Quantification of Spatial and Temporal Trends in Atmospheric Mercury Deposition across Canada over the Past 30 Years.

Mercury (Hg) is a pollutant of concern across Canada and transboundary anthropogenic Hg sources presently account for over 95% of national anthropogenic Hg deposition. This study applies novel statistical analyses of 82 high-resolution dated lake sediment cores collected from 19 regions across Canada, including nearby point sources and in remote regions and spanning a full west-east geographical range of ∼4900 km (south of 60°N and between 132 and 64°W) to quantify the recent (1990-2018) spatial and temporal trends in anthropogenic atmospheric Hg deposition. Temporal trend analysis shows significant synchronous decreasing trends in post-1990 anthropogenic Hg fluxes in western Canada in contrast to increasing trends in the east, with spatial patterns largely driven by longitude and proximity to known point source(s). Recent sediment-derived Hg fluxes agreed well with the available wet deposition monitoring. Sediment-derived atmospheric Hg deposition rates also compared well to the modeled values derived from the Hg model, when lake sites located nearby (<100 km) point sources were omitted due to difficulties in comparison between the sediment-derived and modeled values at deposition "hot spots". This highlights the applicability of multi-core approaches to quantify spatio-temporal changes in Hg deposition over broad geographic ranges and assess the effectiveness of regional and global Hg emission reductions to address global Hg pollution concerns.

Atmospheric deposition of mercury and methylmercury to landscapes and waterbodies of the Athabasca oil sands region.

Atmospheric deposition of metals originating from a variety of sources, including bitumen upgrading facilities and blowing dusts from landscape disturbances, is of concern in the Athabasca oil sands region of northern Alberta, Canada. Mercury (Hg) is of particular interest as methylmercury (MeHg), a neurotoxin which bioaccumulates through foodwebs, can reach levels in fish and wildlife that may pose health risks to human consumers. We used spring-time sampling of the accumulated snowpack at sites located varying distances from the major developments to estimate winter 2012 Hg loadings to a ∼20 000 km(2) area of the Athabasca oil sands region. Total Hg (THg; all forms of Hg in a sample) loads were predominantly particulate-bound (79 ± 12%) and increased with proximity to major developments, reaching up to 1000 ng m(-2). MeHg loads increased in a similar fashion, reaching up to 19 ng m(-2) and suggesting that oil sands developments are a direct source of MeHg to local landscapes and water bodies. Deposition maps, created by interpolation of measured Hg loads using geostatistical software, demonstrated that deposition resembled a bullseye pattern on the landscape, with areas of maximum THg and MeHg loadings located primarily between the Muskeg and Steepbank rivers. Snowpack concentrations of THg and MeHg were significantly correlated (r = 0.45-0.88, p < 0.01) with numerous parameters, including total suspended solids (TSS), metals known to be emitted in high quantities from the upgraders (vanadium, nickel, and zinc), and crustal elements (aluminum, iron, and lanthanum), which were also elevated in this region. Our results suggest that at snowmelt, a complex mixture of chemicals enters aquatic ecosystems that could impact biological communities of the oil sands region.

IgE-mediated systemic anaphylaxis and impaired tolerance to food antigens in mice with enhanced IL-4 receptor signaling.

BACKGROUND: In atopic subjects food ingestion drives the production of IgE antibodies that can trigger hypersensitivity reactions. The IL-4 pathway plays a critical role in this response, and genetic polymorphisms in its components have been linked to allergy. OBJECTIVE: We sought to test whether an activating mutation in the IL-4 receptor (IL-4R) α chain enhances allergic responses to a food antigen. METHODS: F709 mice, in which the IL-4Rα immunoreceptor tyrosine-based inhibitory motif is inactivated, were gavage fed with ovalbumin (OVA). Reactions to OVA challenge and immune responses, including antibody production and T(H)2 responses, were assessed. RESULTS: F709 mice, but not wild-type control animals, sensitized by means of gavage with OVA and either cholera toxin or staphylococcal enterotoxin B, displayed mast cell activation and systemic anaphylaxis on enteral challenge. Anaphylaxis was elicited even in F709 mice enterally sensitized with OVA alone. Bone marrow chimera experiments established that the increased sensitivity conferred by the F709 genotype was mediated mostly by hematopoietic cells but that nonhematopoietic cells also contributed. F709 mice exhibited increased intestinal permeability to macromolecules. The F709 genotype conferred increased OVA-specific IgE but not IgG1 responses, local and systemic T(H)2 responses, and intestinal mast cell hyperplasia compared with wild-type mice. Anaphylaxis was abrogated in F709 mice lacking IgE or the high-affinity receptor for IgE (FcεRI). CONCLUSION: Augmented IL-4Rα signaling confers increased intestinal permeability and dramatically enhanced sensitivity to food allergens. Unlike anaphylaxis to injected antigens, which in rodents can be mediated by either IgE or IgG antibodies, the food-induced response in F709 mice is solely IgE dependent.

Mercury concentrations in landlocked Arctic char (Salvelinus alpinus) from the Canadian Arctic. Part I: insights from trophic relationships in 18 lakes.

Concentrations of mercury (Hg) have increased slowly in landlocked Arctic char over a 10- to 15-year period in the Arctic. Fluxes of Hg to sediments also show increases in most Arctic lakes. Correlation of Hg with trophic level (TL) was used to investigate and compare biomagnification of Hg in food webs from lakes in the Canadian Arctic sampled from 2002 to 2007. Concentrations of Hg (total Hg and methylmercury [MeHg]) in food webs were compared across longitudinal and latitudinal gradients in relation to delta(13)C and delta(15)N in periphyton, zooplankton, benthic invertebrates, and Arctic char of varying size-classes. Trophic magnification factors (TMFs) were calculated for the food web in each lake and related to available physical and chemical characteristics of the lakes. The relative content of MeHg increased with trophic level from 4.3 to 12.2% in periphyton, 41 to 79% in zooplankton, 59 to 72% in insects, and 74 to 100% in juvenile and adult char. The delta(13)C signatures of adult char indicated coupling with benthic invertebrates. Cannibalism among char lengthened the food chain. Biomagnification was confirmed in all 18 lakes, with TMFs ranging from 3.5 +/- 1.1 to 64.3 +/- 0.8. Results indicate that TMFs and food chain length (FCL) are key factors in explaining interlake variability in biomagnification of [Hg] among different lakes.

Sources of atmospheric metal(loid) pollution recorded in Thompson Manitoba lake sediment cores within the Canadian boreal biome.

Global atmospheric emissions and subsequent deposition of numerous metal(loid)s has increased markedly since the industrial revolution. Due to a paucity of long-term metal(loid) flux measurements, the magnitude and timing of change are largely unknown, resulting in limited ability to predict time-scales of ecosystem recovery in response to emission decreases. In the absence of long-term data, palaeo-reconstructions provide continuous records of atmospheric metal(loid) deposition on an ecosystem, and landscape, scale. Here, we use high-resolution dated lake sediment cores to reconstruct the last c. 100 years of atmospheric anthropogenic deposition of a full suite (40) of metal(loid)s near a large nickel (Ni) and copper (Cu) smelter in an other-wise largely "pristine" region of northern Canada (Thompson, Manitoba). Anthropogenic depositional fluxes were compared to other regions of Canada including Kejimkujik National Park in Nova Scotia, Experimental Lakes Area in Ontario, as well as the Flin Flon, Manitoba Cu and zinc (Zn) smelter, located ~200 km southwest of Thompson. Deposition of 12 metal(loid)s were enriched above baseline (pre-1915) levels: antimony (Sb) > palladium (Pd) > bismuth (Bi) > mercury (Hg) > cadmium (Cd) > Ni > lead (Pb) > arsenic (As) > strontium (Sr) > Cu > platinum (Pt) > Zn. Spatio-temporal patterns in depositional fluxes and inventories demonstrate that 6 of these metal(loid)s were sourced primarily from the smelter, while As, Hg, Pb, Pt, Sb and Zn were sourced primarily from global and/or regional sources. Comparison of anthropogenic fluxes and inventories to available emissions data showed that Cu and Ni deposition has plateaued since the late 1970s despite dramatic smelter emission decreases between 2005 and 2014. We hypothesize that this discrepancy is due to releases of terrestrial metal(loid)s by climate-driven permafrost degradation, which is widespread across the region and will likely continue to drive increased metal(loid) fluxes to northern Canadian lakes for unknown time-scales.

The Aftermath of Surviving Acute Radiation Hematopoietic Syndrome and its Mitigation.

Intensive research is underway to find new agents that can successfully mitigate the acute effects of radiation exposure. This is primarily in response to potential counterthreats of radiological terrorism and nuclear accidents but there is some hope that they might also be of value for cancer patients treated with radiation therapy. Research into mitigation countermeasures typically employs classic animal models of acute radiation syndromes (ARS) that develop after whole-body irradiation (WBI). While agents are available that successfully mitigate ARS when given after radiation exposure, their success raises questions as to whether they simply delay lethality or unmask potentially lethal radiation pathologies that may appear later in time. Life shortening is a well-known consequence of WBI in humans and experimental animals, but it is not often examined in a mitigation setting and its causes, other than cancer, are not well-defined. This is in large part because delayed effects of acute radiation exposure (DEARE) do not follow the strict time-dose phenomena associated with ARS and present as a diverse range of symptoms and pathologies with low mortality rates that can be evaluated only with the use of large cohorts of subjects, as in this study. Here, we describe chronically increased mortality rates up to 660 days in large numbers of mice given LD70/30 doses of WBI. Systemic myeloid cell activation after WBI persists in some mice and is associated with late immunophenotypic changes and hematopoietic imbalance. Histopathological changes are largely of a chronic inflammatory nature and variable incidence, as are the clinical symptoms, including late diarrhea that correlates temporally with changes in the content of the microbiome. We also describe the acute and long-term consequences of mitigating hematopoietic ARS (H-ARS) lethality after LD70/30 doses of WBI in multiple cohorts of mice treated uniformly with radiation mitigators that have a common 4-nitro-phenylsulfonamide (NPS) pharmacophore. Effective NPS mitigators dramatically decrease ARS mortality. There is slightly increased subacute mortality, but the rate of late mortalities is slowed, allowing some mice to live a normal life span, which is not the case for WBI controls. The study has broad relevance to radiation late effects and their potential mitigation and epitomizes the complex interaction between radiation-damaged tissues and immune homeostasis.

Induction of colitis and rapid development of colorectal tumors in mice deficient in the neuropeptide PACAP.

Pituitary adenylyl cyclase activating peptide (PACAP) is expressed in central, sensory, autonomic, and enteric neurons. Although it classically acts as a neurotransmitter/neuromodulator, recent studies indicate that PACAP can also regulate immune function. To this effect, PACAP has been shown to reduce clinical symptoms and inflammation in mouse models of human immune-based diseases such as rheumatoid arthritis, Crohn's Disease, septic shock and multiple sclerosis. Despite these findings, the role of the endogenous peptide in regulating immune function is unknown. To determine if endogenous PACAP plays a protective role in inflammatory bowel disease (IBD) and IBD-associated colorectal cancer in mice, PACAP-deficient (KO) mice were subjected to 3 cycles of dextran sulfate sodium (DSS) in drinking water over 2 months, an established mouse model for colitis. Compared to wild type (WT) controls, PACAP KO mice exhibited more severe clinical symptoms of colitis and had significantly higher colonic inflammation on pathological examination. Moreover, 60% of the PACAP KO mice developed colorectal tumors with an aggressive-appearing pathology. Consistent with published data, DSS-treated WT mice did not develop such tumors. The results demonstrate a new mouse model which rapidly develops inflammation-associated colorectal cancer in the absence of a carcinogen.

