 3/16 Balb/c and 13/14 MexTAg mice injected with crocidolite did. Lack of MM development was associated with a decreased acute inflammatory response, as injection of palygorskite resulted in lower percentages of macrophages (p = .006) and neutrophils (p = .02) in the peritoneal cavity 3 d after exposure compared to injection of crocidolite. Additionally, compared to mice injected with crocidolite, palygorskite-injected mice had lower percentages of M2 (tumor-promoting) macrophages (p = .008) in their peritoneal cavities when exposed to fiber for several weeks. Our study indicates that palygorskite found in the environment in southern Nevada does not cause MM in mice, seemingly because palygorskite, in vivo, fails to elicit inflammation that is associated with MM development. Therefore, palygorskite is not a likely contributor to the MM cases observed in southern Nevada.

A mesothelioma epidemic in Cappadocia: scientific developments and unexpected social outcomes.

In Cappadocia, Turkey, an unprecedented mesothelioma epidemic causes 50% of all deaths in three small villages. Initially linked solely to the exposure to a fibrous mineral, erionite, recent studies by scientists from Turkey and the United States have shown that erionite causes mesothelioma mostly in families that are genetically predisposed to mineral fibre carcinogenesis. This manuscript reports, through the eyes of one of the researchers, the resulting scientific advances that have come from these studies and the social improvements that were brought about by both the scientists and members of the Turkish Government.

Erionite exposure in North Dakota and Turkish villages with mesothelioma.

Exposure to erionite, an asbestos-like mineral, causes unprecedented rates of malignant mesothelioma (MM) mortality in some Turkish villages. Erionite deposits are present in at least 12 US states. We investigated whether increased urban development has led to erionite exposure in the United States and after preliminary exploration, focused our studies on Dunn County, North Dakota (ND). In Dunn County, ND, we discovered that over the past three decades, more than 300 miles of roads were surfaced with erionite-containing gravel. To determine potential health implications, we compared erionite from the Turkish villages to that from ND. Our study evaluated airborne point exposure concentrations, examined the physical and chemical properties of erionite, and examined the hallmarks of mesothelial cell transformation in vitro and in vivo. Airborne erionite concentrations measured in ND along roadsides, indoors, and inside vehicles, including school buses, equaled or exceeded concentrations in Boyali, where 6.25% of all deaths are caused by MM. With the exception of outdoor samples along roadsides, ND concentrations were lower than those measured in Turkish villages with MM mortality ranging from 20 to 50%. The physical and chemical properties of erionite from Turkey and ND are very similar and they showed identical biological activities. Considering the known 30- to 60-y latency for MM development, there is reason for concern for increased risk in ND in the future. Our findings indicate that implementation of novel preventive and early detection programs in ND and other erionite-rich areas of the United States, similar to efforts currently being undertaken in Turkey, is warranted.

Quantitative mineralogical properties (morphology-chemistry-structure) of pharmaceutical grade kaolinites and recommendations to regulatory agencies.

The physical and chemical characteristics of kaolinite (kaolin) may be variable, and minor amounts of other clay minerals, nonclay minerals, and other impurities may affect the properties of kaolinites. Thus specific technical properties of pharmaceutical grade kaolinites become very important because these clays are used in medical applications, e.g., as pharmaceutical excipients, and will be consumed by humans. Seven pharmaceutical grade kaolinite specimens were used in this study: K1004, KA105, 2242-01, K2-500, Acros, Acros-mono, and KX0007-1. In addition, two kaolinites from the Clay Minerals Society Source Clays, KGa-1b and KGa-2, were used for comparison purposes. The Acros-mono and 2242-01 kaolinites contained minor amounts of illite, which was demonstrated both compositionally and structurally by using inductively coupled plasma spectroscopy and powder X-ray diffraction. The KX0007-1 kaolinite powder was found to be heavily contaminated with quartz, cristobalite, and alunite. Crystal structure computations also showed excess Si in its tetrahedral site, and the mineral no longer has the typical kaolinite crystal structure. These widely-used industrial standards should be quantitatively characterized morphologically, compositionally, and structurally. Results of the mineralogical characteristics should be clearly labeled on the pharmaceutical grade kaolinites and reported to the relevant regulatory agencies.

Genetic predisposition to fiber carcinogenesis causes a mesothelioma epidemic in Turkey.

Malignant mesothelioma in the western world is often associated with asbestos exposure. It is a relatively rare cancer that causes approximately 2,500 deaths yearly in the United States and 1,000 deaths yearly in the United Kingdom. In contrast, among people born in the Cappadocian (Turkey) villages of Tuzkoy, Karain, and "Old" Sarihidir, approximately 50% of deaths are caused by malignant mesothelioma. This epidemic has been attributed to erionite exposure, a type of fibrous zeolite mineral commonly found in this area of Turkey. In these three villages, malignant mesothelioma occurs in certain houses but not in others. The hypothesis was that a unique and more carcinogenic erionite was present in certain houses and caused malignant mesothelioma. We determined the X-ray diffraction pattern and the crystal structure of erionite from malignant mesothelioma villages and compared the results with the erionite samples from nearby non-malignant mesothelioma villages and from the United States. We found the same type of erionite in Cappadocian villages, with or without a malignant mesothelioma epidemic, in households with high or no incidence of malignant mesothelioma and in the United States. Pedigree studies of the three malignant mesothelioma villages showed that malignant mesothelioma was prevalent in certain families but not in others. When high-risk malignant mesothelioma family members married into families with no history of it, malignant mesothelioma appeared in the descendants. Genetically predisposed family members born and raised outside the malignant mesothelioma villages did not seem to develop malignant mesothelioma. In summary, pedigree and mineralogical studies indicate that the malignant mesothelioma epidemic is caused by erionite exposure in genetically predisposed individuals. This is the first time that genetics is shown to influence mineral fiber carcinogenesis.

Sialolith characterization by scanning electron microscopy and X-ray photoelectron spectroscopy.

The objective of this study has been to characterize sialolith, a calcium phosphate deposit that develops in the human oral cavity, by high-resolution field emission scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). The morphological and chemical data obtained helped in the determination of their formation mechanism in salivary glands. Sialoliths in the submandibular salivary glands may arise secondary to sialodenitis, but not via a luminal organic nidus. We believe this is the first study that characterizes a sialolith by XPS.

Morpho-chemical characterization and surface properties of carcinogenic zeolite fibers.

Erionite belonging to the zeolite family is a human health-hazard, since it was demonstrated to be carcinogenic. Conversely, offretite family zeolites were suspected carcinogenic. Mineralogical, morphological, chemical, and surface characterizations were performed on two erionites (GF1, MD8) and one offretite (BV12) fibrous samples and, for comparison, one scolecite (SC1) sample. The specific surface area analysis indicated a larger availability of surface sites for the adsorption onto GF1, while SC1 shows the lowest one and the presence of large pores in the poorly fibrous zeolite aggregates. Selected spin probes revealed a high adsorption capacity of GF1 compared to the other zeolites, but the polar/charged interacting sites were well distributed, intercalated by less polar sites (Si-O-Si). MD8 surface is less homogeneous and the polar/charged sites are more interacting and closer to each other compared to GF1. The interacting ability of BV12 surface is much lower than that found for GF1 and MD8 and the probes are trapped in small pores into the fibrous aggregates. In comparison with the other zeolites, the non-carcinogenic SC1 shows a poor interacting ability and a lower surface polarity. These results helped to clarify the chemical properties and the surface interacting ability of these zeolite fibers which may be related to their carcinogenicity.

Consensus Report of the 2015 Weinman International Conference on Mesothelioma.

