Dataset Information

Differential sensitivities of bone marrow, spleen and thymus to genotoxicity induced by environmentally relevant concentrations of arsenite.

ABSTRACT: It is known in humans and mouse models, that drinking water exposures to arsenite (As+3) leads to immunotoxicity. Previously, our group showed that certain types of immune cells are extremely sensitive to arsenic induced genotoxicity. In order to see if cells from different immune organs have differential sensitivities to As+3, and if the sensitivities correlate with the intracellular concentrations of arsenic species, male C57BL/6J mice were dosed with 0, 100 and 500ppb?As+3via drinking water for 30d. Oxidation State Specific Hydride Generation- Cryotrapping- Inductively Coupled Plasma- Mass Spectrometry (HG- CT- ICP- MS) was applied to analyze the intracellular arsenic species and concentrations in bone marrow, spleen and thymus cells isolated from the exposed mice. A dose-dependent increase in intracellular monomethylarsonous acid (MMA+3) was observed in both bone marrow and thymus cells, but not spleen cells. The total arsenic and MMA+3 levels were correlated with an increase in DNA damage in bone marrow and thymus cells. An in vitro treatment of 5, 50 and 500nM?As+3 and MMA+3 revealed that bone marrow cells are most sensitive to As+3 treatment, and MMA+3 is more genotoxic than As+3. These results suggest that the differential sensitivities of the three immune organs to As+3 exposure are due to the different intracellular arsenic species and concentrations, and that MMA+3 may play a critical role in immunotoxicity.

SUBMITTER: Xu H

PROVIDER: S-EPMC5077650 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Differential sensitivities of bone marrow, spleen and thymus to genotoxicity induced by environmentally relevant concentrations of arsenite.

Xu Huan H McClain Shea S Medina Sebastian S Lauer Fredine T FT Douillet Christelle C Liu Ke Jian KJ Hudson Laurie G LG Stýblo Miroslav M Burchiel Scott W SW

Toxicology letters 20160919

It is known in humans and mouse models, that drinking water exposures to arsenite (As<sup>+3</sup>) leads to immunotoxicity. Previously, our group showed that certain types of immune cells are extremely sensitive to arsenic induced genotoxicity. In order to see if cells from different immune organs have differential sensitivities to As<sup>+3</sup>, and if the sensitivities correlate with the intracellular concentrations of arsenic species, male C57BL/6J mice were dosed with 0, 100 and 500ppb As ...[more]

PMID: 27659730

Similar Datasets

Project description:Numerous studies report active pharmaceutical compounds detected in both wastewater effluent and surface waters. Exposure to statin drugs in general, and atorvastatin in particular, is likely to be a concern. We hypothesized that chronic exposure to low concentrations of atorvastatin in water would result in an adverse effect on production of steroids regulating growth and development of the model amphibian Xenopus laevis. To assess the potential for impacts we used three experimental assays. The FETAX assay was used to evaluate the effects of a range of doses of atorvastatin on developing embryos. A 60 day metamorphosis assay assessed the effects of aqueous atorvastatin exposure at environmentally concentrations on metamorphosing tadpoles. A 60 day chronic flow-through exposure evaluated the effects of chronic low concentrations of atorvastatin on adults. The data from the FETAX assay confirmed uptake, activity, and effect of atorvastatin in X. laevis tadpoles. The results of the 60-day flow-through exposure on metamorphosing tadpoles showed significant evidence of altered cholesterol biosynthesis. The dose-dependent increase in cyp19a1 expression also indicated that the steroidogenesis pathway was affected. The RNAseq analysis confirmed that exposure to environmentally relevant concentrations of atorvastatin does cause significant alterations to global transcriptional profiles in a manner consistent with dysregulation of the cholesterol biosynthesis pathway, both through the downregulation of many genes involved in that pathway, but also in the impacts to other, related pathways. The qPCR data for both adult males and adult females indicated only slight changes in expression with the exception that hmgcr was significantly downregulated in males, and cyp3a4 expression was significantly downregulated in females. The data we present here indicated that chronic exposure to environmentally relevant concentrations of atorvastatin does have the potential to impact early life stage frogs, particularly by altering expression of genes involved in critical molecular pathways.