Comparison of 2-Ethyl-Cyanoacrylate and 2-Butyl-Cyanoacrylate for Use on the Calvaria of CD1 Mice.

Short-chain cyanoacrylates (SCCA), such as ethyl-2-cyanoacrylate (KrazyGlue, Aron Alpha, Columbus, OH) are commonly used as commercial fast-acting glues. Although once used in clinical medicine as skin adhesives, these products caused tissue toxicity and thus their use in live tissue was discontinued. SCCA were replaced by longer-chain versions (LCCA), such as butyl-cyanoacrylate (Vetbond, 3M, St Paul, Minnesota), which were found to be less toxic than the short-chain formulations. Some researchers prefer to use SCCA due to the belief that they create a stronger bond than do the longer-chain counterparts. In survival surgeries, we compared the bone thickness, bone necrosis, fibrosis, inflammation, and bone regeneration in the calvaria of control (naïve), surgery-only, SCCA-treated, and LCCA-treated mice (n = 20 per group). At 1 and 14 d after surgery, all mice except those treated with SCCA showed statistically similar bone measurements to those of the naive control group. The SCCA group had significantly less bone regeneration than did all other groups. These results suggest that the application of SCCA causes bone damage resulting in the loss of bone regeneration. This finding may assist investigators in choosing a tissue glue for their studies and may support the IACUC in advocating the use of pharmaceutical-grade tissue glues.

Intravesical administration of doxorubicin to swine bladder using magnetically targeted carriers.

PURPOSE: The feasibility of using magnetic targeted carriers (MTC) to deliver doxorubicin intravesically was studied in normal swine bladder. MTCs are microparticles consisting of metallic iron and activated carbon. Doxorubicin is adsorbed to the activated carbon component of the MTCs (MTC-DOX) while the iron component provides magnetic susceptibility. This technology is designed for site-specific delivery of a drug to a tumor in the presence of an externally applied magnetic field in order to achieve prolonged release of high localized drug concentrations by retention of MTCs in the region of interest. An intravesical route of administration was evaluated as intravesical chemotherapy is used in the treatment of bladder cancer. METHODS: The urethras of six swine were catheterized and Foley catheters were placed in their bladders. The effects of doses ranging from 10 to 80 mg doxorubicin adsorbed onto 300 to 800 mg MTCs were studied. A 30-min period of magnetic targeting immediately followed dosing, in which an external magnet was placed on the skin surface over a predetermined site on the bladder. The subsequent retention and distribution of test material was evaluated by measurement of doxorubicin levels in plasma and histopathological examination of the bladder following treatment. Blood samples were taken prior to treatment and at 15 and 30 min after infusion for measurement of doxorubicin. The bladder was drained and rinsed thoroughly following the procedure. RESULTS: Plasma doxorubicin concentrations were less than the assay limit of detection (10 ng/ml) during the 30 min following dosing. MTCs were found within the bladder walls, predominantly at the targeted site where they were present at greater depths within the layers of the epithelium. The study results show that MTC-DOX can be targeted and retained within specific locations in the bladder using magnetic targeting. CONCLUSIONS: MTC delivery may allow greater exposure and specific deposition of drug at a defined site over intravesical administration of doxorubicin alone. The feasibility of this novel method of drug delivery was demonstrated and the results support further study for its potential use in treating bladder cancer.

Protective effect of hydroferrate fluid, MRN-100, against lethality and hematopoietic tissue damage in γ-radiated Nile tilapia, Oreochromis niloticus.

Hydroferrate fluid, MRN-100, an iron-based compound derived from bivalent and trivalent ferrates, is a potent antioxidant compound. Therefore, we examined the protective effect of MRN-100 against γ-radiation-induced lethality and damage to hematopoietic tissues in fish. A total of 216 Nile tilapia fish (Oreochromis niloticus) were randomly divided into four groups. Group 1 served as a control that was administered no radiation and no MRN-100 treatment. Group 2 was exposed only to γ-radiation (15 Gy). Groups 3 and 4 were pre-treated with MRN-100 at doses of either 1 ml/l or 3 ml/l in water for 1 week, and subsequently exposed to radiation while continuing to receive MRN-100 for 27 days. The survival rate was measured, and biochemical and histopathological analyses of hematopoietic tissues were performed for the different treatment groups at 1 and 4 weeks post-radiation. Exposure to radiation reduced the survival rate to 27.7%, while treatment with MRN-100 maintained the survival rate at 87.2%. In addition, fish exposed to γ-radiation for 1 week showed a significant decrease in the total number of white blood cells (WBCs) and red blood cells (RBCs) series. However, treatment with MRN-100 protected the total WBC count and the RBCs series when compared with irradiated fish. Furthermore, significant histological lesions were observed in the hepatopancreas, spleen and gills of irradiated fish. However, treatment with MRN-100 protected the histopathology of various organs. We conclude that MRN-100 is a radioprotective agent in fish and may be useful as an adjuvant treatment to counteract the adverse side effects associated with radiation exposure.

Ulcerative dermatitis in C57BL/6 mice exhibits an oxidative stress response consistent with normal wound healing.

Ulcerative dermatitis (UD) is a common syndrome of unknown etiology that results in profound morbidity in C57BL/6 mice and lines on a C57BL/6 background. The lesions are due to severe pruritus-induced self-trauma, progressing from superficial excoriations to deep ulcerations. UD may be behavioral in origin, with ulcerative lesions resulting from self-mutilating behavior in response to unresolved inflammation or compulsion. Alternatively, abnormal oxidative damage may be a mechanism underlying UD. To evaluate whether UD behaves similarly to normal wounds, consistent with a secondary self-inflicted lesion, or is a distinct disorder with abnormal wound response, we evaluated expression levels of genes representing various arms of the oxidative stress response pathway UD-affected and unwounded C57BL/6J mice. No evidence indicated that UD wounds have a defect in the oxidative stress response. Our findings are consistent with an understanding of C57BL/6 UD lesions as typical rather than atypical wounds.

MyD88 is critically involved in immune tolerance breakdown at environmental interfaces of Foxp3-deficient mice.

Tregs expressing the transcription factor Foxp3 suppress self-reactive T cells, prevent autoimmunity, and help contain immune responses to foreign antigens, thereby limiting the potential for inadvertent tissue damage. Mutations in the FOXP3 gene result in Treg deficiency in mice and humans, which leads to the development of a multisystem autoimmune inflammatory disease. The contribution of dysregulated innate immune responses to the pathogenesis of Foxp3 deficiency disease is unknown. In this study, we examined the role of microbial signals in the pathogenesis of Foxp3 deficiency disease by studying Foxp3 mutant mice that had concurrent deficiencies in TLR signaling pathways. Global deficiency of the common TLR adaptor MyD88 offered partial protection from Foxp3 deficiency disease. Specifically, it protected from disease at the environmental interfaces of the skin, lungs, and gut. In contrast, systemic disease, in the form of unrestrained lymphoproliferation, continued unabated. The effect of MyD88 deficiency at environmental interfaces involved the disruption of chemokine gradients that recruit effector T cells and DCs, resulting in their entrapment in secondary lymphoid tissues. These results suggests that Tregs have a key role in maintaining tolerance at host-microbial interfaces by restraining tonic MyD88-dependent proinflammatory signals. Moreover, microbial factors may play a substantial role in the pathogenesis of human autoimmune disease resulting from Treg deficiency.