On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant input from staff at the U.S. National Cancer Institute and National Institute of Environmental Health Sciences. A multidisciplinary group of participants presented updates reflecting a range of disciplinary perspectives, including mineralogy, geology, epidemiology, toxicology, biochemistry, molecular biology, genetics, public health, and clinical oncology. The group identified knowledge gaps that are barriers to preventing and treating malignant mesothelioma (MM) and the required next steps to address barriers. This manuscript reports the group's efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored: genetic risk, environmental exposure, biomarkers, and clinical interventions. Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations. Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers. MM is an almost entirely preventable malignancy as it is most often caused by exposure to commercial asbestos or mineral fibers with asbestos-like health effects, such as erionite. In the past in North America and in Europe, the most prominent source of exposure was related to occupation. Present regulations have reduced occupational exposure in these countries; however, some people continue to be exposed to previously installed asbestos in older construction and other settings. Moreover, an increasing number of people are being exposed in rural areas that contain noncommercial asbestos, erionite, and other mineral fibers in soil or rock (termed naturally occurring asbestos [NOA]) and are being developed. Public health authorities, scientists, residents, and other affected groups must work together in the areas where exposure to asbestos, including NOA, has been documented in the environment to mitigate or reduce this exposure. Although a blood biomarker validated to be effective for use in screening and identifying MM at an early stage in asbestos/NOA-exposed populations is not currently available, novel biomarkers presented at the meeting, such as high mobility group box 1 and fibulin-3, are promising. There was general agreement that current treatment for MM, which is based on surgery and standard chemotherapy, has a modest effect on the overall survival (OS), which remains dismal. Additionally, although much needed novel therapeutic approaches for MM are being developed and explored in clinical trials, there is a critical need to invest in prevention research, in which there is a great opportunity to reduce the incidence and mortality from MM.

Germline BAP1 mutations predispose to malignant mesothelioma.

Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing factors. We discovered germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) in two families with a high incidence of mesothelioma, and we observed somatic alterations affecting BAP1 in familial mesotheliomas, indicating biallelic inactivation. In addition to mesothelioma, some BAP1 mutation carriers developed uveal melanoma. We also found germline BAP1 mutations in 2 of 26 sporadic mesotheliomas; both individuals with mutant BAP1 were previously diagnosed with uveal melanoma. We also observed somatic truncating BAP1 mutations and aberrant BAP1 expression in sporadic mesotheliomas without germline mutations. These results identify a BAP1-related cancer syndrome that is characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved and that mesothelioma predominates upon asbestos exposure. These findings will help to identify individuals at high risk of mesothelioma who could be targeted for early intervention.

Re-evaluation and re-classification of erionite series minerals.

Governments and industries have introduced regulatory measures requiring safety controls to limit asbestos exposure of the general public and asbestos workers. Although erionite is a more potent health hazard mineral than asbestos, it has received far less attention. Precise definition of erionite, types of these fibrous minerals, and most importantly, characterization requirements still raise questions and often lead to arguments and even legal disputes. Many bulk erionite samples used in animal and cell experiments for carcinogenicity are not mineralogically pure. To test this hypothesis, we characterized two erionite standards from Rome, Oregon, and Pine Valley, Nevada, USA. These standards were characterized quantitatively using modern analytical techniques, and one of them, the erionite standard from Rome, Oregon, passed the required tests for positive identification, but the other, the erionite standard from Pine Valley, Nevada, did not. Furthermore, we observed ambiguous definitions, incorrect identifications, and inaccurate reporting of clinical investigations. To address this problem, we established characterization guidelines for positive identification of erionite using a modified balance error formula, and we re-evaluated and re-classified published erionite data from the literature as erionite-Ca, erionite-Na, and erionite-K. If data did not pass either the E% or Mg-content test, then we propose that reference to them in the literature be disregarded. Erionite requires special attention from the mineralogical community to help establish its true carcinogenetic properties. We believe that the characterization guidelines established in this paper will contribute to setting up rules and regulations for evaluation of erionite by regulatory agencies.

Erionite series minerals: mineralogical and carcinogenic properties.

Erionite is a human and animal carcinogen and one of the most toxic minerals known. Erionite deposits have been reported in many countries; however, it is only in the area of three villages of Cappadocia, Turkey, that environmental exposure to erionite has been demonstrated to be the cause of an epidemic of the disease mesothelioma. In the USA, no cases of mesothelioma have been reliably proven to be the result of erionite exposure, though the possibility exists. Erionite samples from three villages of the Cappadocia region were characterized mineralogically and compared with three different standards from the USA. Micro morphological details of erionite minerals using a high-resolution field-emission SEM showed that microstructures of "bundles", "fibers", and "fibrils" are important physical properties of fibrous erionite minerals. Typical lung burden of erionite and asbestos fibers were compared in terms of number of fibers. Assuming the lung burden of fibers in a human mesothelioma victim is about 1 mg, and the hazardous fibers are approximately 1 mum in diameter and 10 mum long, that milligram contains approximately 40 million asbestos and 50 million erionite fibers. These microstructures of erionite minerals draw attention to the concepts of surface area or surface-area-to-volume ratio and their relationship to the carcinogenicity of the mineral. The larger surface area creates a wider platform for mineral-cell interaction and thus more possibilities of proliferative transformation of mesothelial cells. Consequently, understanding the exact mineralogical properties will help determination of the true carcinogenic mechanism(s) of the mineral for prevention and possibly treatment of malignant mesothelioma.