Project description:Nano-sized titanium dioxide (nTiO2) represents the highest produced nanomaterial by mass worldwide and, due to its prevalent industrial and commercial use, it inevitably reaches the natural environment. Previous work has revealed a negative impact of nTiO2 upon marine phytoplankton growth, however, studies are typically carried out at concentrations far exceeding those measured and predicted to occur in the environment currently. Here, a series of experiments were carried out to assess the effects of both research-grade nTiO2 and nTiO2 extracted from consumer products upon the marine dominant cyanobacterium, Prochlorococcus, and natural marine communities at environmentally relevant and supra-environmental concentrations (i.e., 1 μg L-1 to 100 mg L-1). Cell declines observed in Prochlorococcus cultures were associated with the extensive aggregation behaviour of nTiO2 in saline media and the subsequent entrapment of microbial cells. Hence, higher concentrations of nTiO2 particles exerted a stronger decline of cyanobacterial populations. However, within natural oligotrophic seawater, cultures were able to recover over time as the nanoparticles aggregated out of solution after 72 h. Subsequent shotgun proteomic analysis of Prochlorococcus cultures exposed to environmentally relevant concentrations confirmed minimal molecular features of toxicity, suggesting that direct physical effects are responsible for short-term microbial population decline. In an additional experiment, the diversity and structure of natural marine microbial communities showed negligible variations when exposed to environmentally relevant nTiO2 concentrations (i.e., 25 μg L-1). As such, the environmental risk of nTiO2 towards marine microbial species appears low, however the potential for adverse effects in hotspots of contamination exists. In future, research must be extended to consider any effect of other components of nano-enabled product formulations upon nanomaterial fate and impact within the natural environment.

Project description:Assessing the risk of resistance associated with biocide exposure commonly involves exposing microorganisms to biocides at concentrations close to the MIC. With the aim of representing exposure to environmental biocide residues, Escherichia coli MG1655 was grown for 20 passages in the presence or absence of benzalkonium chloride (BAC) at 100 ng/liter and 1,000 ng/liter (0.0002% and 0.002% of the MIC, respectively). BAC susceptibility, planktonic growth rates, motility, and biofilm formation were assessed, and differentially expressed genes were determined via transcriptome sequencing. Planktonic growth rate and biofilm formation were significantly reduced (P < 0.001) following BAC adaptation, while BAC minimum bactericidal concentration increased 2-fold. Transcriptomic analysis identified 289 upregulated and 391 downregulated genes after long-term BAC adaptation compared with the respective control organism passaged in BAC-free medium. When the BAC-adapted bacterium was grown in BAC-free medium, 1,052 genes were upregulated and 753 were downregulated. Repeated passage solely in biocide-free medium resulted in 460 upregulated and 476 downregulated genes compared with unexposed bacteria. Long-term exposure to environmentally relevant BAC concentrations increased the expression of genes associated with efflux and reduced the expression of genes associated with outer-membrane porins, motility, and chemotaxis. This was manifested phenotypically through the loss of function (motility). Repeated passage in a BAC-free environment resulted in the upregulation of multiple respiration-associated genes, which was reflected by increased growth rate. In summary, repeated exposure of E. coli to BAC residues resulted in significant alterations in global gene expression that were associated with minor decreases in biocide susceptibility, reductions in growth rate and biofilm formation, and loss of motility.IMPORTANCE Exposure to very low concentrations of biocides in the environment is a poorly understood risk factor for antimicrobial resistance. Repeated exposure to trace levels of the biocide benzalkonium chloride (BAC) resulted in loss of function (motility) and a general reduction in bacterial fitness but relatively minor decreases in susceptibility. These changes were accompanied by widespread changes in the Escherichia coli transcriptome. These results demonstrate the importance of including phenotypic characterization in studies designed to assess the risks of biocide exposure.