Arsenic mineralization, source, distribution, and abundance in the Kutahya region of the western Anatolia, Turkey.

Environmental exposure to arsenic (As) in the Kutahya region of the western Anatolia, Turkey has been reported to cause various types of arsenic-associated skin disorders (Dogan, Dogan, Celebi, & Baris, 2005). A geological and mineralogical study was conducted to find the sources and distribution of the As. Geogenic (background) levels were measured in samples collected from various sources in the Gediz, Simav, Tavsanli, Emet, Yoncali, Yenicekoy, and Muratdagi areas of the Kutahya region. Based on this analysis, we determined that natural sources are a domineering factor affecting the distribution of As, which was found: (1) mainly in evaporitic minerals, including colemanite (269-3900 ppm) and gypsum (11-99,999 ppm), but also in alunite (7-10 ppm) and chert (54-219 ppm); (2) in secondary epithermal gypsum, which has a high concentration of As in the form of realgar and orpiment along fracture zones of Mesozoic and Cenozoic carbonate aquifers; (3) in rocks, including limestone/dolomite (3-699 ppm) and travertine (5-4736 ppm), which are relatively more enriched in As than volcanics (2-14 ppm), probably because of secondary enrichment through hydrological systems; (4) in coal (1.9-46.5 ppm) in the sedimentary successions of the Tertiary basins; (5) in thermal waters, where As is unevenly distributed at concentrations varying from 0.0-0.9 mg/l. The highest As concentrations in thermal water (Gediz and Simav) correlate to the higher pH (7-9.3) and T (60-83 degrees C) conditions and to the type of water (Na-HCO3-SO4 with high concentration of Ca, Mg, K, SiO2, and Cl in the water). Changes in pH can be related to some redox reactions, such as the cation exchange reactions driving the dissolution of carbonates and silicates. Fe-oxidation, high pH values (7-9.3), presence of other trace metals (Ni, Co, Pb, Zn, Al), increased salinity (Na, Cl), high B, Li, F, and SiO, high Fe, SO4 (magnetite, specularite-hematite, gypsum), and graphite, and the presence of U, Fe, Cu, Pb, Zn, and B, especially in the Emet, Gediz, and Simav areas, are the typical indicators for the geothermally affected water with high As content. A sixth source of As in this region is the ground (0.0-10.7 mg/l) and the surface waters (0.0022-0.01 mg/l), which are controlled by water-rock interaction, fracture system, and mixing/dilution of thermal waters. The high As concentration in groundwater corresponds to the areas where pathological changes are greatest in the habitants. Arsenic in ground water also effects ecology. For example, only Juriperus oxycedrus and J. varioxycedrus types of vegetation are observed in locations with the highest concentration of As in the region. Branches and roots of these plants are enriched in As.

Short-term effects of arsenic sulfur in deficits of contractile and relaxant responses on urinary bladder: pharmacological and structural changes.

INTRODUCTION: Our goal was to investigate the effects of arsenic sulfur (AsS) on the detrusor smooth muscle reactivity. MATERIAL AND METHODS: AsS (100 ppm microg/g) in drinking water was administered for 2 weeks to two groups of female Wistar rats. The contractile responses of urinary bladders to electrical field stimulation, carbachol, ATP and KCl, and the relaxant responses to ATP, adenosine and isoproterenol were examined. Urinary bladder strips were collected for light microscopic examination. RESULTS: Our results demonstrate that oral inorganic AsS exposure induced enhanced contractile and reduced relaxant responses in rats. We hypothesize that AsS is involved in deficiencies of isolated urinary bladder in rats. CONCLUSION: These functional and morphological changes may be important as an intermediate link in urinary bladder oncogenesis induced by AsS.