Project description:Study questionIs the environmental endocrine disruptor p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) able to induce non-genomic changes in human sperm and consequently affect functional sperm parameters?Summary answerp,p'-DDE promoted Ca(2+) flux into human sperm by activating CatSper channels even at doses found in human reproductive fluids, ultimately compromising sperm parameters important for fertilization.What is known alreadyp,p'-DDE may promote non-genomic actions and interact directly with pre-existing signaling pathways, as already observed in other cell types. However, although often found in both male and female reproductive fluids, its effects on human spermatozoa function are not known.Study design, size, durationNormozoospermic sperm samples from healthy individuals were included in this study. Samples were exposed to several p,p'-DDE concentrations for 3 days at 37°C and 5% CO2 in vitro to mimic the putative continuous exposure to this toxicant in the female reproductive tract in vivo. Shorter p,p'-DDE incubation periods were also performed in order to monitor sperm rapid Ca(2+) responses. All experiments were repeated on a minimum of five sperm samples from different individuals.Participants/materials, setting, methodsAll healthy individuals were recruited at the Biosciences School, University of Birmingham, the Medical Research Institute, University of Dundee and in the Human Reproduction Service at University Hospitals of Coimbra. Intracellular Ca(2+) concentration ([Ca(2+)]i) was monitored by imaging single spermatozoa loaded with Oregon Green BAPTA-1AM and further whole-cell patch-clamp recordings were performed to validate our results. Sperm viability and acrosomal integrity were assessed using the LIVE/DEAD sperm vitality kit and the acrosomal content marker PSA-FITC, respectively.Main results and the role of chancep,p'-DDE rapidly increased [Ca(2+)]i (P < 0.05) even at extremely low doses (1 pM and 1 nM), with magnitudes of response up to 200%, without affecting sperm viability, except after 3 days of continuous exposure to the highest concentration tested (P < 0.05). Furthermore, experiments performed in a low Ca(2+) medium demonstrated that extracellular Ca(2+) influx was responsible for this Ca(2+) increase (P < 0.01). Mibefradil and NNC 55-0396, both inhibitors of the sperm-specific CatSper channel, reversed the p,p'-DDE-induced [Ca(2+)]i rise, suggesting the participation of CatSper in this process (P < 0.05). In fact, whole-cell patch-clamp recordings confirmed CatSper as a target of p,p'-DDE action by monitoring an increase in CatSper currents of >100% (P < 0.01). Finally, acrosomal integrity was adversely affected after 2 days of exposure to p,p'-DDE concentrations, suggesting that [Ca(2+)]i rise may cause premature acrosome reaction (P < 0.05).Limitations, reasons for cautionThis is an in vitro study, and caution must be taken when extrapolating the results.Wider implications of the findingsA novel non-genomic p,p'-DDE mechanism specific to sperm is shown in this study. p,p'-DDE was able to induce [Ca(2+)]i rise in human sperm through the opening of CatSper consequently compromising male fertility. The promiscuous nature of CatSper activation may predispose human sperm to the action of some persistent endocrine disruptors.Study funding/competing interest(s)The study was supported by both the Portuguese National Science Foundation (FCT; PEst-C/SAU/LA0001/2011) and the UK Wellcome Trust (Grant #86470). SM was supported by the Infertility Research Trust. RST is a recipient of a PhD fellowship from FCT (SFRH/BD/46002/2008). None of the authors has any conflict of interest to declare.

Dataset Information

Differential sensitivities of bone marrow, spleen and thymus to genotoxicity induced by environmentally relevant concentrations of arsenite.

Publications

Differential sensitivities of bone marrow, spleen and thymus to genotoxicity induced by environmentally relevant concentrations of arsenite.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure