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Sample records for exposure induced hormesis

  1. Exposure to Nanoparticles and Hormesis

    PubMed Central

    Iavicoli, Ivo; Calabrese, Edward J.; Nascarella, Marc A.

    2010-01-01

    Nanoparticles are particles with lengths that range from 1 to 100 nm. They are increasingly being manufactured and used for commercial purpose because of their novel and unique physicochemical properties. Although nanotechnology-based products are generally thought to be at a pre-competitive stage, an increasing number of products and materials are becoming commercially available. Human exposure to nanoparticles is therefore inevitable as they become more widely used and, as a result, nanotoxicology research is now gaining attention. However, there are many uncertainties as to whether the unique properties of nanoparticles also pose occupational health risks. These uncertainties arise because of gaps in knowledge about the factors that are essential for predicting health risks such as routes of exposure, distribution, accumulation, excretion and dose-response relationship of the nanoparticles. In particular, uncertainty remains with regard to the nature of the dose-response curve at low level exposures below the toxic threshold. In fact, in the literature, some studies that investigated the biological effects of nanoparticles, observed a hormetic dose-response. However, currently available data regarding this topic are extremely limited and fragmentary. It therefore seems clear that future studies need to focus on this issue by studying the potential adverse health effects caused by low-level exposures to nanoparticles. PMID:21191487

  2. Do toxic ions induce hormesis in plants?

    PubMed

    Poschenrieder, Charlotte; Cabot, Catalina; Martos, Soledad; Gallego, Berta; Barceló, Juan

    2013-11-01

    The concept of hormesis in plants is critically reviewed, taking growth stimulation by low concentrations of toxic trace elements as a reference. The importance of both non-adaptive and adaptive mechanisms underlying ion-induced hormetic growth responses is highlighted. The activation of defense mechanisms by metal ions and pathogenic elicitors and the cross talk between the signals induced by metal ions and biotic stressors are considered. The production of reactive oxygen species and, consequently, the induction of stress-induced antioxidants, are key mechanisms in metal ion-induced hormesis in plants. It is concluded that in the current scientific literature, hormesis is used as an "umbrella" term that includes a wide range of different mechanisms. It is recommended that the term hormesis be used in plant toxicology as a descriptive term for the stimulated phase in growth response curves that is induced by low concentrations of toxic metal ions without evidence of the underlying mechanisms. If the mechanisms underlying the stimulated growth phase have been identified, specific terms, such as amelioration, defense gene activation, priming or acclimation, should be used. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  3. Insecticide-induced hormesis and arthropod pest management.

    PubMed

    Guedes, Raul Narciso C; Cutler, G Christopher

    2014-05-01

    Ecological backlashes such as insecticide resistance, resurgence and secondary pest outbreaks are frequent problems associated with insecticide use against arthropod pest species. The last two have been particularly important in sparking interest in the phenomenon of insecticide-induced hormesis within entomology and acarology. Hormesis describes a biphasic dose-response relationship that is characterized by a reversal of response between low and high doses of a stressor (e.g. insecticides). Although the concept of insecticide-induced hormesis often does not receive sufficient attention, or has been subject to semantic confusion, it has been reported in many arthropod pest species and natural enemies, and has been linked to pest outbreaks and potential problems with insecticide resistance. The study of hormesis remains largely neglected in entomology and acarology. Here, we examined the concept of insecticide-induced hormesis in arthropods, its functional basis and potential fitness consequences, and its importance in arthropod pest management and other areas. © 2013 Society of Chemical Industry.

  4. Hormesis in aging.

    PubMed

    Rattan, Suresh I S

    2008-01-01

    Hormesis in aging is represented by mild stress-induced stimulation of protective mechanisms in cells and organisms resulting in biologically beneficial effects. Single or multiple exposure to low doses of otherwise harmful agents, such as irradiation, food limitation, heat stress, hypergravity, reactive oxygen species and other free radicals have a variety of anti-aging and longevity-extending hormetic effects. Detailed molecular mechanisms that bring about the hormetic effects are being increasingly understood, and comprise a cascade of stress response and other pathways of maintenance and repair. Although the extent of immediate hormetic effects after exposure to a particular stress may only be moderate, the chain of events following initial hormesis leads to biologically amplified effects that are much larger, synergistic and pleiotropic. A consequence of hormetic amplification is an increase in the homeodynamic space of a living system in terms of increased defence capacity and reduced load of damaged macromolecules. Hormetic strengthening of the homeodynamic space provides wider margins for metabolic fluctuation, stress tolerance, adaptation and survival. Hormesis thus counter-balances the progressive shrinkage of the homeodynamic space, which is the ultimate cause of aging, diseases and death. Healthy aging may be achieved by hormesis through mild and periodic, but not severe or chronic, physical and mental challenges, and by the use of nutritional hormesis incorporating mild stress-inducing molecules called hormetins. The established scientific foundations of hormesis are ready to pave the way for new and effective approaches in aging research and intervention.

  5. Life extension after heat shock exposure: assessing meta-analytic evidence for hormesis.

    PubMed

    Lagisz, Malgorzata; Hector, Katie L; Nakagawa, Shinichi

    2013-03-01

    Hormesis is the response of organisms to a mild stressor resulting in improved health and longevity. Mild heat shocks have been thought to induce hormetic response because they promote increased activity of heat shock proteins (HSPs), which may extend lifespan. Using data from 27 studies on 12 animal species, we performed a comparative meta-analysis to quantify the effect of heat shock exposure on longevity. Contrary to our expectations, heat shock did not measurably increase longevity in the overall meta-analysis, although we observed much heterogeneity among studies. Thus, we explored the relative contributions of different experimental variables (i.e. moderators). Higher temperatures, longer durations of heat shock exposure, increased shock repeat and less time between repeat shocks, all decreased the likelihood of a life-extending effect, as would be expected when a hormetic response crosses the threshold to being a damaging exposure. We conclude that there is limited evidence that mild heat stress is a universal way of promoting longevity at the whole-organism level. Life extension via heat-induced hormesis is likely to be constrained to a narrow parameter window of experimental conditions.

  6. Modulating exercise-induced hormesis: Does less equal more?

    PubMed

    Peake, Jonathan M; Markworth, James F; Nosaka, Kazunori; Raastad, Truls; Wadley, Glenn D; Coffey, Vernon G

    2015-08-01

    Hormesis encompasses the notion that low levels of stress stimulate or upregulate existing cellular and molecular pathways that improve the capacity of cells and organisms to withstand greater stress. This notion underlies much of what we know about how exercise conditions the body and induces long-term adaptations. During exercise, the body is exposed to various forms of stress, including thermal, metabolic, hypoxic, oxidative, and mechanical stress. These stressors activate biochemical messengers, which in turn activate various signaling pathways that regulate gene expression and adaptive responses. Historically, antioxidant supplements, nonsteroidal anti-inflammatory drugs, and cryotherapy have been favored to attenuate or counteract exercise-induced oxidative stress and inflammation. However, reactive oxygen species and inflammatory mediators are key signaling molecules in muscle, and such strategies may mitigate adaptations to exercise. Conversely, withholding dietary carbohydrate and restricting muscle blood flow during exercise may augment adaptations to exercise. In this review article, we combine, integrate, and apply knowledge about the fundamental mechanisms of exercise adaptation. We also critically evaluate the rationale for using interventions that target these mechanisms under the overarching concept of hormesis. There is currently insufficient evidence to establish whether these treatments exert dose-dependent effects on muscle adaptation. However, there appears to be some dissociation between the biochemical/molecular effects and functional/performance outcomes of some of these treatments. Although several of these treatments influence common kinases, transcription factors, and proteins, it remains to be determined if these interventions complement or negate each other, and whether such effects are strong enough to influence adaptations to exercise.

  7. Mobile phone signal exposure triggers a hormesis-like effect in Atm(+/+) and Atm(-/-) mouse embryonic fibroblasts.

    PubMed

    Sun, Chuan; Wei, Xiaoxia; Fei, Yue; Su, Liling; Zhao, Xinyuan; Chen, Guangdi; Xu, Zhengping

    2016-11-18

    Radiofrequency electromagnetic fields (RF-EMFs) have been classified by the International Agency for Research on Cancer as possible carcinogens to humans; however, this conclusion is based on limited epidemiological findings and lacks solid support from experimental studies. In particular, there are no consistent data regarding the genotoxicity of RF-EMFs. Ataxia telangiectasia mutated (ATM) is recognised as a chief guardian of genomic stability. To address the debate on whether RF-EMFs are genotoxic, we compared the effects of 1,800 MHz RF-EMF exposure on genomic DNA in mouse embryonic fibroblasts (MEFs) with proficient (Atm(+/+)) or deficient (Atm(-/-)) ATM. In Atm(+/+) MEFs, RF-EMF exposure for 1 h at an average special absorption rate of 4.0 W/kg induced significant DNA single-strand breaks (SSBs) and activated the SSB repair mechanism. This effect reduced the DNA damage to less than that of the background level after 36 hours of exposure. In the Atm(-/-) MEFs, the same RF-EMF exposure for 12 h induced both SSBs and double-strand breaks and activated the two repair processes, which also reduced the DNA damage to less than the control level after prolonged exposure. The observed phenomenon is similar to the hormesis of a toxic substance at a low dose. To the best of our knowledge, this study is the first to report a hormesis-like effect of an RF-EMF.

  8. Mobile phone signal exposure triggers a hormesis-like effect in Atm+/+ and Atm−/− mouse embryonic fibroblasts

    PubMed Central

    Sun, Chuan; Wei, Xiaoxia; Fei, Yue; Su, Liling; Zhao, Xinyuan; Chen, Guangdi; Xu, Zhengping

    2016-01-01

    Radiofrequency electromagnetic fields (RF-EMFs) have been classified by the International Agency for Research on Cancer as possible carcinogens to humans; however, this conclusion is based on limited epidemiological findings and lacks solid support from experimental studies. In particular, there are no consistent data regarding the genotoxicity of RF-EMFs. Ataxia telangiectasia mutated (ATM) is recognised as a chief guardian of genomic stability. To address the debate on whether RF-EMFs are genotoxic, we compared the effects of 1,800 MHz RF-EMF exposure on genomic DNA in mouse embryonic fibroblasts (MEFs) with proficient (Atm+/+) or deficient (Atm−/−) ATM. In Atm+/+ MEFs, RF-EMF exposure for 1 h at an average special absorption rate of 4.0 W/kg induced significant DNA single-strand breaks (SSBs) and activated the SSB repair mechanism. This effect reduced the DNA damage to less than that of the background level after 36 hours of exposure. In the Atm−/− MEFs, the same RF-EMF exposure for 12 h induced both SSBs and double-strand breaks and activated the two repair processes, which also reduced the DNA damage to less than the control level after prolonged exposure. The observed phenomenon is similar to the hormesis of a toxic substance at a low dose. To the best of our knowledge, this study is the first to report a hormesis-like effect of an RF-EMF. PMID:27857169

  9. Hormesis depends upon the life-stage and duration of exposure: Examples for a pesticide and a nanomaterial.

    PubMed

    Tyne, William; Little, Simon; Spurgeon, David J; Svendsen, Claus

    2015-10-01

    Tests to assess toxic effects on the reproduction of adult C. elegans after 72h exposure for two chemicals, (3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU)), also known as diuron, and silver nanoparticles (Ag NPs) indicated potential, although not significant hormesis. Follow up toxicity tests comparing the potential hormesis concentrations with controls at high replication confirmed that the stimulatory effect was repeatable and also statistically significant within the test. To understand the relevance of the hormesis effects for overall population fitness, full life-cycle toxicity tests were conducted for each chemical. When nematodes were exposed to DCMU over the full life-span, the hormesis effect for reproduction seen in short-term tests was no longer evident. Further at the putative hormesis concentrations, a negative effect of DCMU on time to maturation was also seen. For the Ag NPs, the EC50 for effects on reproduction in the life-cycle exposure was substantially lower than in the short-term test, the EC50s estimated by a three parameter log logistic model being 2.9mg/L and 0.75mg/L, respectively. This suggests that the level of toxicity for Ag NPs for C. elegans reproduction is dependant on the life stage exposed and possibly the duration of the exposure. Further, in the longer duration exposures, hormesis effects on reproduction seen in the short-term exposures were no longer apparent. Instead, all concentrations reduced both overall brood size and life-span. These results for both chemicals suggest that the hormesis observed for a single endpoint in short-term exposure may be the result of a temporary reallocation of resources between traits that are not sustained over the full life-time. Such reallocation is consistent with energy budget theories for organisms subject to toxic stress. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Sex specific effects of heat induced hormesis in Hsf-deficient Drosophila melanogaster.

    PubMed

    Sørensen, J G; Kristensen, T N; Kristensen, K V; Loeschcke, V

    2007-12-01

    In insects mild heat stress early in life has been reported to increase life span and heat resistance later in life, a phenomenon termed hormesis. Here, we test if the induction of the heat shock response by mild heat stress is mediating hormesis in longevity and heat resistance at older age. To test this hypothesis we used two heat shock transcription factor (Hsf) mutant stocks. One stock harbours a mutation giving rise to a heat sensitive Hsf which inactivates the heat shock response at high temperature and the other is a rescued mutant giving rise to a wild-type phenotype. We measured longevity, heat resistance and expression level of a heat shock protein, Hsp70, in controls and mildly heat treated flies. We found a marked difference between males and females with males showing a beneficial effect of the early heat treatment on longevity and heat resistance later in life in the rescued line, seemingly mediated by the production of heat shock proteins (Hsps). The results indicate that heat inducible Hsps are important for heat induced hormesis in longevity and heat stress resistance. However, the results also suggest that other processes are involved and that different mechanisms might have marked sex specific impact.

  11. Anti-oxidative cellular protection effect of fasting-induced autophagy as a mechanism for hormesis.

    PubMed

    Moore, Michael N; Shaw, Jennifer P; Ferrar Adams, Dawn R; Viarengo, Aldo

    2015-06-01

    The aim of this investigation was to test the hypothesis that fasting-induced augmented lysosomal autophagic turnover of cellular proteins and organelles will reduce potentially harmful lipofuscin (age-pigment) formation in cells by more effectively removing oxidatively damaged proteins. An animal model (marine snail--common periwinkle, Littorina littorea) was used to experimentally test this hypothesis. Snails were deprived of algal food for 7 days to induce an augmented autophagic response in their hepatopancreatic digestive cells (hepatocyte analogues). This treatment resulted in a 25% reduction in the cellular content of lipofuscin in the digestive cells of the fasting animals in comparison with snails fed ad libitum on green alga (Ulva lactuca). Similar findings have previously been observed in the digestive cells of marine mussels subjected to copper-induced oxidative stress. Additional measurements showed that fasting significantly increased cellular health based on lysosomal membrane stability, and reduced lipid peroxidation and lysosomal/cellular triglyceride. These findings support the hypothesis that fasting-induced augmented autophagic turnover of cellular proteins has an anti-oxidative cytoprotective effect by more effectively removing damaged proteins, resulting in a reduction in the formation of potentially harmful proteinaceous aggregates such as lipofuscin. The inference from this study is that autophagy is important in mediating hormesis. An increase was demonstrated in physiological complexity with fasting, using graph theory in a directed cell physiology network (digraph) model to integrate the various biomarkers. This was commensurate with increased health status, and supportive of the hormesis hypothesis. The potential role of enhanced autophagic lysosomal removal of damaged proteins in the evolutionary acquisition of stress tolerance in intertidal molluscs is discussed and parallels are drawn with the growing evidence for the involvement of

  12. Herbicides and plant hormesis.

    PubMed

    Belz, Regina G; Duke, Stephen O

    2014-05-01

    Herbicide hormesis is commonly observed at subtoxic doses of herbicides and other phytotoxins. The occurrence and magnitude of this phenomenon are influenced by plant growth stage and physiological status, environmental factors, the endpoint measured and the timing between treatment and endpoint measurement. The mechanism in some cases of herbicide hormesis appears to be related to the target site of the herbicide, whereas in other examples hormesis may be by overcompensation to moderate stress induced by the herbicides or a response to disturbed homeostasis. Theoretically, herbicide hormesis could be used in crop production, but this has been practical only in the case of the use of herbicides as sugar cane 'ripeners' to enhance sucrose accumulation. The many factors that can influence the occurrence, the magnitude and the dose range of hormetic increases in yield for most crops make it too unpredictable and risky as a production practice with the currently available knowledge. Herbicide hormesis can cause undesired effects in situations in which weeds are unintentionally exposed to hormetic doses (e.g. in adjacent fields, when shielded by crop vegetation). Some weeds that have evolved herbicide resistance may have hormetic responses to recommended herbicide application rates. Little is known about such effects under field conditions. A more complete understanding of herbicide hormesis is needed to exploit its potential benefits and to minimize its potential harmful effects in crop production. © 2014 Society of Chemical Industry.

  13. Gene Expression During Imidacloprid-Induced Hormesis in Green Peach Aphid

    PubMed Central

    Ayyanath, Murali-Mohan; Cutler, G. Christopher; Scott-Dupree, Cynthia D.; Prithiviraj, Balakrishnan; Kandasamy, Saveetha; Prithiviraj, Kalyani

    2014-01-01

    Imidacloprid-induced hormesis in the form of stimulated reproduction has previously been reported in green peach aphid, Myzus persicae. Changes in gene expression accompanying this hormetic response have not been previously investigated. In this study, expression of stress response (Hsp60), dispersal (OSD, TOL and ANT), and developmental (FPPS I) genes were examined for two generations during imidacloprid-induced reproductive stimulation in M. persicae. Global DNA methylation was also measured to test the hypothesis that changes in gene expression are heritable. At hormetic concentrations, down-regulation of Hsp60 was followed by up-regulation of this gene in the subsequent generation. Likewise, expression of dispersal-related genes and FPPS I varied with concentration, life stage, and generation. These results indicate that reproductive hormesis in M. persicae is accompanied by a complex transgenerational pattern of up- and down-regulation of genes that likely reflects trade-offs in gene expression and related physiological processes during the phenotypic dose-response. Moreover, DNA methylation in second generation M. persicae occurred at higher doses than in first-generation aphids, suggesting that heritable adaptability to low doses of the stressor might have occurred. PMID:25249837

  14. Molecular mechanisms of low dose ionizing radiation-induced hormesis, adaptive responses, radioresistance, bystander effects, and genomic instability.

    PubMed

    Tang, Feng Ru; Loke, Weng Keong

    2015-01-01

    To review research progress on the molecular mechanisms of low dose ionizing radiation (LDIR)-induced hormesis, adaptive responses, radioresistance, bystander effects, and genomic instability in order to provide clues for therapeutic approaches to enhance biopositive effects (defined as radiation-induced beneficial effects to the organism), and control bionegative effects (defined as radiation-induced harmful effects to the organism) and related human diseases. Experimental studies have indicated that Ataxia telangiectasia-mutated (ATM), extracellular signal-related kinase (ERK), mitogen-activated protein kinase (MAPK), phospho-c-Jun NH(2)-terminal kinase (JNK) and protein 53 (P53)-related signal transduction pathways may be involved in LDIR-induced hormesis; MAPK, P53 may be important for adaptive response; ATM, cyclooxygenase-2 (COX-2), ERK, JNK, reactive oxygen species (ROS), P53 for radioresistance; COX-2, ERK, MAPK, ROS, tumor necrosis factor receptor alpha (TNFα) for LDIR-induced bystander effect; whereas ATM, ERK, MAPK, P53, ROS, TNFα-related signal transduction pathways are involved in LDIR-induced genomic instability. These results suggest that different manifestations of LDIR-induced cellular responses may have different signal transduction pathways. On the other hand, LDIR-induced different responses may also share the same signal transduction pathways. For instance, P53 has been involved in LDIR-induced hormesis, adaptive response, radioresistance and genomic instability. Current data therefore suggest that caution should be taken when designing therapeutic approaches using LDIR to induce beneficial effects in humans.

  15. Hormesis and stage specific toxicity induced by cadmium in an insect model, the queen blowfly, Phormia regina Meig.

    PubMed

    Nascarella, Marc A; Stoffolano, John G; Stanek, Edward J; Kostecki, Paul T; Calabrese, Edward J

    2003-01-01

    Hormesis is an adaptive response, commonly characterized by a biphasic dose-response that can be either directly induced, or the result of compensatory biological processes following an initial disruption in homeostasis [Calabrese and Baldwin, Hum. Exp.Toxicol., 21 (2002), 91]. Low and environmentally relevant levels of dietary cadmium significantly enhanced the pupation rate of blowfly larvae, while higher doses inhibited pupation success. However, dietary cadmium at all exposure levels adversely affected the emergence of the adult fly from the pupal case. Such findings represent the first report of a heavy metal displaying a hormetic-like biphasic response for pupation success, while at the same time displaying stage-specific toxicity at a later developmental period. These conclusions are based on substantial experimentation of over 1750 blowflies, in seven replicate experiments, involving 10 concentrations per experiment. These findings indicate the need to assess the impact of environmental stressors over a broad range of potential exposures as well as throughout the entire life cycle.

  16. Sexual Success after Stress? Imidacloprid-Induced Hormesis in Males of the Neotropical Stink Bug Euschistus heros

    PubMed Central

    Haddi, Khalid; Mendes, Marcos V.; Lino-Neto, José; Freitas, Hemerson L.; Guedes, Raul Narciso C.; Oliveira, Eugênio E.

    2016-01-01

    Environmental stress in newly-emerged adult insects can have dramatic consequences on their life traits (e.g., dispersion, survival and reproduction) as adults. For instance, insects sublethally exposed to environmental stressors (e.g., insecticides) can gain fitness benefits as a result of hormesis (i.e., benefits of low doses of compounds that would be toxic at higher doses). Here, we experimentally tested whether sublethal exposure to the insecticide imidacloprid would hormetically affect the sexual fitness of newly-emerged adults of the Neotropical brown stink bug Euschistus heros (Hemiptera: Heteroptera: Pentatomidae), which is the most abundant and prevalent insect pest in Neotropical soybean fields. We evaluated the sexual fitness of four couple combinations: unexposed couples, exposed females, exposed males, and exposed couples. Sublethal exposure to dry residues (i.e., contact) of imidacloprid (at 1% of recommended field rate) did not affect insect survival, but led to higher mating frequencies when at least one member of the couple was exposed. However, the average mating duration was shortened when only females were exposed to imidacloprid. Moreover, exposed males showed higher locomotory (walking) activity, lower respiration rates and induced higher fecundity rates when mated to unexposed females. Although the reproductive tracts of exposed males did not differ morphometrically from unexposed males, their accessory glands exhibited positive reactions for acidic and basic contents. Our findings suggest that males of the Neotropical brown stink bug hormetically increase their sexual fitness when cued by impending insecticidal stress in early adulthood. PMID:27284906

  17. Hormesis and Paradoxical Effects of Wheat Seedling (Triticum Aestivum L.) Parameters Upon Exposure to Different Pollutants in a Wide Range of Doses

    PubMed Central

    Erofeeva, Elena A.

    2014-01-01

    Chlorophyll and carotenoid content (ChCar), lipid peroxidation (LP) and growth parameters (GP) in plants are often used for environmental pollution estimation. However, the nonmonotonic dose–response dependences (hormesis and paradoxical effects) of these indices are insufficiently explored following exposure to different pollutants. In this experiment, we studied nonmonotonic changes in ChCar, LP, GP in wheat seedlings (Triticum aestivum L.) upon exposure to lead, cadmium, copper, manganese, formaldehyde, the herbicide glyphosate, and sodium chloride in a wide range from sublethal concentration to 102–105 times lower concentrations. 85.7% of dose–response dependences were nonmonotonic (of these, 5.5% were hormesis and paradoxical effects comprised 94.5%). Multiphasic dependences were the most widespread type of paradoxical effect. Hormesis was a part of some multiphasic responses (i.e. paradoxical effects), which indicates a relationship between these phenomena. Sublethal pollutant concentrations significantly increased LP (to 2.0–2.4 times, except for manganese and glyphosate) and decreased GP (to 2.1–36.6 times, except for glyphosate), while ChCar was reduced insignificantly, normalized or even increased. Lower pollutant concentrations caused a moderate deviation in all parameters from the control (not more than 62%) for hormesis and paradoxical effects. The seedling parameters could have different types of nonmonotonic responses upon exposure to the same pollutant. PMID:24659937

  18. Photon hormesis deactivates alpha-particle induced bystander effects between zebrafish embryos

    NASA Astrophysics Data System (ADS)

    Ng, C. Y. P.; Cheng, S. H.; Yu, K. N.

    2017-04-01

    In the present work, we studied the effects of low-dose X-ray photons on the alpha-particle induced bystander effects between embryos of the zebrafish, Danio rerio. The effects on the naive whole embryos were studied through quantification of apoptotic signals (amounts of cells undergoing apoptosis) at 24 h post fertilization (hpf) using vital dye acridine orange staining, followed by counting the stained cells under a fluorescent microscope. We report data showing that embryos at 5 hpf subjected to a 4.4 mGy alpha-particle irradiation could release a stress signal into the medium, which could induce bystander effect in partnered naive embryos sharing the same medium. We also report that the bystander effect was deactivated when the irradiated embryos were subjected to a concomitant irradiation of 10 or 14 mGy of X-rays, but no such deactivation was achieved if the concomitant X-ray dose dropped to 2.5 or 5 mGy. In the present study, the significant drop in the amount of apoptotic signals on the embryos having received 4.4 mGy alpha particles together X-rays irradiation from 2.5 or 5 mGy to 10 or 14 mGy, together with the deactivation of RIBE with concomitant irradiation of 10 or 14 mGy of X-rays supported the participation of photon hormesis with an onset dose between 5 and 10 mGy, which might lead to removal of aberrant cells through early apoptosis or induction of high-fidelity DNA repair. As we found that photons and alpha particles could have opposite biological effects when these were simultaneously irradiated onto living organisms, these ionizing radiations could be viewed as two different environmental stressors, and the resultant effects could be regarded as multiple stressor effects. The present work presented the first study on a multiple stressor effect which occurred on bystander organisms. In other words, this was a non-targeted multiple stressor effect. The photon hormesis could also explain some failed attempts to observe neutron-induced bystander

  19. Heat Stress and Hormetin-Induced Hormesis in Human Cells: Effects on Aging, Wound Healing, Angiogenesis, and Differentiation

    PubMed Central

    Rattan, Suresh I. S.; Fernandes, Ricardo A.; Demirovic, Dino; Dymek, Barbara; Lima, Cristovao F.

    2009-01-01

    Accumulation of molecular damage and increased molecular heterogeneity are hallmarks of cellular aging. Mild stress-induced hormesis can be an effective way for reducing the accumulation of molecular damage, and thus slowing down aging from within. We have shown that repeated mild heat stress (RMHS) has anti-aging effects on growth and various other cellular and biochemical characteristics of normal human skin fibroblasts and keratinocytes undergoing aging in vitro. RMHS given to human cells increased the basal levels of various chaperones, reduced the accumulation of damaged proteins, stimulated proteasomal activities, increased the cellular resistance to other stresses, enhanced the levels of various antioxidant enzymes, enhanced the activity and amounts of sodium-potassium pump, and increased the phosphorylation-mediated activities of various stress kinases. We have now observed novel hormetic effects of mild heat stress on improving the wound healing capacity of skin fibroblasts and on enhancing the angiogenic ability of endothelial cells. We have also tested potential hormetins, such as curcumin and rosmarinic acid in bringing about their beneficial effects in human cells by inducing stress response pathways involving heat shock proteins and hemeoxygenase HO-1. These data further support the view that mild stress-induced hormesis can be applied for the modulation, intervention and prevention of aging and age-related impairments. PMID:19343114

  20. Evidence for Radiation Hormesis After In Vitro Exposure of Human Lymphocytes to Low Doses of Ionizing Radiation§

    PubMed Central

    Rithidech, Kanokporn Noy; Scott, Bobby R.

    2008-01-01

    Previous research has demonstrated that adding a very small gamma-ray dose to a small alpha radiation dose can completely suppress lung cancer induction by alpha radiation (a gamma-ray hormetic effect). Here we investigated the possibility of gamma-ray hormesis during low-dose neutron irradiation, since a small contribution to the total radiation dose from neutrons involves gamma rays. Using binucleated cells with micronuclei (micronucleated cells) among in vitro monoenergetic-neutron-irradiated human lymphocytes as a measure of residual damage, we investigated the influence of the small gamma-ray contribution to the dose on suppressing residual damage. We used residual damage data from previous experiments that involved neutrons with five different energies (0.22-, 0.44-, 1.5-, 5.9-, and 13.7-million electron volts [MeV]). Corresponding gamma-ray contributions to the dose were approximately 1%, 1%, 2%, 6%, and 6%, respectively. Total absorbed radiation doses were 0, 10, 50, and 100 mGy for each neutron source. We demonstrate for the first time a protective effect (reduced residual damage) of the small gamma-ray contribution to the neutron dose. Using similar data for exposure to gamma rays only, we also demonstrate a protective effect of 10 mGy (but not 50 or 100 mGy) related to reducing the frequency of micronucleated cells to below the spontaneous level. PMID:18846261

  1. Azadirachtin-induced hormesis mediating shift in fecundity-longevity trade-off in the Mexican bean weevil (Chrysomelidae: Bruchinae).

    PubMed

    Mallqui, K S Vilca; Vieira, J L; Guedes, R N C; Gontijo, L M

    2014-04-01

    Insecticides can have lethal or sublethal effects upon targeted pest species, and sublethal effects may even favor pest outbreaks if insecticide-induced hormesis occurs. Hormesis is a biphasic dose-response of a given chemical compound that is stimulatory at low doses and toxic at high doses. The former response may result from the disruption of animal homeostasis leading to trade-off shifts between basic ecophysiological processes. A growing interest in the use of biorational insecticides, such as azadirachtin to control stored-product pests, raises concerns about potential sublethal effects. In this study, we explored the hypothesis that azadirachtin can negatively impact the reproductive capacity of the Mexican bean weevil, Zabrotes subfasciatus (Boheman) (Chrysomelidae: Bruchinae), a key pest of stored beans. In addition, we investigated whether adults of this species could compensate for any sublethal effect that might have affected any of their reproductive parameters by adjusting the allocation of its reproductive efforts. The results showed that females of Z. subfasciatus increased fecundity daily to compensate for azadirachtin-induced decreased longevity. In addition, a stage-structured matrix study revealed that populations of Z. subfasciatus engendered from females exposed to azadirachtin exhibited a higher rate of population increase (r) and a higher net reproductive rate (R(o)). Finally, a projection matrix analysis showed notably higher densities along the generations for azadirachtin-exposed Z. subfasciatus populations. Thus, our study provides empirical evidence for the capacity of Z. subfasciatus to adapt to sublethal effects caused by biorational insecticides; consequently, this study highlights the importance of understanding this phenomenon when devising pest management strategies.

  2. Effect of Photon Hormesis on Dose Responses to Alpha Particles in Zebrafish Embryos.

    PubMed

    Ng, Candy Yuen Ping; Cheng, Shuk Han; Yu, Kwan Ngok

    2017-02-11

    Photon hormesis refers to the phenomenon where the biological effect of ionizing radiation with a high linear energy transfer (LET) value is diminished by photons with a low LET value. The present paper studied the effect of photon hormesis from X-rays on dose responses to alpha particles using embryos of the zebrafish (Danio rerio) as the in vivo vertebrate model. The toxicity of these ionizing radiations in the zebrafish embryos was assessed using the apoptotic counts at 20, 24, or 30 h post fertilization (hpf) revealed through acridine orange (AO) staining. For alpha-particle doses ≥ 4.4 mGy, the additional X-ray dose of 10 mGy significantly reduced the number of apoptotic cells at 24 hpf, which proved the presence of photon hormesis. Smaller alpha-particle doses might not have inflicted sufficient aggregate damages to trigger photon hormesis. The time gap T between the X-ray (10 mGy) and alpha-particle (4.4 mGy) exposures was also studied. Photon hormesis was present when T ≤ 30 min, but was absent when T = 60 min, at which time repair of damage induced by alpha particles would have completed to prevent their interactions with those induced by X-rays. Finally, the drop in the apoptotic counts at 24 hpf due to photon hormesis was explained by bringing the apoptotic events earlier to 20 hpf, which strongly supported the removal of aberrant cells through apoptosis as an underlying mechanism for photon hormesis.

  3. Effect of Photon Hormesis on Dose Responses to Alpha Particles in Zebrafish Embryos

    PubMed Central

    Ng, Candy Yuen Ping; Cheng, Shuk Han; Yu, Kwan Ngok

    2017-01-01

    Photon hormesis refers to the phenomenon where the biological effect of ionizing radiation with a high linear energy transfer (LET) value is diminished by photons with a low LET value. The present paper studied the effect of photon hormesis from X-rays on dose responses to alpha particles using embryos of the zebrafish (Danio rerio) as the in vivo vertebrate model. The toxicity of these ionizing radiations in the zebrafish embryos was assessed using the apoptotic counts at 20, 24, or 30 h post fertilization (hpf) revealed through acridine orange (AO) staining. For alpha-particle doses ≥ 4.4 mGy, the additional X-ray dose of 10 mGy significantly reduced the number of apoptotic cells at 24 hpf, which proved the presence of photon hormesis. Smaller alpha-particle doses might not have inflicted sufficient aggregate damages to trigger photon hormesis. The time gap T between the X-ray (10 mGy) and alpha-particle (4.4 mGy) exposures was also studied. Photon hormesis was present when T ≤ 30 min, but was absent when T = 60 min, at which time repair of damage induced by alpha particles would have completed to prevent their interactions with those induced by X-rays. Finally, the drop in the apoptotic counts at 24 hpf due to photon hormesis was explained by bringing the apoptotic events earlier to 20 hpf, which strongly supported the removal of aberrant cells through apoptosis as an underlying mechanism for photon hormesis. PMID:28208665

  4. Hormesis, hotspots and emissions trading.

    PubMed

    Wiener, Jonathan B

    2004-06-01

    Instrument choice--the comparison of technology standards, performance standards, taxes and tradable permits--has been a major topic in environmental law and environmental economics. Most analyses assume that emissions and health effects are positively and linearly related. If they are not, this complicates the instrument choice analysis. This article analyses the effects of a nonlinear dose-response function on instrument choice. In particular, it examines the effects of hormesis (high-dose harm but low-dose benefit) on the choice between fixed performance standards and tradable emissions permits. First, the article distinguishes the effects of hormesis from the effects of local emissions. Hormesis is an attribute of the dose-response or exposure-response relationship. Hotspots are an attribute of the emissions-exposure relationship. Some pollutants may be hormetic and cause local emissions-exposure effects; others may be hormetic without causing local emissions-exposure effects. It is only the local exposure effects of emissions that pose a problem for emissions trading. Secondly, the article shows that the conditions under which emissions trading would perform less well or even perversely under hormesis, depend on how stringent a level of protection is set. Only when the regulatory standard is set at the nadir of the hormetic curve would emissions trading be seriously perverse (assuming other restrictive conditions as well), and such a standard is unlikely. Moreover, the benefits of the overall programme may justify the risk of small perverse effects around this nadir. Thirdly, the article argues that hotspots can be of concern for two distinct reasons, harmfulness and fairness. Lastly, the paper argues that the solution to these problems may not be to abandon market-based incentive instruments and their cost-effectiveness gains, but to improve them further by moving from emissions trading and emissions taxes to risk trading and risk taxes. In short, the article

  5. Nutritional hormesis and aging.

    PubMed

    Hayes, Daniel P

    2009-11-16

    Nutritional hormesis has the potential to serve as a pro-healthy aging intervention by reducing the susceptibility of the elderly to various chronic degenerative diseases and thereby extending human healthspan. Supportive evidence for nutritional hormesis arising from essential nutrients (vitamins and minerals), dietary pesticides (natural and synthetic), dioxin and other herbicides, and acrylamide will be reviewed and discussed.

  6. Nutritional Hormesis and Aging

    PubMed Central

    Hayes, Daniel P.

    2009-01-01

    Nutritional hormesis has the potential to serve as a pro-healthy aging intervention by reducing the susceptibility of the elderly to various chronic degenerative diseases and thereby extending human healthspan. Supportive evidence for nutritional hormesis arising from essential nutrients (vitamins and minerals), dietary pesticides (natural and synthetic), dioxin and other herbicides, and acrylamide will be reviewed and discussed. PMID:20221283

  7. Herbicide-mediated hormesis

    USDA-ARS?s Scientific Manuscript database

    Hormesis is the stimulatory effect of a subtoxic level of a toxin. This phenomenon is common with most herbicides on most plant species, although the effect is generally difficult to quantitatively repeat, even under laboratory conditions. The magnitude of and the dose required for hormesis is influ...

  8. Smoking and Hormesis as Confounding Factors in Radiation Pulmonary Carcinogenesis

    PubMed Central

    Sanders, Charles L.; Scott, Bobby R.

    2008-01-01

    Confounding factors in radiation pulmonary carcinogenesis are passive and active cigarette smoke exposures and radiation hormesis. Significantly increased lung cancer risk from ionizing radiation at lung doses < 1 Gy is not observed in never smokers exposed to ionizing radiations. Residential radon is not a cause of lung cancer in never smokers and may protect against lung cancer in smokers. The risk of lung cancer found in many epi-demiological studies was less than the expected risk (hormetic effect) for nuclear weapons and power plant workers, shipyard workers, fluoroscopy patients, and inhabitants of high-dose background radiation. The protective effect was noted for low- and mixed high- and low-linear energy transfer (LET) radiations in both genders. Many studies showed a protection factor (PROFAC) > 0.40 (40% avoided) against the occurrence of lung cancer. The ubiquitous nature of the radiation hormesis response in cellular, animal, and epidemio-logical studies negates the healthy worker effect as an explanation for radiation hormesis. Low-dose radiation may stimulate DNA repair/apoptosis and immunity to suppress and eliminate cigarette-smoke-induced transformed cells in the lung, reducing lung cancer occurrence in smokers. PMID:18648572

  9. Smoking and hormesis as confounding factors in radiation pulmonary carcinogenesis.

    PubMed

    Sanders, Charles L; Scott, Bobby R

    2006-12-06

    Confounding factors in radiation pulmonary carcinogenesis are passive and active cigarette smoke exposures and radiation hormesis. Significantly increased lung cancer risk from ionizing radiation at lung doses < 1 Gy is not observed in never smokers exposed to ionizing radiations. Residential radon is not a cause of lung cancer in never smokers and may protect against lung cancer in smokers. The risk of lung cancer found in many epidemiological studies was less than the expected risk (hormetic effect) for nuclear weapons and power plant workers, shipyard workers, fluoroscopy patients, and inhabitants of high-dose background radiation. The protective effect was noted for low- and mixed high- and low-linear energy transfer (LET) radiations in both genders. Many studies showed a protection factor (PROFAC) > 0.40 (40% avoided) against the occurrence of lung cancer. The ubiquitous nature of the radiation hormesis response in cellular, animal, and epidemio-logical studies negates the healthy worker effect as an explanation for radiation hormesis. Low-dose radiation may stimulate DNA repair/apoptosis and immunity to suppress and eliminate cigarette-smoke-induced transformed cells in the lung, reducing lung cancer occurrence in smokers.

  10. Beyond selectivity: are behavioral avoidance and hormesis likely causes of pyrethroid-induced outbreaks of the southern red mite Oligonychus ilicis?

    PubMed

    Cordeiro, E M G; de Moura, I L T; Fadini, M A M; Guedes, R N C

    2013-10-01

    Secondary pest outbreak is a counterintuitive ecological backlash of pesticide use in agriculture that takes place with the increase in abundance of a non-targeted pest species after pesticide application against a targeted pest species. Although the phenomenon was well recognized, its alternative causes are seldom considered. Outbreaks of the southern red mite Oligonychus ilicis are frequently reported in Brazilian coffee farms after the application of pyrethroid insecticides against the coffee leaf miner Leucoptera coffeella. Selectivity favoring the red mite against its main predatory mites is generally assumed as the outbreak cause, but this theory has never been tested. Here, we assessed the toxicity (and thus the selectivity) of deltamethrin against both mite species: the southern red mite and its phytoseid predator Amblyseius herbicolus. Additionally, behavioral avoidance and deltamethrin-induced hormesis were also tested as potential causes of red mite outbreak using free-choice behavioral walking bioassays with the predatory mite and life-table experiments with both mite species, respectively. Lethal toxicity bioassays indicated that the predatory mite was slightly more susceptible than its prey (1.5×), but in more robust demographic bioassays, the predator was three times more tolerant to deltamethrin than its prey, indicating that predator susceptibility to deltamethrin is not a cause of the reported outbreaks. The predator did not exhibit behavioral avoidance to deltamethrin; however insecticide-induced hormesis in the red mite led to its high population increase under low doses, which was not observed for the predatory mite. Therefore, deltamethrin-induced hormesis is a likely cause of the reported red mite outbreaks. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Herbicides and plant hormesis

    USDA-ARS?s Scientific Manuscript database

    Herbicide hormesis is commonly observed at sub-toxic doses of herbicides and other phytotoxins. The occurrence and magnitude of this phenomenon is influenced by plant growth stage and physiological status, environmental factors, the endpoint measured, and the timing between treatment and endpoint me...

  12. When less is more: hormesis against stress and disease

    PubMed Central

    Zimmermann, Andreas; Bauer, Maria A.; Kroemer, Guido; Madeo, Frank; Carmona-Gutierrez, Didac

    2014-01-01

    All living organisms need to adapt to ever changing adverse conditions in order to survive. The phenomenon termed hormesis describes an evolutionarily conserved process by which a cell or an entire organism can be preconditioned, meaning that previous exposure to low doses of an insult protects against a higher, normally harmful or lethal dose of the same stressor. Growing evidence suggests that hormesis is directly linked to an organism’s (or cell’s) capability to cope with pathological conditions such as aging and age-related diseases. Here, we condense the conceptual and potentially therapeutic importance of hormesis by providing a short overview of current evidence in favor of the cytoprotective impact of hormesis, as well as of its underlying molecular mechanisms. PMID:28357237

  13. Hormesis and medicine

    PubMed Central

    Calabrese, Edward J

    2008-01-01

    Evidence is presented which supports the conclusion that the hormetic dose–response model is the most common and fundamental in the biological and biomedical sciences, being highly generalizable across biological model, endpoint measured and chemical class and physical agent. The paper provides a broad spectrum of applications of the hormesis concept for clinical medicine including anxiety, seizure, memory, stroke, cancer chemotherapy, dermatological processes such as hair growth, osteoporosis, ocular diseases, including retinal detachment, statin effects on cardiovascular function and tumour development, benign prostate enlargement, male sexual behaviours/dysfunctions, and prion diseases. PMID:18662293

  14. Historical foundations of hormesis.

    PubMed

    Calabrese, Edward J

    2015-04-01

    The present paper provides an historical assessment of the concept of hormesis and its relationship to homeopathy and modern medicine. It is argued that the dose-response concept was profoundly influenced by the conflict between homeopathy and traditional medicine and that decisions on which dose-response model to adopt were not based on "science" but rater on historical antipathies. While the historical dispute between homeopathy and traditional medicine has long since subsided, their impact upon the field has been enduring and generally unappreciated, profoundly adversely affecting current drug development, therapeutic strategies and environmental risk assessment strategies and policies.

  15. Hormesis: a fundamental concept in biology

    PubMed Central

    Calabrese, Edward J.

    2014-01-01

    This paper assesses the hormesis dose response concept, including its historical foundations, frequency, generality, quantitative features, mechanistic basis and biomedical, pharmaceutical and environmental health implications. The hormetic dose response is highly generalizable, being independent of biology model (i.e. common from plants to humans), level of biological organization (i.e. cell, organ and organism), endpoint, inducing agent and mechanism, providing the first general and quantitative description of plasticity. The hormetic dose response describes the limits to which integrative endpoints (e.g. cell proliferation, cell migration, growth patterns, tissue repair, aging processes, complex behaviors such as anxiety, learning, memory, and stress, preconditioning responses, and numerous adaptive responses) can be modulated (i.e., enhanced or diminished) by pharmaceutical, chemical and physical means. Thus, the hormesis concept is a fundamental concept in biology with a wide range of biological implications and biomedical applications. PMID:28357236

  16. Hormesis and Paradoxical Effects of Drooping Birch (Betula pendula Roth) Parameters Under Motor Traffic Pollution.

    PubMed

    Erofeeva, Elena A

    2015-01-01

    Various plant indexes are used or recommended for bioindication. However, the nonmonotonic dose-response dependences (hormesis and paradoxical effects) of these indexes are insufficiently explored upon exposure to pollution. We studied the dependences of these Betula pendula indexes on the intensity of motor traffic pollution. Regression analysis did not reveal any dependence of chlorophyll and carotenoid content on traffic intensity (in 2008 and 2010-2013). Lipid peroxidation rate had different versions of paradoxical effects in 2008 and 2010 to 2012 and increased in comparison with control under an increase in pollution level in 2013. In 2010 to 2012, all dose-response dependences for total protein and thiol group content were biphasic and multiphasic paradoxical effects. In 2013, an increase in traffic intensity induced a linear reduction in protein content and an increase in thiol group level in comparison with the control. In most cases, the studied phenological indexes and seed production decreased monotonically in comparison with the control following an increase in traffic intensity. Only in 2010 and 2013, share of fallen leaves had hormesis and paradoxical effect accordingly. Fluctuating asymmetry had a paradoxical effect and hormesis in 2008 and 2012, accordingly, and increased in comparison with the control under an increase in the level of pollution in 2010 to 2011.

  17. Hormesis and Paradoxical Effects of Drooping Birch (Betula pendula Roth) Parameters Under Motor Traffic Pollution

    PubMed Central

    2015-01-01

    Various plant indexes are used or recommended for bioindication. However, the nonmonotonic dose–response dependences (hormesis and paradoxical effects) of these indexes are insufficiently explored upon exposure to pollution. We studied the dependences of these Betula pendula indexes on the intensity of motor traffic pollution. Regression analysis did not reveal any dependence of chlorophyll and carotenoid content on traffic intensity (in 2008 and 2010-2013). Lipid peroxidation rate had different versions of paradoxical effects in 2008 and 2010 to 2012 and increased in comparison with control under an increase in pollution level in 2013. In 2010 to 2012, all dose–response dependences for total protein and thiol group content were biphasic and multiphasic paradoxical effects. In 2013, an increase in traffic intensity induced a linear reduction in protein content and an increase in thiol group level in comparison with the control. In most cases, the studied phenological indexes and seed production decreased monotonically in comparison with the control following an increase in traffic intensity. Only in 2010 and 2013, share of fallen leaves had hormesis and paradoxical effect accordingly. Fluctuating asymmetry had a paradoxical effect and hormesis in 2008 and 2012, accordingly, and increased in comparison with the control under an increase in the level of pollution in 2010 to 2011. PMID:26676071

  18. Hormesis results in trade-offs with immunity.

    PubMed

    McClure, Colin D; Zhong, Weihao; Hunt, Vicky L; Chapman, Fiona M; Hill, Fiona V; Priest, Nicholas K

    2014-08-01

    Many have argued that we may be able to extend life and improve human health through hormesis, the beneficial effects of low-level toxins and other stressors. But, studies of hormesis in model systems have not yet established whether stress-induced benefits are cost free, artifacts of inbreeding, or come with deleterious side effects. Here, we provide evidence that hormesis results in trade-offs with immunity. We find that a single topical dose of dead spores of the entomopathogenic fungus, Metarhizium robertsii, increases the longevity of the fruit fly, Drosophila melanogaster, without significant decreases in fecundity. We find that hormetic benefits of pathogen challenge are greater in lines that lack key components of antifungal immunity (Dif and Turandot M). And, in outbred fly lines, we find that topical pathogen challenge enhances both survival and fecundity, but reduces ability to fight off live infections. The results provide evidence that hormesis is manifested by stress-induced trade-offs with immunity, not cost-free benefits or artifacts of inbreeding. Our findings illuminate mechanisms underlying pathogen-induced life-history trade-offs, and indicate that reduced immune function may be an ironic side effect of the "elixirs of life."

  19. HORMESIS RESULTS IN TRADE-OFFS WITH IMMUNITY

    PubMed Central

    McClure, Colin D; Zhong, Weihao; Hunt, Vicky L; Chapman, Fiona M; Hill, Fiona V; Priest, Nicholas K

    2014-01-01

    Many have argued that we may be able to extend life and improve human health through hormesis, the beneficial effects of low-level toxins and other stressors. But, studies of hormesis in model systems have not yet established whether stress-induced benefits are cost free, artifacts of inbreeding, or come with deleterious side effects. Here, we provide evidence that hormesis results in trade-offs with immunity. We find that a single topical dose of dead spores of the entomopathogenic fungus, Metarhizium robertsii, increases the longevity of the fruit fly, Drosophila melanogaster, without significant decreases in fecundity. We find that hormetic benefits of pathogen challenge are greater in lines that lack key components of antifungal immunity (Dif and Turandot M). And, in outbred fly lines, we find that topical pathogen challenge enhances both survival and fecundity, but reduces ability to fight off live infections. The results provide evidence that hormesis is manifested by stress-induced trade-offs with immunity, not cost-free benefits or artifacts of inbreeding. Our findings illuminate mechanisms underlying pathogen-induced life-history trade-offs, and indicate that reduced immune function may be an ironic side effect of the “elixirs of life.” PMID:24862588

  20. How prevalent is chemical hormesis in the natural and experimental worlds?

    PubMed

    Mushak, Paul

    2013-01-15

    Hormesis is described as a biological phenomenon showing bidirectional (biphasic) responses to chemical or other stressors: stimulation at low doses and inhibition at high doses or vice-versa. The label applies to either radiation or chemical hormesis. This review addresses certain critical but persisting quantitative questions about chemical hormesis. For example, what is its actual generalizability in nature? Is hormesis generalizable enough to figure in risk analysis and regulatory efforts within human or ecological toxicant exposures? No evidence exists to show that chemical hormesis is a universally distributed biological phenomenon within some law, rule or principle (100% frequency) nor is there a reliable and consistent body of evidence that leads to identifying some significant and reproducible value for frequency of occurrence below the universality standard, i.e., <100% frequency. Lack of reliable and/or consistent evidence arises from diverse limits to study methods, i.e., methods were post-hoc evaluations of published data gathered for other purposes and using ad-hoc characterization approaches, rather than doing new studies. The literature selected for generalizability analyses has not been systematically pre-evaluated as a scientifically reliable representation of hormesis frequency in nature. Furthermore, database evaluations have used certain criteria not validated for this specific purpose, so that metric and what was measured are objects of scrutiny and ambiguity. Finally, simultaneous estimates of frequency of non-hormetic dose-response relationships, required for reliable determinations of hormesis frequency, were not done in these analyses. Chemical hormesis frequency estimates vary with conditions for characterization. For all these reasons, chemical hormesis still has limited use in health policy and regulatory thinking. Copyright © 2012 Elsevier B.V. All rights reserved.

  1. Transcript expression patterns illuminate the mechanistic background of hormesis in caenorhabditis elegans maupas.

    PubMed

    Steinberg, Christian E W; Pietsch, Kerstin; Saul, Nadine; Menzel, Stefanie; Swain, Suresh C; Stürzenbaum, Stephen R; Menzel, Ralph

    2013-01-01

    The animal model Caenorhabditis elegans was employed to study polyphenol- and humic substances-induced hormetic changes in lifespan. A detailed insight into the underlying mechanism of hormesis was uncovered by applying whole genome DNA microarray experimentation over a range of quercetin (Q), tannic acid (TA), and humic substances (HuminFeed(®), HF) concentrations. The transcriptional response to all exposures followed a non-linear mode which highlighted differential signaling and metabolic pathways. While low Q concentrations regulated processes improving the health of the nematodes, higher concentrations extended lifespan and modulated substantially the global transcriptional response. Over-represented transcripts were notably part of the biotransformation process: enhanced catabolism of toxic intermediates possibly contributes to the lifespan extension. The regulation of transcription, Dauer entry, and nucleosome suggests the presence of distinct exposure dependent differences in transcription and signaling pathways. TA- and HF-mediated transcript expression patterns were overall similar to each other, but changed across the concentration range indicating that their transcriptional dynamics are complex and cannot be attributed to a simple adaptive response. In contrast, Q-mediated hormesis was well aligned to fit the definition of an adaptive response. Simple molecules are more likely to induce an adaptive response than more complex molecules.

  2. Mitochondrial Hormesis in Pancreatic β Cells: Does Uncoupling Protein 2 Play a Role?

    PubMed Central

    Li, Ning; Stojanovski, Suzana; Maechler, Pierre

    2012-01-01

    In pancreatic β cells, mitochondrial metabolism translates glucose sensing into signals regulating insulin secretion. Chronic exposure of β cells to excessive nutrients, namely, glucolipotoxicity, impairs β-cell function. This is associated with elevated ROS production from overstimulated mitochondria. Mitochondria are not only the major source of cellular ROS, they are also the primary target of ROS attacks. The mitochondrial uncoupling protein UCP2, even though its uncoupling properties are debated, has been associated with protective functions against ROS toxicity. Hormesis, an adaptive response to cellular stresses, might contribute to the protection against β-cell death, possibly limiting the development of type 2 diabetes. Mitochondrial hormesis, or mitohormesis, is a defense mechanism observed in ROS-induced stress-responses by mitochondria. In β cells, mitochondrial damages induced by sublethal exogenous H2O2 can induce secondary repair and defense mechanisms. In this context, UCP2 is a marker of mitohormesis, being upregulated following stress conditions. When overexpressed in nonstressed naïve cells, UCP2 confers resistance to oxidative stress. Whether treatment with mitohormetic inducers is sufficient to restore or ameliorate secretory function of β cells remains to be determined. PMID:23029600

  3. Reductive stress impairs myoblasts mitochondrial function and triggers mitochondrial hormesis.

    PubMed

    Singh, François; Charles, Anne-Laure; Schlagowski, Anna-Isabel; Bouitbir, Jamal; Bonifacio, Annalisa; Piquard, François; Krähenbühl, Stephan; Geny, Bernard; Zoll, Joffrey

    2015-07-01

    Even though oxidative stress damage from excessive production of ROS is a well known phenomenon, the impact of reductive stress remains poorly understood. This study tested the hypothesis that cellular reductive stress could lead to mitochondrial malfunction, triggering a mitochondrial hormesis (mitohormesis) phenomenon able to protect mitochondria from the deleterious effects of statins. We performed several in vitro experiments on L6 myoblasts and studied the effects of N-acetylcysteine (NAC) at different exposure times. Direct NAC exposure (1mM) led to reductive stress, impairing mitochondrial function by decreasing maximal mitochondrial respiration and increasing H₂O₂production. After 24h of incubation, the reactive oxygen species (ROS) production was increased. The resulting mitochondrial oxidation activated mitochondrial biogenesis pathways at the mRNA level. After one week of exposure, mitochondria were well-adapted as shown by the decrease of cellular ROS, the increase of mitochondrial content, as well as of the antioxidant capacities. Atorvastatin (ATO) exposure (100μM) for 24h increased ROS levels, reduced the percentage of live cells, and increased the total percentage of apoptotic cells. NAC exposure during 3days failed to protect cells from the deleterious effects of statins. On the other hand, NAC pretreatment during one week triggered mitochondrial hormesis and reduced the deleterious effect of statins. These results contribute to a better understanding of the redox-dependant pathways linked to mitochondria, showing that reductive stress could trigger mitochondrial hormesis phenomenon.

  4. Hormesis: a conversation with a critic.

    PubMed

    Calabrese, Edward J

    2009-09-01

    In this commentary I respond to points raised in the commentary by Mushak [Ad hoc and fast forward: the science and control of hormesis growth and development. Environ Health Perspect 117:1333-1338 (2009)], which principally concerns studies by me and my colleagues concerning the frequency of hormesis in toxicology. In this commentary I demonstrate that Mushak's analysis contains critical statistical errors and misunderstandings of statistical concepts that invalidate its conclusions concerning the frequency of hormesis in the toxicologic literature. In his commentary Mushak offers no significant new conceptual insights, and his key technical criticisms of hormesis frequency findings are unfounded.

  5. [Metabolic memory enhances hormesis effect to the copper ions in age-depended manner].

    PubMed

    Bozhkov, A I; Sidorov, V I; Kurguzova, N I; Dlubovskaia, V L

    2014-01-01

    The ability of young and old rats to manifest the hormesis effect to lethal doses of copper sulphate and the ability to save the induced "adaptive" pattern of redistribution of copper ions after the transfer of animals in the standard conditions is the mechanism of metabolic memory. It was found that pretreatment of animals with low-dose (1 mg per 100 g body mass, i.e. 33% of the lethal dose) of copper sulfate induced the formation of their resistance to lethal doses (3 mg per 100 g), so the hormesis effect was manifested. Hormesis effect depended on the number of pre injections of small doses of copper sulphate in an S-shaped manner. The protective effect increased after 1 to 3 of preliminary injections of copper sulfate, and after four or more injections the hormesis effect decreased. It is shown that the cardinal role in intracellular pattern of copper ion redistribution play heat-stable copper binding proteins 12 kDa cytosolic proteins. The formed "adaptive" pattern of intracellular distribution of the copper ions may be reproduced, after at least, one month. The prolonged hormesis effect can be attributed to the forming metabolic memory. The intracellular distribution pattern of the copper ions was age-dependent. Age-related differences were found in hormesis effect induced by copper ions, which results in increased binding capacity of copper binding proteins in old animals, with a higher content of copper ions in the mitochondria and microsomes as compared to young animals.

  6. Sex hormonal regulation and hormesis in aging and longevity: role of vitagenes.

    PubMed

    Calabrese, V; Scapagnini, G; Davinelli, S; Koverech, G; Koverech, A; De Pasquale, C; Salinaro, A Trovato; Scuto, M; Calabrese, E J; Genazzani, A R

    2014-12-01

    Aging process is accompanied by hormonal changes characterized by an imbalance between catabolic hormones, such as cortisol and thyroid hormones which remain stable and hormones with anabolic effects (testosterone, insulin like growth factor-1 (IGF-1) and dehydroepiandrosterone sulphate (DHEAS), that decrease with age. Deficiencies in multiple anabolic hormones have been shown to predict health status and longevity in older persons.Unlike female menopause, which is accompanied by an abrupt and permanent cessation of ovarian function (both folliculogenesis and estradiol production), male aging does not result in either cessation of testosterone production nor infertility. Although the circulating serum testosterone concentration does decline with aging, in most men this decrease is small, resulting in levels that are generally within the normal range. Hormone therapy (HT) trials have caused both apprehension and confusion about the overall risks and benefits associated with HT treatment. Stress-response hormesis from a molecular genetic perspective corresponds to the induction by stressors of an adaptive, defensive response, particularly through alteration of gene expression. Increased longevity can be associated with greater resistance to a range of stressors. During aging, a gradual decline in potency of the heat shock response occur and this may prevent repair of protein damage. Conversely, thermal stress or pharmacological agents capable of inducing stress responses, by promoting increased expression of heat-shock proteins, confer protection against denaturation of proteins and restoration of proteome function. If induction of stress resistance increases life span and hormesis induces stress resistance, hormesis most likely result in increased life span. Hormesis describes an adaptive response to continuous cellular stresses, representing a phenomenon where exposure to a mild stressor confers resistance to subsequent, otherwise harmful, conditions of increased

  7. Ecological risk assessment: implications of hormesis.

    PubMed

    van der Schalie, W H; Gentile, J H

    2000-01-01

    Hormesis is a widespread phenomenon across many taxa and chemicals, and, at the single species level, issues regarding the application of hormesis to human health and ecological risk assessment are similar. For example, convincing the public of a 'beneficial' effect of environmental chemicals may be problematic, and the design and analysis of laboratory studies may require modifications to detect hormesis. However, interpreting the significance of hormesis for even a single species in an ecological risk assessment can be complicated by considerations of competition with other species, predation effects, etc. Ecological risk assessments involve more than a single species; they may involve communities of hundreds or thousands of species as well as a range of ecological processes. Applying hormetic adjustments to threshold effect levels for chemicals derived from sensitivity distributions for a large number of species is impractical. For ecological risks, chemical stressors are frequently of lessor concern than physical stressors such as habitat alteration or biological stressors such as introduced species, but the relevance of hormesis to non-chemical stressors is unclear. Although ecological theories such as the intermediate disturbance hypothesis offer some intriguing similarities between chemical hormesis and hormetic-like responses resulting from physical disturbances, mechanistic explanations are lacking. Further exploration of the relevance of hormesis to ecological risk assessment is desirable. Aspects deserving additional attention include developing a better understanding of the hormetic effects of chemical mixtures, the relevance of hormesis to physical and biological stressors and the development of criteria for determining when hormesis is likely to be relevant to ecological risk assessments.

  8. Hormesis: why it is important to biogerontologists.

    PubMed

    Calabrese, Edward J; Iavicoli, Ivo; Calabrese, Vittorio

    2012-06-01

    This paper offers a broad assessment of the hormetic dose response and its relevance to biogerontology. The paper provides detailed background information on the historical foundations of hormesis, its quantitative features, mechanistic foundations, as well as how the hormesis concept could be further applied in the development of new therapeutic advances in the treatment of age-related diseases. The concept of hormesis has direct application to biogerontology not only affecting the quality of the aging process but also experimental attempts to extend longevity.

  9. Bioreactivity of municipal solid waste landfill leachates-Hormesis and DNA damage.

    PubMed

    Koshy, Lata; Jones, Tim; BéruBé, Kelly

    2008-04-01

    The issue of domestic waste is recognised as one of the most serious environmental problems facing the nation. With the UK producing 35 million tonnes of municipal solid waste per annum, an understanding of the ranges of toxicity of landfill emissions is crucial to determine the degree of concern we should have about the potential effects these waste sites could have upon nearby populations and the surrounding environment. The aim of this study was to evaluate the bioreactivity of landfill leachates in terms of their capacity to damage ROS-sensitive bacteriophage plasmid DNA and induce toxicity in a commercial photobacterium toxicity assay, based on the light emission of Vibrio fischeri bacteria (ROTAS). The bacterial assay revealed widespread biostimulation and a hormesis response in the bacteria, with alpha-, beta- and gamma-response curves observed following exposure to the different landfill leachates. Different biological mechanisms lead to variations in bioreactivity, as seen in the plasmid DNA scission and ROTAS assays.

  10. Adaptation to acrolein through upregulating the protection by glutathione in human bronchial epithelial cells: the materialization of the hormesis concept.

    PubMed

    Sthijns, Mireille M J P E; Randall, Matthew J; Bast, Aalt; Haenen, Guido R M M

    2014-04-18

    Acrolein is a thiol reactive compound present in cigarette smoke and plays a pivotal role in the deleterious effects of smoking. Acrolein causes toxicity in human bronchial epithelial cells in a dose dependent manner. GSH forms the first line of defense against acrolein-induced toxicity. At high doses of acrolein (⩾10 μM) the capacity of the cellular protection by GSH is overwhelmed and GSH is not able to quench all the acrolein, resulting in cytotoxicity. At a relatively low dose of acrolein (3 μM), no cytotoxicity is observed due to protection by GSH. Moreover we found that exposure to a low dose of acrolein protects cells against the toxic effect of a second higher dose of acrolein. The adaptation to acrolein is induced via Nrf2 mediated gene expression of γ-glutamylcysteine synthetase leading to elevated GSH levels. This upregulation of the protection by GSH demonstrates a hormetic response to acrolein. Hormesis is an adaptive or compensatory response induced by a relatively subtle challenge of homeostasis by a toxic compound. Insight into the mechanism of hormesis is mandatory for a more accurate societal regulation of toxic compounds.

  11. Toxicological awakenings: the rebirth of hormesis as a central pillar of toxicology

    SciTech Connect

    Calabrese, Edward J. . E-mail: edwardc@schoolph.umass.edu

    2005-04-01

    This paper assesses historical reasons that may account for the marginalization of hormesis as a dose-response model in the biomedical sciences in general and toxicology in particular. The most significant and enduring explanatory factors are the early and close association of the concept of hormesis with the highly controversial medical practice of homeopathy and the difficulty in assessing hormesis with high-dose testing protocols which have dominated the discipline of toxicology, especially regulatory toxicology. The long-standing and intensely acrimonious conflict between homeopathy and 'traditional' medicine (allopathy) lead to the exclusion of the hormesis concept from a vast array of medical- and public health-related activities including research, teaching, grant funding, publishing, professional societal meetings, and regulatory initiatives of governmental agencies and their advisory bodies. Recent publications indicate that the hormetic dose-response is far more common and fundamental than the dose-response models [threshold/linear no threshold (LNT)] used in toxicology and risk assessment, and by governmental regulatory agencies in the establishment of exposure standards for workers and the general public. Acceptance of the possibility of hormesis has the potential to profoundly affect the practice of toxicology and risk assessment, especially with respect to carcinogen assessment.

  12. Radiation Hormesis: Historical and Current Perspectives.

    PubMed

    Baldwin, Jonathan; Grantham, Vesper

    2015-12-01

    The purpose of this article is to provide the reader with a better understanding of radiation hormesis, the investigational research that supports or does not support the theory, and the relationship between the theory and current radiation safety guidelines and practices. The concept of radiation hormesis is known to nuclear medicine technologists, but understanding its complexities and the historical development of the theory may bring about a better understanding of radiation safety and regulations.

  13. Hormesis does not make sense except in the light of TOR-driven aging.

    PubMed

    Blagosklonny, Mikhail V

    2011-11-01

    Weak stresses (including weak oxidative stress, cytostatic agents, heat shock, hypoxia, calorie restriction) may extend lifespan. Known as hormesis, this is the most controversial notion in gerontology. For one, it is believed that aging is caused by accumulation of molecular damage. If so, hormetic stresses (by causing damage) must shorten lifespan. To solve the paradox, it was suggested that, by activating repair, hormetic stresses eventually decrease damage. Similarly, Baron Munchausen escaped from a swamp by pulling himself up by his own hair. Instead, I discuss that aging is not caused by accumulation of molecular damage. Although molecular damage accumulates, organisms do not live long enough to age from this accumulation. Instead, aging is driven by overactivated signal-transduction pathways including the TOR (Target of Rapamycin) pathway. A diverse group of hormetic conditions can be divided into two groups. "Hormesis A" inhibits the TOR pathway. "Hormesis B" increases aging-tolerance, defined as the ability to survive catastrophic complications of aging. Hormesis A includes calorie restriction, resveratrol, rapamycin, p53-inducing agents and, in part, physical exercise, heat shock and hypoxia. Hormesis B includes ischemic preconditioning and, in part, physical exercise, heat shock, hypoxia and medical interventions.

  14. Hormesis does not make sense except in the light of TOR-driven aging

    PubMed Central

    Blagosklonny, Mikhail V.

    2011-01-01

    Weak stresses (including weak oxidative stress, cytostatic agents, heat shock, hypoxia, calorie restriction) may extend lifespan. Known as hormesis, this is the most controversial notion in gerontology. For one, it is believed that aging is caused by accumulation of molecular damage. If so, hormetic stresses (by causing damage) must shorten lifespan. To solve the paradox, it was suggested that, by activating repair, hormetic stresses eventually decrease damage. Similarly, Baron Munchausen escaped from a swamp by pulling himself up by his own hair. Instead, I discuss that aging is not caused by accumulation of molecular damage. Although molecular damage accumulates, organisms do not live long enough to age from this accumulation. Instead, aging is driven by overactivated signal-transduction pathways including the TOR (Target of Rapamycin) pathway. A diverse group of hormetic conditions can be divided into two groups. “Hormesis A” inhibits the TOR pathway. “Hormesis B” increases aging-tolerance, defined as the ability to survive catastrophic complications of aging. Hormesis A includes calorie restriction, resveratrol, rapamycin, p53-inducing agents and, in part, physical exercise, heat shock and hypoxia. Hormesis B includes ischemic preconditioning and, in part, physical exercise, heat shock, hypoxia and medical interventions. PMID:22166724

  15. Radiation hormesis. Its emerging significance in medical practice.

    PubMed

    Loken, M K; Feinendegen, L E

    1993-05-01

    Because of the strong scientific evidence in support of radiation hormesis, we can no longer ignore this concept. There is, however, need for additional, carefully documented investigations in selected biological systems exposed to LLIR if the matter of radiation hormesis is to be settled once and for all. This need should be addressed without delay, as the matter of benefits derived from LLIR exposure could have major economic and epidemiologic implications. If radiation hormesis becomes firmly established, the requirements for LLIR protection might be relaxed, leading to a sizable cost saving, and the fear of nuclear energy should abate. If this happens, the evergrowing problems associated with energy production from fossil fuels on the one hand and the continued improvements in nuclear reactor technology on the other, will force a world-wide reassessment of risks and benefits associated with nuclear energy. Furthermore, as discussed herein, the major source of exposure from background radiation comes from the inhalation of radon gas. The very high cost associated with effective radon abatement would lead to an abandonment of this mitigation effort so that the limited funds available to improve public health world wide could be used more effectively elsewhere. Thus, we conclude that the time is now to consider eliminating the concept of the radiation paradigm from scientific thinking. We must not continue to unequivocally accept the propositions that 1) all radiation is harmful and 2) that the health effects of LLIR may be directly inferred by scaling down from known deleterious high-dose effects, in as much as there is no scientific basis for an agent not to cause multiple effects.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Radiation hormesis. Its emerging significance in medical practice [see comments

    SciTech Connect

    Loken, M.K.; Feinendegen, L.E. )

    1993-05-01

    Because of the strong scientific evidence in support of radiation hormesis, we can no longer ignore this concept. There is, however, need for additional, carefully documented investigations in selected biological systems exposed to LLIR if the matter of radiation hormesis is to be settled once and for all. This need should be addressed without delay, as the matter of benefits derived from LLIR exposure could have major economic and epidemiologic implications. If radiation hormesis becomes firmly established, the requirements for LLIR protection might be relaxed, leading to a sizable cost saving, and the fear of nuclear energy should abate. If this happens, the evergrowing problems associated with energy production from fossil fuels on the one hand and the continued improvements in nuclear reactor technology on the other, will force a world-wide reassessment of risks and benefits associated with nuclear energy. Furthermore, as discussed herein, the major source of exposure from background radiation comes from the inhalation of radon gas. The very high cost associated with effective radon abatement would lead to an abandonment of this mitigation effort so that the limited funds available to improve public health world wide could be used more effectively elsewhere. Thus, we conclude that the time is now to consider eliminating the concept of the radiation paradigm from scientific thinking. We must not continue to unequivocally accept the propositions that (1) all radiation is harmful and (2) that the health effects of LLIR may be directly inferred by scaling down from known deleterious high-dose effects, in as much as there is no scientific basis for an agent not to cause multiple effects.

  17. Optimal experimental design strategies for detecting hormesis.

    PubMed

    Dette, Holger; Pepelyshev, Andrey; Wong, Weng Kee

    2011-12-01

    Hormesis is a widely observed phenomenon in many branches of life sciences, ranging from toxicology studies to agronomy, with obvious public health and risk assessment implications. We address optimal experimental design strategies for determining the presence of hormesis in a controlled environment using the recently proposed Hunt-Bowman model. We propose alternative models that have an implicit hormetic threshold, discuss their advantages over current models, and construct and study properties of optimal designs for (i) estimating model parameters, (ii) estimating the threshold dose, and (iii) testing for the presence of hormesis. We also determine maximin optimal designs that maximize the minimum of the design efficiencies when we have multiple design criteria or there is model uncertainty where we have a few plausible models of interest. We apply these optimal design strategies to a teratology study and show that the proposed designs outperform the implemented design by a wide margin for many situations.

  18. Unequal brothers : are homeopathy and hormesis linked?

    PubMed

    Oberbaum, Menachem; Frass, Michael; Gropp, Cornelius

    2015-04-01

    The debate between those who believe homeopathy and hormesis derive from the same root and those who believe the two are different phenomena is as old as hormesis. It is an emotionally loaded discussion, with both sides fielding arguments which are far from scientific. Careful analysis of the basic paradigms of the two systems questions the claim of the homeopaths, who find similarities between them. The authors discuss these paradigms, indicating the differences between the claims of homeopathy and hormesis. It is time for thorough and serious research to lay this question to rest. One possible approach is to compare the activity of a hormetic agent, prepared in the usual way, with that of the same agent in the same concentration prepared homeopathically by serial dilution and succussion.

  19. Hormesis: its impact on medicine and health.

    PubMed

    Calabrese, E J; Iavicoli, I; Calabrese, V

    2013-02-01

    This article offers a broad assessment of the hormetic dose response and its relevance to biomedical researchers, physicians, the pharmaceutical industry, and public health scientists. This article contains a series of 61 questions followed by relatively brief but referenced responses that provides support for the conclusion that hormesis is a reproducible phenomenon, commonly observed, with a frequency far greater than other dose-response models such as the threshold and linear nonthreshold dose-response models. The article provides a detailed background information on the historical foundations of hormesis, its quantitative features, mechanistic foundations, as well as how hormesis is currently being used within medicine and identifying how this concept could be further applied in the development of new therapeutic advances and in improved public health practices.

  20. A catechin-enriched green tea extract prevents glucose-induced survival reduction in Caenorhabditis elegans through sir-2.1 and uba-1 dependent hormesis.

    PubMed

    Deusing, Dorothé Jenni; Winter, Sarah; Kler, Adolf; Kriesl, Erwin; Bonnländer, Bernd; Wenzel, Uwe; Fitzenberger, Elena

    2015-04-01

    Hyperglycemia is a hallmark of diabetes mellitus which leads to the onset of complications in the long term. Green tea through its high content of polyphenolic catechins, on the other hand, is suggested to prevent or at least delay such detrimental complications. In the present study we fed the nematode Caenorhabditis elegans on a liquid medium supplemented with 10mM glucose in the absence or presence of a catechin-enriched green tea extract (CEGTE). After exposure of young adults for 48h survival was subsequently measured under heat stress at 37°C. Whereas CEGTE at 0.01% did not affect the survival of wild type nematodes, it completely reversed the glucose-induced survival reduction. Those effects were not achieved through the monomeric catechins included in CEGTE. RNA interference (RNAi) for sir-2.1 not only prevented the survival extension by CEGTE under simultaneous glucose exposure but also caused a further reduction of survival. Likewise, the knockdown of uba-1, encoding the only E1-ubiquitin-activating enzyme in C. elegans, proved that UBA-1 is essential for the survival extension by CEGTE and that its loss of function changes CEGTE from a survival extending into a survival reducing extract. Stimulation of the proteasome by CEGTE was finally proven through measurements of the proteolytic cleavage of a fluorogenic peptide substrate. To conclude, our studies provide evidence that CEGTE reverses glucose-induced damage in C. elegans through activation of adaptive responses mediated by SIR-2.1 and proteasomal degradation. The hormetic mode of action is revealed by a reduction of survival once the adaptive processes were blocked.

  1. The myth and reality of reversal of aging by hormesis.

    PubMed

    Sonneborn, Joan Smith

    2005-12-01

    Hormesis is an adaptive response to low doses of otherwise harmful agents by triggering a cascade of stress-specific resistance pathways. Evidence from protozoa, nematodes, flies, rodents, and primates indicate that stress-induced tolerance modulates survival and longevity. "Reality" is that hormesis can prolong the healthy life span. Genetic background provides the potential for longevity duration induced by stress. Senesence, or aging, is generally thought to be due to a different impact of selection for alleles positive for reproduction during early life but harmful in later life, a process called antagonistic pleiotropy (multiple phenotypic changes by a single gene). After reproduction, life span is "invisible" to selection. I propose the revision that mutations selected for survival until reproduction in early life may also extend later life (protagonistic pleiotropy). The protagonist candidate genes for extended life span are hormetic response genes, which activate the protective effect in both early and later life. My revision of the earlier evolutionary theory implies that natural selection of genes critical for early survival (life span until reproduction) can also be beneficial for extended longevity in old age, tipping the evolutionary balance in favor of a latent inducible life span extension unless excess stressor challenge exceeds the protection capacity. Mimetic triggers of the stress response promise the option of tricking the induction of metabolic pathways that confer resistance to environmental challenges, increased healthy life span, rejuvenation, and disease intervention without the danger of overwhelming damage by the stressor. Public policy should anticipate an increase in healthy life span.

  2. Research status on radiation hormesis at CRIEPI

    SciTech Connect

    Hattori, Sadao

    1996-12-31

    In 1982, Thomas D. Luckey, Prof. Emeritus, University of Missouri published a paper on radiation hormesis. His emphasis was on the beneficial effects of low-level radiation contributing to a healthy body, longer life, vitalization, etc. Radiation hormesis research by the Central Research Institute of Electric Power Industry in Japan was initiated on the rationale that if Luckey`s claim were true, radiation management in Japan was extremely erroneous and the research institutes had to determine the truth. Obtaining many test results from some human data and various animal experiments on the health effects of low-level radiation that support the radiation hormesis hypothesis, the Central Research Institute decided to expand their research activities into a collaborative testing program with 14 universities and 2 other institutes on various subjects. The subjects in which they are now interested are as follows: 1. enhancement of molecular biological activities such as gene repair and apoptosis by low-level radiation; 2. enhancement of the immune system such as the ratio of Helper T cell/Suppressor T cell by low-level radiation; 3. rejuvenation such as cell membrane permeability, superoxide dismutase activity, and the therapy of old-age diseases such as diabetes and high blood pressure.

  3. Hormesis phenomena under Cd stress in a hyperaccumulator--Lonicera japonica Thunb.

    PubMed

    Jia, Lian; He, Xingyuan; Chen, Wei; Liu, Zhouli; Huang, Yanqing; Yu, Shuai

    2013-04-01

    A hydroponic experiment was carried out to investigate possible hormetic response induced by cadmium (Cd) in a potential hyperaccumulator-Lonicera japonica Thunb. The results showed that Cd at low concentrations induced a significant increase in plant growth, leaf water content and content of photosynthetic pigments in L. japonica, but decreased them at high concentrations, displayed inverted U-shaped dose response curves, confirming a typical biphasic hormetic response. The U-shaped dose response curves were displayed in malondialdehyde (MDA) and electrolyte leakage in leaves at low doses of Cd, indicating reduce oxidative stress and toxic effect. The increase of superoxide dismutase (SOD) and catalase (CAT) activities was observed along with the increased Cd concentration, indicative of increase in anti-oxidative capacity that ensures redox homeostasis is maintained. After 28 days exposure to 10 mg L(-1) Cd, stem and leaf Cd concentrations reached 502.96 ± 28.90 and 103.22 ± 5.62 mg kg(-1) DW, respectively and the plant had high bioaccumulation coefficient (BC) and translocation factor (TF'). Moreover, the maximum TF value was found at 2.5 mg L(-1) Cd treatment, implying that low Cd treatment improved the ability to transfer Cd from medium via roots to aerial structures. Taking together, L. japonica could be considered as a new plant to investigate the underlying mechanisms of hormesis and Cd tolerance. Our results suggest that hormetic effects should be taken into consideration in phytoremediation of Cd-contaminated soil.

  4. A CRITIQUE OF THE USE OF HORMESIS IN RISK ASSESSMENT

    EPA Science Inventory

    A critique of the use of hormesis in risk assessment.

    Kitchin, KT; and Drane, Wanzer

    Summary:
    There are severe problems and limitations with the use of hormesis as the principal dose-response default assumption in risk assessment. These problems and limitations i...

  5. A CRITIQUE OF THE USE OF HORMESIS IN RISK ASSESSMENT

    EPA Science Inventory

    A critique of the use of hormesis in risk assessment.

    Kitchin, KT; and Drane, Wanzer

    Summary:
    There are severe problems and limitations with the use of hormesis as the principal dose-response default assumption in risk assessment. These problems and limitations i...

  6. Can poisons stimulate bees? Appreciating the potential of hormesis in bee-pesticide research.

    PubMed

    Cutler, G Christopher; Rix, Rachel R

    2015-10-01

    Hormesis, a biphasic dose response whereby exposure to low doses of a stressor can stimulate biological processes, has been reported in many organisms, including pest insects when they are exposed to low doses of a pesticide. However, awareness of the hormesis phenomenon seems to be limited among bee researchers, in spite of the increased emphasis of late on pollinator toxicology and risk assessment. In this commentary, we show that there are several examples in the literature of substances that are toxic to bees at high doses but stimulatory at low doses. Appreciation of the hormetic dose response by bee researchers will improve our fundamental understanding of how bees respond to low doses of chemical stressors, and may be useful in pollinator risk assessment.

  7. Transgenerational Shifts in Reproduction Hormesis in Green Peach Aphid Exposed to Low Concentrations of Imidacloprid

    PubMed Central

    Ayyanath, Murali-Mohan; Cutler, G. Christopher; Scott-Dupree, Cynthia D.; Sibley, Paul K.

    2013-01-01

    Hormesis is a biphasic phenomenon that in toxicology is characterized by low-dose stimulation and high-dose inhibition. It has been observed in a wide range of organisms in response to many chemical stressors, including insects exposed to pesticides, with potential repercussions for agriculture and pest management. To address questions related to the nature of the dose-response and potential consequences on biological fitness, we examined transgenerational hormesis in the green peach aphid, Myzus persicae, when exposed to sublethal concentrations of the insecticide imidacloprid. A hormetic response in the form of increased reproduction was consistently observed and a model previously developed to test for hormesis adequately fit some of our data. However, the nature of the dose-response differed within and across generations depending upon the duration and mode of exposure. Decreased reproduction in intermediate generations confirmed that fitness tradeoffs were a consequence of the hormetic response. However, recovery to levels of reproduction equal to that of controls in subsequent generations and significantly greater total reproduction after four generations suggested that biological fitness was increased by exposure to low concentrations of the insecticide, even when insects were continuously exposed to the stressor. This was especially evident in a greenhouse experiment where the instantaneous rate of population increase almost doubled and total aphid production more than quadrupled when aphids were exposed to potato plants systemically treated with low amounts of imidacloprid. Our results show that although fitness tradeoffs do occur with hormetic responses, this does not necessarily compromise overall biological fitness. PMID:24040272

  8. Transgenerational shifts in reproduction hormesis in green peach aphid exposed to low concentrations of imidacloprid.

    PubMed

    Ayyanath, Murali-Mohan; Cutler, G Christopher; Scott-Dupree, Cynthia D; Sibley, Paul K

    2013-01-01

    Hormesis is a biphasic phenomenon that in toxicology is characterized by low-dose stimulation and high-dose inhibition. It has been observed in a wide range of organisms in response to many chemical stressors, including insects exposed to pesticides, with potential repercussions for agriculture and pest management. To address questions related to the nature of the dose-response and potential consequences on biological fitness, we examined transgenerational hormesis in the green peach aphid, Myzus persicae, when exposed to sublethal concentrations of the insecticide imidacloprid. A hormetic response in the form of increased reproduction was consistently observed and a model previously developed to test for hormesis adequately fit some of our data. However, the nature of the dose-response differed within and across generations depending upon the duration and mode of exposure. Decreased reproduction in intermediate generations confirmed that fitness tradeoffs were a consequence of the hormetic response. However, recovery to levels of reproduction equal to that of controls in subsequent generations and significantly greater total reproduction after four generations suggested that biological fitness was increased by exposure to low concentrations of the insecticide, even when insects were continuously exposed to the stressor. This was especially evident in a greenhouse experiment where the instantaneous rate of population increase almost doubled and total aphid production more than quadrupled when aphids were exposed to potato plants systemically treated with low amounts of imidacloprid. Our results show that although fitness tradeoffs do occur with hormetic responses, this does not necessarily compromise overall biological fitness.

  9. Hormesis and the Salk Polio Vaccine

    PubMed Central

    Calabrese, Edward J.

    2011-01-01

    The production of the Salk vaccine polio virus by monkey kidney cells was generated using the synthetic tissue culture medium, Mixture 199. In this paper’s retrospective assessment of this process, it was discovered that Mixture 199 was modified by the addition of ethanol to optimize animal cell survival based on experimentation that revealed a hormetic-like biphasic response relationship. This hormesis-based optimization procedure was then applied to all uses of Mixture 199 and modifications of it, including its application to the Salk polio vaccine during preliminary testing and in its subsequent major societal treatment programs. PMID:22423232

  10. A Perspective on the Scientific, Philosophical, and Policy Dimensions of Hormesis

    PubMed Central

    Hoffmann, George R.

    2009-01-01

    The hormesis concept has broad implications for biology and the biomedical sciences. This perspective on hormesis concentrates on toxicology and toxicological risk assessment and secondarily explores observations from other fields. It considers the varied manifestations of hormesis in the context of a broad family of biological stress responses. Evidence for hormesis is reviewed, and the hormesis model is contrasted with more widely accepted dose-response models in toxicology: a linear nonthreshold (LNT) model for mutagenesis and carcinogenesis, and a threshold model for most other toxicologic effects. Scientific, philosophical, and political objections to the hormesis concept are explored, and complications in the hormesis concept are analyzed. The review concludes with a perspective on the current state of hormesis and challenges that the hormesis model poses for risk assessment. PMID:19343115

  11. Hormesis-based anti-aging products: a case study of a novel cosmetic.

    PubMed

    Rattan, Suresh I S; Kryzch, Valérie; Schnebert, Sylvianne; Perrier, Eric; Nizard, Carine

    2013-01-01

    Application of hormesis in aging research and interventions is becoming increasingly attractive and successful. The reason for this is the realization that mild stress-induced activation of one or more stress response (SR) pathways, and its consequent stimulation of repair mechanisms, is effective in reducing the age-related accumulation of molecular damage. For example, repeated heat stress-induced synthesis of heat shock proteins has been shown to have a variety of anti-aging effects on growth and other cellular and biochemical characteristics of normal human skin fibroblasts, keratinocytes and endothelial cells undergoing aging in vitro. Therefore, searching for potential hormetins - conditions and compounds eliciting SR-mediated hormesis - is drawing attention of not only the researchers but also the industry involved in developing healthcare products, including nutriceuticals, functional foods and cosmeceuticals. Here we present the example of a skin care cosmetic as one of the first successful product developments incorporating the ideas of hormesis. This was based on the studies to analyse the molecular effects of active ingredients extracted from the roots of the Chinese herb Sanchi (Panax notoginseng) on gene expression at the level of mRNAs and proteins in human skin cells. The results showed that the ginsenosides extracted from Sanchi induced the transcription of stress genes and increased the synthesis of stress proteins, especially the heat shock protein HSP1A1 or Hsp70, in normal human keratinocytes and dermal fibroblasts. Furthermore, this extract also has significant positive effects against facial wrinkles and other symptoms of facial skin aging as tested clinically, which may be due to its hormetic mode of action by stress-induced synthesis of chaperones involved in protein repair and removal of abnormal proteins. Acceptance of such a hormesis-based product by the wider public could be instrumental in the social recognition of the concept of

  12. Hormesis-Based Anti-Aging Products: A Case Study of a Novel Cosmetic

    PubMed Central

    Rattan, Suresh I. S.; Kryzch, Valérie; Schnebert, Sylvianne; Perrier, Eric; Nizard, Carine

    2013-01-01

    Application of hormesis in aging research and interventions is becoming increasingly attractive and successful. The reason for this is the realization that mild stress-induced activation of one or more stress response (SR) pathways, and its consequent stimulation of repair mechanisms, is effective in reducing the age-related accumulation of molecular damage. For example, repeated heat stress-induced synthesis of heat shock proteins has been shown to have a variety of anti-aging effects on growth and other cellular and biochemical characteristics of normal human skin fibroblasts, keratinocytes and endothelial cells undergoing aging in vitro. Therefore, searching for potential hormetins – conditions and compounds eliciting SR-mediated hormesis – is drawing attention of not only the researchers but also the industry involved in developing healthcare products, including nutriceuticals, functional foods and cosmeceuticals. Here we present the example of a skin care cosmetic as one of the first successful product developments incorporating the ideas of hormesis. This was based on the studies to analyse the molecular effects of active ingredients extracted from the roots of the Chinese herb Sanchi (Panax notoginseng) on gene expression at the level of mRNAs and proteins in human skin cells. The results showed that the ginsenosides extracted from Sanchi induced the transcription of stress genes and increased the synthesis of stress proteins, especially the heat shock protein HSP1A1 or Hsp70, in normal human keratinocytes and dermal fibroblasts. Furthermore, this extract also has significant positive effects against facial wrinkles and other symptoms of facial skin aging as tested clinically, which may be due to its hormetic mode of action by stress-induced synthesis of chaperones involved in protein repair and removal of abnormal proteins. Acceptance of such a hormesis-based product by the wider public could be instrumental in the social recognition of the concept of

  13. Hormesis for fine particulate matter (PM 2.5).

    PubMed

    Cox, Louis Anthony Tony

    2012-01-01

    The hypothesis of hormesis - that substances that harm health at high exposures can reduce risks below background at low exposures, e.g., if they activate defenses without overwhelming them - becomes important for practical policy making if it holds for regulated substances. Recently, the U.S. EPA concluded that reductions in ambient concentrations of fine particulate matter (PM2.5) in air caused trillions of dollars worth of human health benefits for a compliance cost of only about $65 billion per year. This conclusion depends on an unverified assumption of a positive, causal, straight-line relation between PM2.5 concentrations and mortality risks. We review empirical data on PM2.5 and mortality risks (and their precursors, inflammatory responses) and conclude that the PM2.5 concentration-response relation may be J-shaped, rather than linear. This possibility implies that the 1990 Clean Air Act Amendment may well have produced no (or negative) human health benefits, rather than the trillions of dollars worth of reduced mortalities ascribed to it by EPA; and that attempts to achieve further risk-reduction benefits by further reducing PM2.5 concentrations may be counterproductive. This creates a very high value for scientific information that better reveals the true shape of the PM2.5 concentration-response function at and below current ambient levels.

  14. Hormesis for Fine Particulate Matter (PM 2.5)

    PubMed Central

    Cox, Louis Anthony (Tony)

    2012-01-01

    The hypothesis of hormesis – that substances that harm health at high exposures can reduce risks below background at low exposures, e.g., if they activate defenses without overwhelming them – becomes important for practical policy making if it holds for regulated substances. Recently, the U.S. EPA concluded that reductions in ambient concentrations of fine particulate matter (PM2.5) in air caused trillions of dollars worth of human health benefits for a compliance cost of only about $65 billion per year. This conclusion depends on an unverified assumption of a positive, causal, straight-line relation between PM2.5 concentrations and mortality risks. We review empirical data on PM2.5 and mortality risks (and their precursors, inflammatory responses) and conclude that the PM2.5 concentration-response relation may be J-shaped, rather than linear. This possibility implies that the 1990 Clean Air Act Amendment may well have produced no (or negative) human health benefits, rather than the trillions of dollars worth of reduced mortalities ascribed to it by EPA; and that attempts to achieve further risk-reduction benefits by further reducing PM2.5 concentrations may be counterproductive. This creates a very high value for scientific information that better reveals the true shape of the PM2.5 concentration-response function at and below current ambient levels. PMID:22740783

  15. Insects, Insecticides and Hormesis: Evidence and Considerations for Study

    PubMed Central

    Cutler, G. Christopher

    2013-01-01

    Insects are ubiquitous, crucial components of almost all terrestrial and fresh water ecosystems. In agricultural settings they are subjected to, intentionally or unintentionally, an array of synthetic pesticides and other chemical stressors. These ecological underpinnings, the amenability of insects to laboratory and field experiments, and our strong knowledgebase in insecticide toxicology, make the insect-insecticide model an excellent one to study many questions surrounding hormesis. Moreover, there is practical importance for agriculture with evidence of pest population growth being accelerated by insecticide hormesis. Nevertheless, insects have been underutilized in studies of hormesis. Where hormesis hypotheses have been tested, results clearly demonstrate stimulatory effects on multiple taxa as measured through several biological endpoints, both at individual and population levels. However, many basic questions are outstanding given the myriad of chemicals, responses, and ecological interactions that are likely to occur. PMID:23930099

  16. Radiation Hormesis: The Good, the Bad, and the Ugly

    PubMed Central

    Luckey, T.D.

    2006-01-01

    Three aspects of hormesis with low doses of ionizing radiation are presented: the good, the bad, and the ugly. The good is acceptance by France, Japan, and China of the thousands of studies showing stimulation and/or benefit, with no harm, from low dose irradiation. This includes thousands of people who live in good health with high background radiation. The bad is the nonacceptance of radiation hormesis by the U. S. and most other governments; their linear no threshold (LNT) concept promulgates fear of all radiation and produces laws which have no basis in mammalian physiology. The LNT concept leads to poor health, unreasonable medicine and oppressed industries. The ugly is decades of deception by medical and radiation committees which refuse to consider valid evidence of radiation hormesis in cancer, other diseases, and health. Specific examples are provided for the good, the bad, and the ugly in radiation hormesis. PMID:18648595

  17. Hormesis in Aging and Neurodegeneration—A Prodigy Awaiting Dissection

    PubMed Central

    Mao, Lei; Franke, Jacqueline

    2013-01-01

    Hormesis describes the drug action of low dose stimulation and high dose inhibition. The hormesis phenomenon has been observed in a wide range of biological systems. Although known in its descriptive context, the underlying mode-of-action of hormesis is largely unexplored. Recently, the hormesis concept has been receiving increasing attention in the field of aging research. It has been proposed that within a certain concentration window, reactive oxygen species (ROS) or reactive nitrogen species (RNS) could act as major mediators of anti-aging and neuroprotective processes. Such hormetic phenomena could have potential therapeutic applications, if properly employed. Here, we review the current theories of hormetic phenomena in regard to aging and neurodegeneration, with the focus on its underlying mechanism. Facilitated by a simple mathematical model, we show for the first time that ROS-mediated hormesis can be explained by the addition of different biomolecular reactions including oxidative damage, MAPK signaling and autophagy stimulation. Due to their divergent scales, the optimal hormetic window is sensitive to each kinetic parameter, which may vary between individuals. Therefore, therapeutic utilization of hormesis requires quantitative characterizations in order to access the optimal hormetic window for each individual. This calls for a personalized medicine approach for a longer human healthspan. PMID:23799363

  18. Radiation hormesis: the demise of a legitimate hypothesis.

    PubMed

    Calabrese, E J; Baldwin, L A

    2000-01-01

    This paper examines the underlying factors that contributed to the marginalization of radiation hormesis in the early and middle decades of the 20th century. The most critical factor affecting the demise of radiation hormesis was a lack of agreement over how to define the concept of hormesis and quantitatively describe its dose-response features. If radiation hormesis had been defined as a modest overcompensation to a disruption in homeostasis as would have been consistent with the prevailing notion in the area of chemical hormesis, this would have provided the theoretical and practical means to blunt subsequent legitimate criticism of this hypothesis. A second critical factor undermining the radiation hormesis hypothesis was the generally total lack of recognition by radiation scientists of the concept of chemical hormesis which was markedly more advanced, substantiated and generalized than in the radiation domain. The third factor was that major scientific criticism of low dose stimulatory responses was galvanized at the time that the National Research Council (NRC) was organizing a national research agenda on radiation and the hormetic hypothesis was generally excluded from the future planned research opportunities. Furthermore, the criticisms of the leading scientists of the 1930s which undermined the concept of radiation hormesis were limited in scope and highly flawed and then perpetuated over the decades by other 'prestigious' experts who appeared to simply accept the earlier reports. This setting was then linked to a growing fear of radiation as a cause of birth defects, mutation and cancer, factors all reinforced by later concerns over the atomic bomb. Strongly supportive findings on hormetic effects in the 1940s by Soviet scientists were either generally not available to US scientists or disregarded as part of the Cold War mindset without adequate analysis. Finally, a massive, but poorly designed, US Department of Agriculture experiment in the late 1940s

  19. Hormesis: Decoding Two Sides of the Same Coin

    PubMed Central

    Bhakta-Guha, Dipita; Efferth, Thomas

    2015-01-01

    In the paradigm of drug administration, determining the correct dosage of a therapeutic is often a challenge. Several drugs have been noted to demonstrate contradictory effects per se at high and low doses. This duality in function of a drug at different concentrations is known as hormesis. Therefore, it becomes necessary to study these biphasic functions in order to understand the mechanistic basis of their effects. In this article, we focus on different molecules and pathways associated with diseases that possess a duality in their function and thus prove to be the seat of hormesis. In particular, we have highlighted the pathways and factors involved in the progression of cancer and how the biphasic behavior of the molecules involved can alter the manifestations of cancer. Because of the pragmatic role that it exhibits, the imminent need is to draw attention to the concept of hormesis. Herein, we also discuss different stressors that trigger hormesis and how stress-mediated responses increase the overall adaptive response of an individual to stress stimulus. We talk about common pathways through which cancer progresses (such as nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 (Nrf2-Keap1), sirtuin-forkhead box O (SIRT-FOXO) and others), analyzing how diverse molecules associated with these pathways conform to hormesis. PMID:26694419

  20. Herbicide phosphinothricin causes direct stimulation hormesis.

    PubMed

    Dragićević, Milan; Platiša, Jelena; Nikolić, Radomirka; Todorović, Slađana; Bogdanović, Milica; Mitić, Nevena; Simonović, Ana

    2012-01-01

    Herbicide phosphinothricin (PPT) inhibits glutamine synthetase (GS), a key enzyme in nitrogen assimilation, thus causing ammonia accumulation, glutamine depletion and eventually plant death. However, the growth response of Lotus corniculatus L. plants immersed in solutions with a broad range of PPT concentrations is biphasic, with pronounced stimulating effect on biomass production at concentrations ≤ 50 μM and growth inhibition at higher concentrations. The growth stimulation at low PPT concentrations is a result of activation of chloroplastic isoform GS2, while the growth suppression is caused by inhibition of both cytosolic GS1 and GS2 at higher PPT concentrations. Since the results are obtained in cell-free system (e.g. protein extracts), to which the principles of homeostasis are not applicable, this PPT effect is an unambiguous example of direct stimulation hormesis. A detailed molecular mechanism of concentration-dependent interaction of both PPT and a related GS inhibitor, methionine sulfoximine, with GS holoenzymes is proposed. The mechanism is in concurrence with all experimental and literature data.

  1. Herbicide Phosphinothricin Causes Direct Stimulation Hormesis

    PubMed Central

    Dragićević, Milan; Platiša, Jelena; Nikolić, Radomirka; Todorović, Slađana; Bogdanović, Milica; Mitić, Nevena; Simonović, Ana

    2013-01-01

    Herbicide phosphinothricin (PPT) inhibits glutamine synthetase (GS), a key enzyme in nitrogen assimilation, thus causing ammonia accumulation, glutamine depletion and eventually plant death. However, the growth response of Lotus corniculatus L. plants immersed in solutions with a broad range of PPT concentrations is biphasic, with pronounced stimulating effect on biomass production at concentrations ≤ 50 μM and growth inhibition at higher concentrations. The growth stimulation at low PPT concentrations is a result of activation of chloroplastic isoform GS2, while the growth suppression is caused by inhibition of both cytosolic GS1 and GS2 at higher PPT concentrations. Since the results are obtained in cell-free system (e.g. protein extracts), to which the principles of homeostasis are not applicable, this PPT effect is an unambiguous example of direct stimulation hormesis. A detailed molecular mechanism of concentration-dependent interaction of both PPT and a related GS inhibitor, methionine sulfoximine, with GS holoenzymes is proposed. The mechanism is in concurrence with all experimental and literature data. PMID:23983663

  2. Defining hormesis: evaluation of a complex concentration response phenomenon.

    PubMed

    Kendig, Eric L; Le, Hoa H; Belcher, Scott M

    2010-01-01

    Hormesis describes dose-response relationships characterized by a reversal of response between low and high doses of chemicals, biological molecules, physical stressors, or other initiators of a response. Acceptance of hormesis as a viable dose-response theory has been limited until recently, in part, because of poor conceptual understanding, ad hoc and inappropriate use, and lack of a defined mechanism. By examining the history of this dose-response theory, it is clear that both pharmacological and toxicological studies provide evidence for hormetic dose responses, but retrospective examination of studies can be problematic at best. Limited scientific evidence and lack of a common lexicon with which to describe these responses have left hormesis open to inappropriate application to unrelated dose-response relationships. Future studies should examine low-dose effects using unbiased, descriptive criteria to further the scientific understanding of this dose response. A clear, concise definition is required to further the limited scientific evidence for hormetic dose responses.

  3. Linear No-Threshold Model VS. Radiation Hormesis

    PubMed Central

    Doss, Mohan

    2013-01-01

    The atomic bomb survivor cancer mortality data have been used in the past to justify the use of the linear no-threshold (LNT) model for estimating the carcinogenic effects of low dose radiation. An analysis of the recently updated atomic bomb survivor cancer mortality dose-response data shows that the data no longer support the LNT model but are consistent with a radiation hormesis model when a correction is applied for a likely bias in the baseline cancer mortality rate. If the validity of the phenomenon of radiation hormesis is confirmed in prospective human pilot studies, and is applied to the wider population, it could result in a considerable reduction in cancers. The idea of using radiation hormesis to prevent cancers was proposed more than three decades ago, but was never investigated in humans to determine its validity because of the dominance of the LNT model and the consequent carcinogenic concerns regarding low dose radiation. Since cancer continues to be a major health problem and the age-adjusted cancer mortality rates have declined by only ∼10% in the past 45 years, it may be prudent to investigate radiation hormesis as an alternative approach to reduce cancers. Prompt action is urged. PMID:24298226

  4. The occurrence of hormesis in plants and algae.

    PubMed

    Cedergreen, Nina; Streibig, Jens C; Kudsk, Per; Mathiassen, Solvejg K; Duke, Stephen O

    2006-10-17

    This paper evaluated the frequency, magnitude and dose/concentration range of hormesis in four species: The aquatic plant Lemna minor, the micro-alga Pseudokirchneriella subcapitata and the two terrestrial plants Tripleurospermum inodorum and Stellaria media exposed to nine herbicides and one fungicide and binary mixtures thereof. In total 687 dose-response curves were included in the database. The study showed that both the frequency and the magnitude of the hormetic response depended on the endpoint being measured. Dry weight at harvest showed a higher frequency and a larger hormetic response compared to relative growth rates. Evaluating hormesis for relative growth rates for all species showed that 25% to 76% of the curves for each species had treatments above 105% of the control. Fitting the data with a dose-response model including a parameter for hormesis showed that the average growth increase ranged from 9+/-1% to 16+/-16% of the control growth rate, while if measured on a dry weight basis the response increase was 38+/-13% and 43+/-23% for the two terrestrial species. Hormesis was found in >70% of the curves with the herbicides glyphosate and metsulfuron-methyl, and in >50% of the curves for acifluorfen and terbuthylazine. The concentration ranges of the hormetic part of the dose-response curves corresponded well with literature values.

  5. The Synthetic Elicitor 2-(5-Bromo-2-Hydroxy-Phenyl)-Thiazolidine-4-Carboxylic Acid Links Plant Immunity to Hormesis.

    PubMed

    Rodriguez-Salus, Melinda; Bektas, Yasemin; Schroeder, Mercedes; Knoth, Colleen; Vu, Trang; Roberts, Philip; Kaloshian, Isgouhi; Eulgem, Thomas

    2016-01-01

    Synthetic elicitors are drug-like compounds that induce plant immune responses but are structurally distinct from natural defense elicitors. Using high-throughput screening, we previously identified 114 synthetic elicitors that activate the expression of a pathogen-responsive reporter gene in Arabidopsis (Arabidopsis thaliana). Here, we report on the characterization of one of these compounds, 2-(5-bromo-2-hydroxy-phenyl)-thiazolidine-4-carboxylic acid (BHTC). BHTC induces disease resistance of plants against bacterial, oomycete, and fungal pathogens and has a unique mode of action and structure. Surprisingly, we found that low doses of BHTC enhanced root growth in Arabidopsis, while high doses of this compound inhibited root growth, besides inducing defense. These effects are reminiscent of the hormetic response, which is characterized by low-dose stimulatory effects of a wide range of agents that are toxic or inhibitory at higher doses. Like its effects on defense, BHTC-induced hormesis in Arabidopsis roots is partially dependent on the WRKY70 transcription factor. Interestingly, BHTC-induced root hormesis is also affected in the auxin-response mutants axr1-3 and slr-1. By messenger RNA sequencing, we uncovered a dramatic difference between transcriptional profiles triggered by low and high doses of BHTC. Only high levels of BHTC induce typical defense-related transcriptional changes. Instead, low BHTC levels trigger a coordinated intercompartmental transcriptional response manifested in the suppression of photosynthesis- and respiration-related genes in the nucleus, chloroplasts, and mitochondria as well as the induction of development-related nuclear genes. Taken together, our functional characterization of BHTC links defense regulation to hormesis and provides a hypothetical transcriptional scenario for the induction of hormetic root growth.

  6. Effect of low-dose ionizing radiation on luminous marine bacteria: radiation hormesis and toxicity.

    PubMed

    Kudryasheva, N S; Rozhko, T V

    2015-04-01

    The paper summarizes studies of effects of alpha- and beta-emitting radionuclides (americium-241, uranium-235+238, and tritium) on marine microorganisms under conditions of chronic low-dose irradiation in aqueous media. Luminous marine bacteria were chosen as an example of these microorganisms; bioluminescent intensity was used as a tested physiological parameter. Non-linear dose-effect dependence was demonstrated. Three successive stages in the bioluminescent response to americium-241 and tritium were found: 1--absence of effects (stress recognition), 2--activation (adaptive response), and 3--inhibition (suppression of physiological function, i.e. radiation toxicity). The effects were attributed to radiation hormesis phenomenon. Biological role of reactive oxygen species, secondary products of the radioactive decay, is discussed. The study suggests an approach to evaluation of non-toxic and toxic stages under conditions of chronic radioactive exposure.

  7. Stress biology and hormesis: the Yerkes-Dodson law in psychology--a special case of the hormesis dose response.

    PubMed

    Calabrese, Edward J

    2008-01-01

    This article traces the historical foundations of the Yerkes-Dodson Law from its experimental foundations in the first decade of the 20th century, to its recognition as a generalizable phenomenon in multiple species including humans and to more current attempts to understand its molecular basis within the framework of stress-related biological processes. Within this context, the biological and dose-response characteristics of the Yerkes-Dodson Law are evaluated and compared to the hormesis dose-response model. Based on this evaluation, which includes study design analysis, statistical models of multiple factor/chemical interaction, and a comparative assessment of the quantitative features of these respective dose-response relationships and their molecular foundations, the Yerkes-Dodson Law is shown to represent a special case of the general concept of hormesis illustrating the interaction of two independent study variables, which has typically been observed to be an additive response, although not theoretically restricted to one. The conceptual integration of the Yerkes-Dodson Law within the hormetic dose response framework adds further support for the generalization of the hormesis concept.

  8. Low doses of glyphosate change the response of soybean to later glyphosate exposures

    USDA-ARS?s Scientific Manuscript database

    The stimulatory effect of low doses of toxic substances is known as hormesis. Many herbicides that cause severe injury to plants at recommended rates, promote growth or have other stimulatory effects at very low doses. The objective of this study was to evaluate glyphosate-induced hormesis in soyb...

  9. The hormesis effect of plasma-elevated intracellular ROS on HaCaT cells

    NASA Astrophysics Data System (ADS)

    Szili, Endre J.; Harding, Frances J.; Hong, Sung-Ha; Herrmann, Franziska; Voelcker, Nicolas H.; Short, Robert D.

    2015-12-01

    We have examined the link between ionized-gas plasma delivery of reactive oxygen species (ROS) to immortalized keratinocyte (HaCaT) cells and cell fate, defined in terms of cell viability versus death. Phospholipid vesicles were used as cell mimics to measure the possible intracellular ROS concentration, [ROSi], delivered by various plasma treatments. Cells were exposed to a helium cold atmospheric plasma (CAP) jet for different plasma exposure times (5-60 s) and gas flow rates (50-1000 ml min-1). Based upon the [ROSi] data we argue that plasma-generated ROS in the cell culture medium can readily diffuse into real cells. Plasma exposure that equated to an [ROSi] in the range of 3.81  ×  10-10-9.47  ×  10-8 M, measured at 1 h after the plasma exposure, resulted in increased cell viability at 72 h; whereas a higher [ROSi] at 1 h decreased cell viability after 72 h of culture. This may be because of the manner in which the ROS are delivered by the plasma: HaCaT cells better tolerate a low ROS flux over an extended plasma exposure period of 1 min, compared to a high flux delivered in a few seconds, although the final [ROSi] may be the same. Our results suggest that plasma stimulation of HaCaT cells follows the principle of hormesis.

  10. Hormesis and adaptive cellular control systems

    EPA Science Inventory

    Hormetic dose response occurs for many endpoints associated with exposures of biological organisms to environmental stressors. Cell-based U- or inverted U-shaped responses may derive from common processes involved in activation of adaptive responses required to protect cells from...

  11. Hormesis and adaptive cellular control systems

    EPA Science Inventory

    Hormetic dose response occurs for many endpoints associated with exposures of biological organisms to environmental stressors. Cell-based U- or inverted U-shaped responses may derive from common processes involved in activation of adaptive responses required to protect cells from...

  12. Awareness of Hormesis Will Enhance Future Research in Basic and Applied Neuroscience

    PubMed Central

    Mattson, Mark P.

    2008-01-01

    Hormesis is defined operationally as responses of cells or organisms to an exogenous or intrinsic factor (chemical, temperature, psychological challenge, etc.) in which the factor induces stimulatory or beneficial effects at low doses and inhibitory or adverse effects at high doses. The compendium of articles by Calabrese entitled “Neuroscience and Hormesis” provides a broad range of examples of neurobiological processes and responses to environmental factors that exhibit biphasic dose responses, the signature of hormesis. Nerve cell networks are the “first responders” to environmental challenges—they perceive the challenge and orchestrate coordinated adaptive responses that typically involve autonomic, neuroendocrine, and behavioral changes. In addition to direct adaptive responses of neurons to environmental stressors, cells subjected to a stressor produce and release molecules such as growth factors, cytokines, and hormones that alert adjacent and even distant cells to impending danger. The discoveries that some molecules (e.g., carbon monoxide and nitric oxide) and elements (e.g., selenium and iron) that are toxic at high doses play fundamental roles in cellular signaling or metabolism suggest that during evolution, organisms (and their nervous systems) co-opted environmental toxins and used them to their advantage. Neurons also respond adaptively to everyday stressors, including physical exercise, cognitive challenges, and dietary energy restriction, each of which activates pathways linked to the production of neurotrophic factors and cellular stress resistance proteins. The development of interventions that activate hormetic signaling pathways in neurons is a promising new approach for the preventation and treatment of a range of neurological disorders. PMID:18709572

  13. A meta-analysis of evidence for hormesis in animal radiation carcinogenesis, including a discussion of potential pitfalls in statistical analyses to detect hormesis.

    PubMed

    Crump, Kenny S; Duport, Philippe; Jiang, Huixia; Shilnikova, Natalia S; Krewski, Daniel; Zielinski, Jan M

    2012-01-01

    A database containing 800 datasets on the incidence of specific tumor types from 262 radiation carcinogenicity experiments identified in a comprehensive literature search through September 2000 was analyzed for evidence of hormesis. This database includes lifetime studies of tumorigenic responses in mice, rats, and dogs to exposures to alpha, beta, gamma, neutron, or x-ray radiation. A J-shaped dose response, in the form of a significant decreased response at some low dose followed by a significant increased response at a higher dose, was found in only four datasets from three experiments. Three of these datasets involved the same control animals and two also shared dosed animals; the J shape in the fourth dataset appeared to be the result of an outlier within an otherwise monotonic dose response. A meta-analysis was conducted to determine whether there was an excess of dose groups with decreases in tumor response below that in controls at doses below no-observed-effect levels (NOELs) in individual datasets. Because the probability of a decreased response is generally not equal to the probability of an increased response even in the null case, the meta-analysis focused on comparing the number of statistically significant diminished responses to the number expected, assuming no dose effect below the NOEL. Only 54 dose groups out of the total of 2579 in the database had doses below the dataset-specific NOEL and that satisfied an a priori criterion for sufficient power to detect a reduced response. Among these 54, a liberal criterion for defining a significant decreases identified 15 such decreases, versus 54 × 0.2 = 10.8 expected. The excess in significant reductions was accounted for almost entirely by the excess from neutron experiments (10 observed, 6.2 expected). Nine of these 10 dose groups involved only 2 distinct control groups, and 2 pairs from the 10 even shared dosed animals. Given this high degree of overlap, this small excess did not appear remarkable

  14. Selective toxin effects on faster and slower growing individuals in the formation of hormesis at the population level - A case study with Lactuca sativa and PCIB.

    PubMed

    Belz, Regina G; Sinkkonen, Aki

    2016-10-01

    Natural plant populations have large phenotypic plasticity that enhances acclimation to local stress factors such as toxin exposures. While consequences of high toxin exposures are well addressed, effects of low-dose toxin exposures on plant populations are seldom investigated. In particular, the importance of 'selective low-dose toxicity' and hormesis, i.e. stimulatory effects, has not been studied simultaneously. Since selective toxicity can change the size distribution of populations, we assumed that hormesis alters the size distribution at the population level, and investigated whether and how these two low-dose phenomena coexist. The study was conducted with Lactuca sativa L. exposed to the auxin-inhibitor 2-(p-chlorophenoxy)-2-methylpropionic acid (PCIB) in vitro. In two separate experiments, L. sativa was exposed to 12 PCIB doses in 24 replicates (50 plants/replicate). Shoot/root growth responses at the population level were compared to the fast-growing (≥90% percentile) and the slow-growing subpopulations (≤10% percentile) by Mann-Whitney U testing and dose-response modelling. In the formation of pronounced PCIB hormesis at the population level, low-dose effects proved selective, but widely stimulatory which seems to counteract low-dose selective toxicity. The selectivity of hormesis was dose- and growth rate-dependent. Stimulation occurred at lower concentrations and stimulation percentage was higher among slow-growing individuals, but partly or entirely masked at the population level by moderate or negligible stimulation among the faster growing individuals. We conclude that the hormetic effect up to the maximum stimulation may be primarily facilitated by an increase in size of the most slow-growing individuals, while thereafter it seems that mainly the fast-growing individuals contributed to the observed hormesis at the population level. As size distribution within a population is related to survival, our study hints that selective effects on slow

  15. Biphasic toxicodynamic features of some antimicrobial agents on microbial growth: a dynamic mathematical model and its implications on hormesis

    PubMed Central

    2010-01-01

    Background In the present work, we describe a group of anomalous dose-response (DR) profiles and develop a dynamic model that is able to explain them. Responses were obtained from conventional assays of three antimicrobial agents (nisin, pediocin and phenol) against two microorganisms (Carnobacterium piscicola and Leuconostoc mesenteroides). Results Some of these anomalous profiles show biphasic trends which are usually attributed to hormetic responses. But they can also be explained as the result of the time-course of the response from a microbial population with a bimodal distribution of sensitivity to an effector, and there is evidence suggesting this last origin. In light of interest in the hormetic phenomenology and the possibility of confusing it with other phenomena, especially in the bioassay of complex materials we try to define some criteria which allow us to distinguish between sensu stricto hormesis and biphasic responses due to other causes. Finally, we discuss some problems concerning the metric of the dose in connection with the exposure time, and we make a cautionary suggestion about the use of bacteriocins as antimicrobial agents. Conclusions The mathematical model proposed, which combines the basis of DR theory with microbial growth kinetics, can generate and explain all types of anomalous experimental profiles. These profiles could also be described in a simpler way by means of bisigmoidal equations. Such equations could be successfully used in a microbiology and toxicology context to discriminate between hormesis and other biphasic phenomena. PMID:20723220

  16. Biphasic toxicodynamic features of some antimicrobial agents on microbial growth: a dynamic mathematical model and its implications on hormesis.

    PubMed

    Murado, Miguel A; Vázquez, José A

    2010-08-19

    In the present work, we describe a group of anomalous dose-response (DR) profiles and develop a dynamic model that is able to explain them. Responses were obtained from conventional assays of three antimicrobial agents (nisin, pediocin and phenol) against two microorganisms (Carnobacterium piscicola and Leuconostoc mesenteroides). Some of these anomalous profiles show biphasic trends which are usually attributed to hormetic responses. But they can also be explained as the result of the time-course of the response from a microbial population with a bimodal distribution of sensitivity to an effector, and there is evidence suggesting this last origin. In light of interest in the hormetic phenomenology and the possibility of confusing it with other phenomena, especially in the bioassay of complex materials we try to define some criteria which allow us to distinguish between sensu stricto hormesis and biphasic responses due to other causes. Finally, we discuss some problems concerning the metric of the dose in connection with the exposure time, and we make a cautionary suggestion about the use of bacteriocins as antimicrobial agents. The mathematical model proposed, which combines the basis of DR theory with microbial growth kinetics, can generate and explain all types of anomalous experimental profiles. These profiles could also be described in a simpler way by means of bisigmoidal equations. Such equations could be successfully used in a microbiology and toxicology context to discriminate between hormesis and other biphasic phenomena.

  17. Hormesis effects and implicative application in assessment of lead-contaminated soils in roots of Vicia faba seedlings.

    PubMed

    Wang, Cheng-Run; Tian, Yuan; Wang, Xiao-Rong; Yu, Hong-Xia; Lu, Xian-Wen; Wang, Chen; Wang, Hao

    2010-08-01

    Chemical analyses and biological methods were combined to investigate oxidative stress, hormesis effect and concerned mechanism in roots of Viciafaba seedlings grown in 0-2000 mg kg(-1) of Pb-treated soils after germination of 20d. The results showed that U-shaped dose response curves were displayed in superoxide radical (O2-) radicals, guaiacol peroxidase (POD) and ascorbate peroxidase (APX) activities, malondialdehyde (MDA) and carbonyl groups as well as activities of endoproteinase (EP) isoenzymes in the roots at low doses of extraneous Pb, indicating reduced oxidative stress and toxic effect. The inverted U-shaped curves were also exhibited in growth height, superoxide dismutase (SOD) and EP activities as well as inducible heat shock protein70 (HSP70) with the increasing extraneous Pb, indicative of enhanced oxidative stress. The enhancement in HSP70, carbonyl groups and EP activities confirmed intracellular proteotoxicity and proteolytic activity in the roots at higher doses of soil Pb. More interestingly, levels of inducible HSP70 were well correlated with those of growth heights (r=0.809, p<0.05), implying that HSP70 induction may be one of the mechanisms underlying the U-shaped growth curve of V. faba seedlings in the experiment. The results suggest that traditional threshold models ought to be combined with hormesis effect in assessment of Pb-polluted soils and the threshold dose range of Pb-treated soils is proposed rudimentally as 25-125 mg kg(-1). Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  18. Stress and fish reproduction: The roles of allostasis and hormesis

    USGS Publications Warehouse

    Schreck, C.B.

    2010-01-01

    This paper is a review of the effects of stress on reproduction in fishes. I hope to further the development of the concepts of allostasis and hormesis as relevant to understanding reproduction in general and in fish in particular. The main contentions I derive in this review are the following: Stressors affect fish reproduction in a variety of ways depending on the nature and severity of the stressor. The effects are transduced through a hormonal cascade initiated by perception of the stressor and involving the hypothalamus-pituitary-interrenal axis, the catecholamines, and also cytokines. Mounting a stress response and resisting a stressor is an energetically costly process, including costs associated with allostasis, attempting to reset homeostatic norms. Responses in emergency situations (e.g., being chased by a predator or a net) can be different from those where fish can cope (e.g., being in a more crowded environment) with a stressor, but both situations involve energy re-budgeting. Emergency responses happen in concert with the onset of energy limitations (e.g., the fish may not eat), while coping with allostatic overload can happen in a more energy-rich environment (e.g., the fish can continue to eat). Low levels of stress may have a positive effect on reproductive processes while greater stress has negative effects on fish reproduction. The concept of hormesis is a useful way to think about the effect of stressors on fish reproduction since responses can be nonmonotonal, often biphasic.

  19. Factors controlling the hormesis response in irradiated seed

    SciTech Connect

    Sheppard, S.C.; Regitnig, P.J.

    1987-05-01

    Ionizing radiation at very low doses frequently has a stimulating or hormetic effect on the growth of organisms. Irradiation of seed before planting can stimulate early plant growth, leading to advanced maturity and increased yield. The unreliability of this response has limited its application. However, the technique has been extensively studied and now is practiced on a large scale on some farms in certain countries. Our research has addressed various factors that may determine the stimulation response with the goal of developing an ability to predict the occurrence of increased economic yield. In this paper, we discuss several of these factors in light of our data and data from other field studies in Canada. A hormesis response was observed for most species studied, but varied among cultivars and among seed lots within a cultivar. Seed condition may be the underlying factor in these effects. The response was most frequently evident at very early stages of growth and was often masked in subsequent growth. This suggests that the hormesis phenomenon in seeds may be quite common and is not reliably manifest in advanced maturity or yield increases because of environmental effects. Storage time after irradiation must be minimized to gain the greatest response. There is little evidence to suggest that the photon energy or dose rate of the radiation source is an important factor.

  20. Time-dependent hormesis of chemical mixtures: A case study on sulfa antibiotics and a quorum-sensing inhibitor of Vibrio fischeri.

    PubMed

    You, Ruirong; Sun, Haoyu; Yu, Yan; Lin, Zhifen; Qin, Mengnan; Liu, Ying

    2016-01-01

    Sulfa antibiotics (SAs) and quorum-sensing inhibitor (QSI) may pose potential ecological risks because mixed using of them has been proposed to inhibit bacteria from generating antibiotic resistance. This study investigated the time-dependent hormesis of single and binary mixtures of QSI and SAs of Vibrio fischeri (V. fischeri) for 0-24 h. Although the low-dose SAs stimulated the expression of LuxR protein, the high-dose SAs could inhibit bacteria growth by competitively binding to dihydropteroate synthase. Moreover, AinR protein was bound to Benzofuran-3(2H)-one (B3O) with low concentration, thus the N-octanoyl homoserine lactone signal molecules (C8) has chance to bind to LuxR protein to promote light emission. The hormesis effect induced by the mixtures could be deduced that SAs promoted the expression of LuxR protein and B3O increases the chance of C8 binding to LuxR. Our findings facilitate new insight into the mechanistic study of hormesis and ecological risks of the chemical mixtures.

  1. Early Life Hormetic Treatments Decrease Irradiation-Induced Oxidative Damage, Increase Longevity, and Enhance Sexual Performance during Old Age in the Caribbean Fruit Fly

    PubMed Central

    López-Martínez, Giancarlo; Hahn, Daniel A.

    2014-01-01

    Early life events can have dramatic consequences on performance later in life. Exposure to stressors at a young age affects development, the rate of aging, risk of disease, and overall lifespan. In spite of this, mild stress exposure early in life can have beneficial effects on performance later in life. These positive effects of mild stress are referred to as physiological conditioning hormesis. In our current study we used anoxia conditioning hormesis as a pretreatment to reduce oxidative stress and improve organismal performance, lifespan, and healthspan of Caribbean fruit flies. We used gamma irradiation to induce mild oxidative damage in a low-dose experiment, and massive oxidative damage in a separate high-dose experiment, in pharate adult fruit flies just prior to adult emergence. Irradiation-induced oxidative stress leads to reduced adult emergence, flight ability, mating performance, and lifespan. We used a hormetic approach, one hour of exposure to anoxia plus irradiation in anoxia, to lower post-irradiation oxidative damage. We have previously shown that this anoxic-conditioning treatment elevates total antioxidant capacity and lowers post-irradiation oxidative damage to lipids and proteins. In this study, conditioned flies had lower mortality rates and longer lifespan compared to those irradiated without hormetic conditioning. As a metric of healthspan, we tracked mating both at a young age (10 d) and old age (30 d). We found that anoxia-conditioned male flies were more competitive at young ages when compared to unconditioned irradiation stressed male flies, and that the positive effects of anoxic conditioning hormesis on mating success were even more pronounced in older males. Our data shows that physiological conditioning hormesis at a young age, not only improves immediate metrics of organismal performance (emergence, flight, mating), but the beneficial effects also carry into old age by reducing late life oxidative damage and improving lifespan and

  2. Radiation Hormesis: The Link to Nanomolar Hydrogen Peroxide.

    PubMed

    Sies, Helmut; Feinendegen, Ludwig E

    2017-09-20

    Hydrogen peroxide (H2O2) is a stable product of water radiolysis, occurring at nanomolar concentration upon low-dose ionizing radiation (LDIR) (<100 mGy). In view of the recent recognition of H2O2 as a central redox signaling molecule that, likewise, is maintained in the nanomolar range in cells, we propose a role for H2O2 in radiation hormesis. LDIR is capable of utilizing known molecular redox master switches such as Nrf2/Keap1 or NF-κB/IκB to effect adaptive resistance. This leads to the hypothesis that, as a normal component of the exposome, LDIR mediates hormetic effects by H2O2 signaling. Antioxid. Redox Signal. 27, 596-598.

  3. Research Findings on Radiation Hormesis and Radon Therapy

    SciTech Connect

    Hattori, Sadao

    1999-06-06

    Radiation hormesis research in Japan to determine the validity of Luckey's claims has revealed information on the health effects of low-level radiation. The scientific data of animal tests we obtained and successful results actually brought by radon therapy on human patients show us a clearer understanding of the health effects of low-level radiation. We obtained many animal test results and epidemiological survey data through our research activities cooperating with more than ten universities in Japan, categorized as follows: 1. suppression of cancer by enhancement of the immune system based on gene activation; 2. rejuvenation and suppression of aging by increasing cell membrane permeability and enzyme syntheses; 3. adaptive response by activation of gene expression on DNA repair and cell apoptosis; 4. pain relief and stress moderation by hormone formation in the brain and central nervous system; 5. avoidance and therapy of obstinate diseases by enhancing damage control systems and form one formation.

  4. The Synthetic Elicitor 2-(5-Bromo-2-Hydroxy-Phenyl)-Thiazolidine-4-Carboxylic Acid Links Plant Immunity to Hormesis1

    PubMed Central

    Rodriguez-Salus, Melinda; Bektas, Yasemin; Schroeder, Mercedes; Knoth, Colleen; Vu, Trang; Roberts, Philip; Kaloshian, Isgouhi

    2016-01-01

    Synthetic elicitors are drug-like compounds that induce plant immune responses but are structurally distinct from natural defense elicitors. Using high-throughput screening, we previously identified 114 synthetic elicitors that activate the expression of a pathogen-responsive reporter gene in Arabidopsis (Arabidopsis thaliana). Here, we report on the characterization of one of these compounds, 2-(5-bromo-2-hydroxy-phenyl)-thiazolidine-4-carboxylic acid (BHTC). BHTC induces disease resistance of plants against bacterial, oomycete, and fungal pathogens and has a unique mode of action and structure. Surprisingly, we found that low doses of BHTC enhanced root growth in Arabidopsis, while high doses of this compound inhibited root growth, besides inducing defense. These effects are reminiscent of the hormetic response, which is characterized by low-dose stimulatory effects of a wide range of agents that are toxic or inhibitory at higher doses. Like its effects on defense, BHTC-induced hormesis in Arabidopsis roots is partially dependent on the WRKY70 transcription factor. Interestingly, BHTC-induced root hormesis is also affected in the auxin-response mutants axr1-3 and slr-1. By messenger RNA sequencing, we uncovered a dramatic difference between transcriptional profiles triggered by low and high doses of BHTC. Only high levels of BHTC induce typical defense-related transcriptional changes. Instead, low BHTC levels trigger a coordinated intercompartmental transcriptional response manifested in the suppression of photosynthesis- and respiration-related genes in the nucleus, chloroplasts, and mitochondria as well as the induction of development-related nuclear genes. Taken together, our functional characterization of BHTC links defense regulation to hormesis and provides a hypothetical transcriptional scenario for the induction of hormetic root growth. PMID:26530314

  5. Non-linear uptake and hormesis effects of selenium in red-winged blackbirds (Agelaius phoeniceus).

    PubMed

    Harding, Lee E

    2008-01-25

    Effects of selenium on reproductive success were assessed in red-winged blackbirds (Agelaius phoeniceus). Mean egg selenium (MES) ranged from 2.96 to 21.7 mg/kg dry weight with individual eggs up to 40 mg/kg. Uptake was non-linear: increments in MES declined as aqueous selenium increased; the asymptote was approximately 23 mg/kg. Eggs were heavier and more were laid in 2004 compared to 2005, a year of record rainfall and below-normal temperatures. Mortality of embryos that were incubated to full term was low (2.6% in 2004 and 3.2% in 2005), as was the prevalence of embryonic defects (2.7% in 2004 and 5.1% in 2005). Abnormalities in nestlings were also rare. Egg mortality was caused by predation, weather, and parental abandonment. Nestlings died from predation, starvation, and hypothermia associated with rain and cold, drowning, and bacterial infections. Nestling liver concentrations reached 81 mg/kg dry wt. selenium and were highest at the most highly selenium-exposed sites. Blood glutathione peroxidase (a selenium-dependent enzyme indicative of selenium exposure) was unrelated to liver selenium concentrations, egg selenium, or ambient selenium exposure. The selenium concentration in prey that parents fed to nestlings was higher at the selenium-exposed sites (up to 37 mg/kg dry wt. Se) compared to reference sites. Aqueous selenate:selenite ratios were related to redox differences and were much higher at the site with the highest MES, liver selenium, and prey item selenium concentrations. Hatchability showed U-shaped, or hormesis, relationships with MES: productivity increased with selenium concentrations at low exposures and decreased at high exposures. The effects threshold was approximately 22 mg/kg dry wt. MES.

  6. Lung cancer hormesis in high impact states where nuclear testing occurred.

    PubMed

    Lehrer, Steven; Rosenzweig, Kenneth E

    2015-03-01

    Hormesis is a favorable biological response to low toxin exposure. In the case of radiation, large doses are carcinogenic, but low doses might be protective. In the current study, we analyzed lung cancer incidence in high-impact radiation states where nuclear testing occurred and compared it with lung cancer incidence in the remaining normal-impact radiation states and the District of Columbia. Lung cancer incidence data were from the American Cancer Society. Tobacco use 2012 data were from the Centers for Disease Control and Prevention. The distribution of states grouped according to lung cancer incidence interval was from the Centers for Disease Control and Prevention. Total background radiation measurements (terrestrial + cosmic + radon) were from Assessment of Variations in Radiation Exposure in the United States (2005). Data on high- and normal-impact states were from the National Radiation Exposure Screening & Education Program (RESEP). Congress passed the Radiation Exposure Compensation Act Amendments of 2000, creating RESEP, to help thousands of people diagnosed with cancer and other diseases caused by exposure to nuclear fallout or radioactive materials such as uranium. These people live in 12 high-impact states where nuclear testing had occurred. High-impact states were not designated according to measurements of background radiation. Lung cancer incidence is significantly lower in high-impact states in men (t = 5.4 for unequal variance; P < .001) and women (t = 3.0; P < .001). The clustering of the 12 high-impact states in the 2 lowest lung cancer incidence intervals (26.8-56.9 and 57.0-63.2) is statistically significant (P < .001, Fisher exact test, 2-tailed). Because cigarette smoking is ordinarily the most powerful risk factor for lung cancer, multivariate linear regression analysis of the effect of U.S. state group (normal-impact, high-impact, or extra high-impact for Nevada, Utah, and Arizona) on lung cancer incidence in men and women was

  7. Nuclear Energy and Health: And the Benefits of Low-Dose Radiation Hormesis

    PubMed Central

    Cuttler, Jerry M.; Pollycove, Myron

    2009-01-01

    Energy needs worldwide are expected to increase for the foreseeable future, but fuel supplies are limited. Nuclear reactors could supply much of the energy demand in a safe, sustainable manner were it not for fear of potential releases of radioactivity. Such releases would likely deliver a low dose or dose rate of radiation, within the range of naturally occurring radiation, to which life is already accustomed. The key areas of concern are discussed. Studies of actual health effects, especially thyroid cancers, following exposures are assessed. Radiation hormesis is explained, pointing out that beneficial effects are expected following a low dose or dose rate because protective responses against stresses are stimulated. The notions that no amount of radiation is small enough to be harmless and that a nuclear accident could kill hundreds of thousands are challenged in light of experience: more than a century with radiation and six decades with reactors. If nuclear energy is to play a significant role in meeting future needs, regulatory authorities must examine the scientific evidence and communicate the real health effects of nuclear radiation. Negative images and implications of health risks derived by unscientific extrapolations of harmful effects of high doses must be dispelled. PMID:19343116

  8. Sublethal and hormesis effects of imidacloprid on the soybean aphid Aphis glycines.

    PubMed

    Qu, Yanyan; Xiao, Da; Li, Jinyu; Chen, Zhou; Biondi, Antonio; Desneux, Nicolas; Gao, Xiwu; Song, Dunlun

    2015-04-01

    The soybean aphid, Aphis glycines Matsumura, is a major pest in soybean crop. Current management of this pest relies mainly on insecticides applications, and the neonicotinoid imidacloprid has been proposed as an effective insecticide to control A. glycines in soybean field. Imidacloprid at lethal concentrations not only exerts acute toxicity to A. glycines, but also cause various biological changes when aphids are chronically exposed to lower concentrations. In this study, we assessed the effects of a low-lethal (0.20 mg L(-1)) and two sublethal (0.05 and 0.10 mg L(-1)) imidacloprid concentrations on various A. glycines life history traits. Aphid exposure to 0.20 mg L(-1) imidacloprid caused slower juvenile development, shorter reproductive period, and reduced adult longevity, fecundity and total lifespan. Stimulatory effects, i.e. hormesis, on reproduction and immature development duration were observed in aphids exposed to the lower sublethal imidacloprid concentrations. Consequently, the net reproduction rate (R 0) was significantly higher than in the control aphids. These findings stress the importance of the actual imidacloprid concentration in its toxicological properties on A. glycines. Therefore, our results would be useful for assessing the overall effects of imidacloprid on A. glycines and for optimizing integrated pest management programs targeting this pest.

  9. Nuclear energy and health: and the benefits of low-dose radiation hormesis.

    PubMed

    Cuttler, Jerry M; Pollycove, Myron

    2009-01-01

    Energy needs worldwide are expected to increase for the foreseeable future, but fuel supplies are limited. Nuclear reactors could supply much of the energy demand in a safe, sustainable manner were it not for fear of potential releases of radioactivity. Such releases would likely deliver a low dose or dose rate of radiation, within the range of naturally occurring radiation, to which life is already accustomed. The key areas of concern are discussed. Studies of actual health effects, especially thyroid cancers, following exposures are assessed. Radiation hormesis is explained, pointing out that beneficial effects are expected following a low dose or dose rate because protective responses against stresses are stimulated. The notions that no amount of radiation is small enough to be harmless and that a nuclear accident could kill hundreds of thousands are challenged in light of experience: more than a century with radiation and six decades with reactors. If nuclear energy is to play a significant role in meeting future needs, regulatory authorities must examine the scientific evidence and communicate the real health effects of nuclear radiation. Negative images and implications of health risks derived by unscientific extrapolations of harmful effects of high doses must be dispelled.

  10. Interpreting 'dose-response' curves using homeodynamic data: with an improved explanation for hormesis.

    PubMed

    Stebbing, A R D

    2009-04-15

    A re-interpretation of the 'dose-response' curve is given that accommodates homeostasis. The outcome, or overall effect, of toxicity is the consequence of toxicity that is moderated by homeodynamic responses. Equilibrium is achieved by a balance of opposing forces of toxic inhibition countered by a stimulatory response. A graphical model is given consisting of two linked curves (response vs concentration and effect vs concentration), which provide the basis for a re-interpretation of the 'dose-response' curve. The model indicates that such relationships are non-linear with a threshold, which is due to homeodynamic responses. Subthreshold concentrations in 'dose-response' curves provide the sum of toxic inhibition minus the homeodynamic response; the response itself is unseen in serving its purpose of neutralizing perturbation. This interpretation suggests why the alpha- and beta-curves are non-linear. The beta-curve indicates adaptive overcorrection to toxicity that confers greater resistance to subsequent toxic exposure, with hormesis as an epiphenomenon.

  11. Pest Insect Olfaction in an Insecticide-Contaminated Environment: Info-Disruption or Hormesis Effect

    PubMed Central

    Tricoire-Leignel, Hélène; Thany, Steeve Hervé; Gadenne, Christophe; Anton, Sylvia

    2012-01-01

    Most animals, including pest insects, live in an “odor world” and depend strongly on chemical stimuli to get information on their biotic and abiotic environment. Although integrated pest management strategies including the use of insect growth regulators (IGRs) are increasingly developed, most insect pest treatments rely on neurotoxic chemicals. These molecules are known to disrupt synaptic transmission, affecting therefore sensory systems. The wide-spread use of neurotoxic insecticides and the growing use of IGRs result in residual accumulation of low concentrations in the environment. These insecticide residues could act as an “info-disruptor” by modifying the chemical communication system, and therefore decrease chances of reproduction in target insects. However, residues can also induce a non-expected hormesis effect by enhancing reproduction abilities. Low insecticide doses might thus induce adaptive processes in the olfactory pathway of target insects, favoring the development of resistance. The effect of sublethal doses of insecticides has mainly been studied in beneficial insects such as honeybees. We review here what is known on the effects of sublethal doses of insecticides on the olfactory system of insect pests. PMID:22457653

  12. Tales of two similar hypotheses: the rise and fall of chemical and radiation hormesis.

    PubMed

    Calabrese, E J; Baldwin, L A

    2000-01-01

    This paper compares the historical developments of chemical and radiation hormesis from their respective inceptions in the late 1880's for chemical hormesis and early 1900's for radiation hormesis to the mid 1930's to 1940 during which both hypotheses rose to some prominence but then became marginalized within the scientific community. This analysis documents that there were marked differences in their respective temporal developments, and the direction and maturity of research. In general, the formulation of the chemical hormesis hypothesis displayed an earlier, more-extensive and more sophisticated development than the radiation hormesis hypothesis. It was able to attract prestigious researchers with international reputations from leading institutions, to be the subject of numerous dissertations, to have its findings published in leading journals, and to have its concepts incorporated into leading microbiological texts. While both areas became the object of criticism from leading scientists, the intensity of the challenge was greatest for chemical hormesis due to its more visible association with the medical practice of homeopathy. Despite the presence of legitimate and flawed criticism, the most significant limitations of both chemical and radiation hormesis and their respective ultimate undoing were due to their: (1) lack of development of a coherent dose-response theory using data of low dose stimulation from both the chemical and radiation domains; (2) difficulty in replication of low dose stimulatory responses without an adequate study design especially with respect to an appropriate number and properly spaced doses below the toxic threshold; (3) modest degree of stimulation even under optimal conditions which was difficult to distinguish from normal variation; and (4) lack of appreciation of the practical and/or commercial applications of the concepts of low dose stimulation.

  13. Complex mixture-associated hormesis and toxicity: the case of leather tanning industry.

    PubMed

    Pagano, Giovanni; Castello, Giuseppe; Gallo, Marialuisa; Borriello, Ilaria; Guida, Marco

    2008-01-01

    A series of studies investigated the toxicities of tannery-derived complex mixtures, i.e. vegetable tannin (VT) from Acacia sp. or phenol-based synthetic tannin (ST), and waste-water from tannin-based vs. chromium-based tanneries. Toxicity was evaluated by multiple bioassays including developmental defects and loss of fertilization rate in sea urchin embryos and sperm (Paracentrotus lividus and Sphaerechinus granularis), and algal growth inhibition (Dunaliella tertiolecta and Selenastrum capricornutum). Both VT and ST water extracts resulted in hormetic effects at concentrations ranging 0.1 to 0.3%, and toxicity at levels > or =1%, both in sea urchin embryo and sperm, and in algal growth bioassays. When comparing tannin-based tannery wastewater (TTW) vs. chromium-based tannery effluent (CTE), a hormesis to toxicity trend was observed for TTW both in terms of developmental and fertilization toxicity in sea urchins, and in algal growth inhibition, with hormetic effects at 0.1 to 0.2% TTW, and toxicity at TTW levels > or =1%. Unlike TTW, CTE showed a monotonic toxicity increase from the lowest tested level (0.1%) and CTE toxicity at higher levels was significantly more severe than TTW-induced toxicity. The results support the view that leather production utilizing tannins might be regarded as a more environmentally friendly procedure than chromium-based tanning process.

  14. Complex Mixture-Associated Hormesis and Toxicity: The Case of Leather Tanning Industry

    PubMed Central

    Pagano, Giovanni; Castello, Giuseppe; Gallo, Marialuisa; Borriello, Ilaria; Guida, Marco

    2008-01-01

    A series of studies investigated the toxicities of tannery-derived complex mixtures, i.e. vegetable tannin (VT) from Acacia sp. or phenol-based synthetic tannin (ST), and waste-water from tannin-based vs. chromium-based tanneries. Toxicity was evaluated by multiple bioassays including developmental defects and loss of fertilization rate in sea urchin embryos and sperm (Paracentrotus lividus and Sphaerechinus granularis), and algal growth inhibition (Dunaliella tertiolecta and Selenastrum capricornutum). Both VT and ST water extracts resulted in hormetic effects at concentrations ranging 0.1 to 0.3%, and toxicity at levels ≥1%, both in sea urchin embryo and sperm, and in algal growth bioassays. When comparing tannin-based tannery wastewater (TTW) vs. chromium-based tannery effluent (CTE), a hormesis to toxicity trend was observed for TTW both in terms of developmental and fertilization toxicity in sea urchins, and in algal growth inhibition, with hormetic effects at 0.1 to 0.2% TTW, and toxicity at TTW levels ≥1%. Unlike TTW, CTE showed a monotonic toxicity increase from the lowest tested level (0.1%) and CTE toxicity at higher levels was significantly more severe than TTW-induced toxicity. The results support the view that leather production utilizing tannins might be regarded as a more environmentally friendly procedure than chromium-based tanning process. PMID:19088903

  15. Cadmium exposure induces hematuria in Korean adults

    SciTech Connect

    Han, Seung Seok; Kim, Myounghee; Lee, Su Mi; Lee, Jung Pyo; Kim, Sejoong; Joo, Kwon Wook; Lim, Chun Soo; Kim, Yon Su; Kim, Dong Ki

    2013-07-15

    Introduction: Toxic heavy metals have adverse effects on human health. However, the risk of hematuria caused by heavy metal exposure has not been evaluated. Methods: Data from 4701 Korean adults were obtained in the Korean National Health and Nutritional Examination Survey (2008–2010). Blood levels of the toxic heavy metals cadmium, lead, and mercury were measured. Hematuria was defined as a result of ≥+1 on a urine dipstick test. The odds ratios (ORs) for hematuria were measured according to the blood heavy metal levels after adjusting for multiple variables. Results: Individuals with blood cadmium levels in the 3rd and 4th quartiles had a greater OR for hematuria than those in the 1st quartile group: 3rd quartile, 1.35 (1.019–1.777; P=0.037); 4th quartile, 1.52 (1.140–2.017; P=0.004). When blood cadmium was considered as a log-transformed continuous variable, the correlation between blood cadmium and hematuria was significant: OR, 1.97 (1.224–3.160; P{sub trend}=0.005). In contrast, no significant correlations between hematuria and blood lead or mercury were found in the multivariate analyses. Discussion: The present study shows that high cadmium exposure is associated with a risk of hematuria. -- Highlights: • A high level of blood cadmium is associated with a high risk of hematuria. • This correlation is independent of several confounding factors. • Blood levels of lead and mercury are not associated with risk of hematuria. • This is the first study on the correlation between cadmium exposure and hematuria risk.

  16. Environmental law applications of hormesis concepts: risk assessment and cost-benefit implications.

    PubMed

    Juni, R L; McElveen, J C

    2000-01-01

    This article focuses on legal structures that influence the degree to which hormesis can be incorporated into environmental law and policy. Three statutes-the Occupational Safety and Health Act, the Food Quality Protection Act, and the Clean Air Act-are used to illustrate the varied ways in which Congress, agencies and the courts have approached risk assessment and cost-benefit analyses that are relevant to the hormesis issue. This discussion features several examples of regulations and judicial decisions that have begun to recognize hormetic effects. The article concludes that hormesis concepts could be incorporated effectively into present risk assessment and cost-benefit mechanisms. In the context of agency action, an express policy decision might be made to broaden the typical scope of risk assessment and cost-benefit processes by including hormetic effects. In the judicial context, recognition of hormesis may occur where relevant statutory language is read to contemplate that an agency will consider both the beneficial and the detrimental effects of a particular substance in formulating regulations; in this circumstance, a reviewing court could reverse an agency decision that focuses solely on detrimental effects and ignores hormetic effects. Based on these evolving trends, the time may be ripe to seek further incorporation of hormesis concepts into environmental law and policy decisions.

  17. Structured Development and Promotion of a Research Field: Hormesis in Biology, Toxicology, and Environmental Regulatory Science.

    PubMed

    Mushak, Paul; Elliott, Kevin C

    2015-12-01

    The ability of powerful and well-funded interest groups to steer scientific research in ways that advance their goals has become a significant social concern. This steering ability is increasingly being recognized in the peer-reviewed scientific literature and in findings of deliberative scientific bodies. This paper provides a case study that illustrates some of the major strategies that can be used to structure and advance a controversial research field. It focuses on hormesis, described as a type of dose-response relationship in toxicology and biology showing low-dose stimulation but high-dose inhibition, or the reverse. Hormesis proponents tout its significance, arguing that substances toxic at high doses and beneficial at lower doses should be regulated less stringently. We identify five strategies employed by hormesis proponents to foster its acceptance: (1) creating institutions focused on supporting hormesis; (2) developing terminology, study designs, and data interpretations that cast it in a favorable light; (3) using bibliometric techniques and surveys to attract attention; (4) aggressively advocating for the phenomenon and challenging critics; and (5) working with outside interest groups to apply the hormesis phenomenon in the economic and political spheres. We also suggest a number of oversight strategies that can be implemented to help promote credible and socially responsible research in cases like this one.

  18. Kinase Inhibition Leads to Hormesis in a Dual Phosphorylation-Dephosphorylation Cycle

    PubMed Central

    Rashkov, Peter; Barrett, Ian P.; Beardmore, Robert E.; Bendtsen, Claus

    2016-01-01

    Many antimicrobial and anti-tumour drugs elicit hormetic responses characterised by low-dose stimulation and high-dose inhibition. While this can have profound consequences for human health, with low drug concentrations actually stimulating pathogen or tumour growth, the mechanistic understanding behind such responses is still lacking. We propose a novel, simple but general mechanism that could give rise to hormesis in systems where an inhibitor acts on an enzyme. At its core is one of the basic building blocks in intracellular signalling, the dual phosphorylation-dephosphorylation motif, found in diverse regulatory processes including control of cell proliferation and programmed cell death. Our analytically-derived conditions for observing hormesis provide clues as to why this mechanism has not been previously identified. Current mathematical models regularly make simplifying assumptions that lack empirical support but inadvertently preclude the observation of hormesis. In addition, due to the inherent population heterogeneities, the presence of hormesis is likely to be masked in empirical population-level studies. Therefore, examining hormetic responses at single-cell level coupled with improved mathematical models could substantially enhance detection and mechanistic understanding of hormesis. PMID:27898662

  19. Kinase Inhibition Leads to Hormesis in a Dual Phosphorylation-Dephosphorylation Cycle.

    PubMed

    Rashkov, Peter; Barrett, Ian P; Beardmore, Robert E; Bendtsen, Claus; Gudelj, Ivana

    2016-11-01

    Many antimicrobial and anti-tumour drugs elicit hormetic responses characterised by low-dose stimulation and high-dose inhibition. While this can have profound consequences for human health, with low drug concentrations actually stimulating pathogen or tumour growth, the mechanistic understanding behind such responses is still lacking. We propose a novel, simple but general mechanism that could give rise to hormesis in systems where an inhibitor acts on an enzyme. At its core is one of the basic building blocks in intracellular signalling, the dual phosphorylation-dephosphorylation motif, found in diverse regulatory processes including control of cell proliferation and programmed cell death. Our analytically-derived conditions for observing hormesis provide clues as to why this mechanism has not been previously identified. Current mathematical models regularly make simplifying assumptions that lack empirical support but inadvertently preclude the observation of hormesis. In addition, due to the inherent population heterogeneities, the presence of hormesis is likely to be masked in empirical population-level studies. Therefore, examining hormetic responses at single-cell level coupled with improved mathematical models could substantially enhance detection and mechanistic understanding of hormesis.

  20. Minimal Peroxide Exposure of Neuronal Cells Induces Multifaceted Adaptive Responses

    PubMed Central

    Chadwick, Wayne; Zhou, Yu; Park, Sung-Soo; Wang, Liyun; Mitchell, Nicholas; Stone, Matthew D.; Becker, Kevin G.; Martin, Bronwen; Maudsley, Stuart

    2010-01-01

    Oxidative exposure of cells occurs naturally and may be associated with cellular damage and dysfunction. Protracted low level oxidative exposure can induce accumulated cell disruption, affecting multiple cellular functions. Accumulated oxidative exposure has also been proposed as one of the potential hallmarks of the physiological/pathophysiological aging process. We investigated the multifactorial effects of long-term minimal peroxide exposure upon SH-SY5Y neural cells to understand how they respond to the continued presence of oxidative stressors. We show that minimal protracted oxidative stresses induce complex molecular and physiological alterations in cell functionality. Upon chronic exposure to minimal doses of hydrogen peroxide, SH-SY5Y cells displayed a multifactorial response to the stressor. To fully appreciate the peroxide-mediated cellular effects, we assessed these adaptive effects at the genomic, proteomic and cellular signal processing level. Combined analyses of these multiple levels of investigation revealed a complex cellular adaptive response to the protracted peroxide exposure. This adaptive response involved changes in cytoskeletal structure, energy metabolic shifts towards glycolysis and selective alterations in transmembrane receptor activity. Our analyses of the global responses to chronic stressor exposure, at multiple biological levels, revealed a viable neural phenotype in-part reminiscent of aged or damaged neural tissue. Our paradigm indicates how cellular physiology can subtly change in different contexts and potentially aid the appreciation of stress response adaptations. PMID:21179406

  1. Postconditioning Hormesis Put in Perspective: An Overview of Experimental and Clinical Studies

    PubMed Central

    Wiegant, F.A.C.; Prins, H.A.B.; Van Wijk, R.

    2010-01-01

    A beneficial effect of applying mild stress to cells or organisms, that were initially exposed to a high dose of stress, has been referred to as ‘postconditioning hormesis’. The initial high dose of stress activates intrinsic self-recovery mechanisms. Modulation of these endogenous adaptation strategies by administration of a subsequent low dose of stress can confer effects that are beneficial to the biological system. Owing to its potentially therapeutic applications, postconditioning hormesis is subject to research in various scientific disciplines. This paper presents an overview of the dynamics of postconditioning hormesis and illustrates this phenomenon with a number of examples in experimental and clinical research. PMID:21731537

  2. The Maturing of Hormesis as a Credible Dose-Response Model

    PubMed Central

    Calabrese, Edward J.

    2003-01-01

    Hormesis is a dose-response phenomenon that has received little recognition, credibility and acceptance as evidenced by its absence from major toxicological/risk assessment texts, governmental regulatory dose-response modeling for risk assessment, and non-visibility in major professional toxicological society national meetings. This paper traces the historical evolution of the hormetic dose-response hypothesis, why this model is not only credible but also more common than the widely accepted threshold model in direct comparative evaluation, and how the toxicological community made a critical error in rejecting hormesis, a rejection sustained over 70 years. PMID:19330138

  3. Prenatal music exposure induces long-term neural effects.

    PubMed

    Partanen, Eino; Kujala, Teija; Tervaniemi, Mari; Huotilainen, Minna

    2013-01-01

    We investigated the neural correlates induced by prenatal exposure to melodies using brains' event-related potentials (ERPs). During the last trimester of pregnancy, the mothers in the learning group played the 'Twinkle twinkle little star'-melody 5 times per week. After birth and again at the age of 4 months, we played the infants a modified melody in which some of the notes were changed while ERPs to unchanged and changed notes were recorded. The ERPs were also recorded from a control group, who received no prenatal stimulation. Both at birth and at the age of 4 months, infants in the learning group had stronger ERPs to the unchanged notes than the control group. Furthermore, the ERP amplitudes to the changed and unchanged notes at birth were correlated with the amount of prenatal exposure. Our results show that extensive prenatal exposure to a melody induces neural representations that last for several months.

  4. Prenatal Music Exposure Induces Long-Term Neural Effects

    PubMed Central

    Partanen, Eino; Kujala, Teija; Tervaniemi, Mari; Huotilainen, Minna

    2013-01-01

    We investigated the neural correlates induced by prenatal exposure to melodies using brains' event-related potentials (ERPs). During the last trimester of pregnancy, the mothers in the learning group played the ‘Twinkle twinkle little star’ -melody 5 times per week. After birth and again at the age of 4 months, we played the infants a modified melody in which some of the notes were changed while ERPs to unchanged and changed notes were recorded. The ERPs were also recorded from a control group, who received no prenatal stimulation. Both at birth and at the age of 4 months, infants in the learning group had stronger ERPs to the unchanged notes than the control group. Furthermore, the ERP amplitudes to the changed and unchanged notes at birth were correlated with the amount of prenatal exposure. Our results show that extensive prenatal exposure to a melody induces neural representations that last for several months. PMID:24205353

  5. [Evaluation of rounded atelectasis induced by exposure to asbestos].

    PubMed

    Kishimoto, Takumi; Gemba, Kenichi; Fujimoto, Nobukazu; Nishi, Hideyuki; Ozaki, Shinji

    2008-09-01

    We encountered 19 patients of rounded atelectasis induced by exposure to asbestos from 2000 to 2007. All patients were men whose ages arranged from 60 to 89 years with a mean of 74.2 years. Twenty rounded atelectasis were present in the right lung and 5 in the left lung. Five patients had 2 rounded atelectasis. In 21 rounded atelectasis were found in Segment 10 and while other 2 found in S1 and each in S5 and 9. Eleven patients were diagnosed with no symptoms through medical examinations. Other 8 patients complained of dyspnea, chest pain and cough. Thirteen patients complicated with benign asbestos pleurisy and only 3 patients accompanied asbestosis. Eighteen patients (95%) displayed pleural plaques and 15 patients with calcified plaques. Ten patients had been exposed to asbestos in the shipyards and 4 in construction works and other 5 patients had also exposed by occupational exposure to asbestos. The mean period of exposure to asbestos was 26.6 years and the mean latency periods from the first asbestos exposure to the diagnosis of rounded atelectasis were 51.6 years. An autopsied patient had 18,100 asbestos bodies per 1 g of dry lung tissue which meant the heavy asbestos exposure. High incidence of pleural plaques and long period of latency from the first exposure to the appearance of rounded atelectasis in this study suggested that rounded atelectasis might appear less high-dose exposure to asbestos than former patients who were reported 6 years ago.

  6. Cell membrane potentials induced during exposure to EMP fields

    SciTech Connect

    Gailey, P.C.; Easterly, C.E.

    1994-09-01

    Internal current densities and electric fields induced in the human body during exposure to EMP fields are reviewed and used to predict resulting cell membrane potentials. Using several different approaches, membrane potentials of about 100 mV are predicted. These values are comparable to the static membrane potentials maintained by cells as a part of normal physiological function, but the EMP-induced potentials persist for only about 10 ns. Possible biological implications of EMP-induced membrane potentials including conformational changes and electroporation are discussed.

  7. Arsenic exposure induces the Warburg effect in cultured human cells

    SciTech Connect

    Zhao, Fei; Severson, Paul; Pacheco, Samantha; Futscher, Bernard W.; Klimecki, Walter T.

    2013-08-15

    Understanding how arsenic exacts its diverse, global disease burden is hampered by a limited understanding of the particular biological pathways that are disrupted by arsenic and underlie pathogenesis. A reductionist view would predict that a small number of basic pathways are generally perturbed by arsenic, and manifest as diverse diseases. Following an initial observation that arsenite-exposed cells in culture acidify their media more rapidly than control cells, the report here shows that low level exposure to arsenite (75 ppb) is sufficient to induce aerobic glycolysis (the Warburg effect) as a generalized phenomenon in cultured human primary cells and cell lines. Expanded studies in one such cell line, the non-malignant pulmonary epithelial line, BEAS-2B, established that the arsenite-induced Warburg effect was associated with increased accumulation of intracellular and extracellular lactate, an increased rate of extracellular acidification, and inhibition by the non-metabolized glucose analog, 2-deoxy-D-glucose. Associated with the induction of aerobic glycolysis was a pathway-wide induction of glycolysis gene expression, as well as protein accumulation of an established glycolysis master-regulator, hypoxia-inducible factor 1A. Arsenite-induced alteration of energy production in human cells represents the type of fundamental perturbation that could extend to many tissue targets and diseases. - Highlights: • Chronic arsenite exposure induces aerobic glycolysis, dubbed the “Warburg effect”. • Arsenite-induced Warburg effect is a general phenomenon in cultured human cells. • HIF-1A may mediate arsenite induced Warburg effect.

  8. Exposure of Mice to Topical Bovine Thrombin Induces Systemic Autoimmunity

    PubMed Central

    Schoenecker, Jonathan G.; Johnson, Rachel K.; Lesher, Aaron P.; Day, Jarrod D.; Love, Stephanie D.; Hoffman, Maureane R.; Ortel, Thomas L.; Parker, William; Lawson, Jeffrey H.

    2001-01-01

    Bovine thrombin is used as an aid to hemostasis in medical and surgical procedures. At least 500,000 Americans are exposed to this therapeutic annually and reports suggest that exposure is associated with the development of autoreactive antibodies. To determine whether bovine thrombin can induce pathological autoimmunity we exposed nonautoimmune-prone galactose-α1-3-galactose-deficient mice to the two bovine thrombin preparations currently approved for use in the United States. We found that, like humans exposed to bovine thrombin, mice developed an immune response against the therapeutic and the xenogeneic carbohydrate galactose-α1-3-galactose, and some mice developed autoantibodies against clotting factors. Further, unexpectedly, a single exposure to this therapeutic also induced autoimmunity with features characteristic of systemic lupus erythematosus including antibodies against nuclear antigens, native DNA, double-stranded DNA, and cardiolipin. High levels of these autoantibodies correlated with glomerulonephritis in all mice evaluated. This autoimmune syndrome was detected in mice 15 weeks after a secondary exposure to bovine thrombin and female mice were found to develop the syndrome at a significantly greater frequency than males. Thus, these studies indicate that exposure to bovine thrombin preparations can induce a pathological systemic autoimmune syndrome with lupus-like serology. PMID:11696457

  9. Secondhand smoke exposure induces acutely airway acidification and oxidative stress.

    PubMed

    Kostikas, Konstantinos; Minas, Markos; Nikolaou, Eftychia; Papaioannou, Andriana I; Liakos, Panagiotis; Gougoura, Sofia; Gourgoulianis, Konstantinos I; Dinas, Petros C; Metsios, Giorgos S; Jamurtas, Athanasios Z; Flouris, Andreas D; Koutedakis, Yiannis

    2013-02-01

    Previous studies have shown that secondhand smoke induces lung function impairment and increases proinflammatory cytokines. The aim of the present study was to evaluate the acute effects of secondhand smoke on airway acidification and airway oxidative stress in never-smokers. In a randomized controlled cross-over trial, 18 young healthy never-smokers were assessed at baseline and 0, 30, 60, 120, 180 and 240 min after one-hour secondhand smoke exposure at bar/restaurant levels. Exhaled NO and CO measurements, exhaled breath condensate collection (for pH, H(2)O(2) and NO(2)(-)/NO(3)(-) measurements) and spirometry were performed at all time-points. Secondhand smoke exposure induced increases in serum cotinine and exhaled CO that persisted until 240 min. Exhaled breath condensate pH decreased immediately after exposure (p < 0.001) and returned to baseline by 180 min, whereas H(2)O(2) increased at 120 min and remained increased at 240 min (p = 0.001). No changes in exhaled NO and NO(2)/NO(3) were observed, while decreases in FEV(1) (p < 0.001) and FEV(1)/FVC (p < 0.001) were observed after exposure and returned to baseline by 180 min. A 1-h exposure to secondhand smoke induced airway acidification and increased airway oxidative stress, accompanied by significant impairment of lung function. Despite the reversal in EBC pH and lung function, airway oxidative stress remained increased 4 h after the exposure. Clinical trial registration number (EudraCT): 2009-013545-28. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits

    PubMed Central

    Vieira-Brock, Paula L.; McFadden, Lisa M.; Nielsen, Shannon M.; Ellis, Jonathan D.; Walters, Elliot T.; Stout, Kristen A.; McIntosh, J. Michael; Wilkins, Diana G.; Hanson, Glen R.

    2015-01-01

    Repeated methamphetamine (METH) administrations cause persistent dopaminergic deficits resembling aspects of Parkinson’s disease. Many METH abusers smoke cigarettes and thus self-administer nicotine; yet few studies have investigated the effects of nicotine on METH-induced dopaminergic deficits. This interaction is of interest because preclinical studies demonstrate that nicotine can be neuroprotective, perhaps owing to effects involving α4β2 and α6β2 nicotinic acetylcholine receptors (nAChRs). This study revealed that oral nicotine exposure beginning in adolescence [postnatal day (PND) 40] through adulthood [PND 96] attenuated METH-induced striatal dopaminergic deficits when METH was administered at PND 89. This protection did not appear to be due to nicotine-induced alterations in METH pharmacokinetics. Short-term (i.e., 21-day) high-dose nicotine exposure also protected when administered from PND 40 to PND 61 (with METH at PND 54), but this protective effect did not persist. Short-term (i.e., 21-day) high-dose nicotine exposure did not protect when administered postadolescence (i.e., beginning at PND 61, with METH at PND 75). However, protection was engendered if the duration of nicotine exposure was extended to 39 days (with METH at PND 93). Autoradiographic analysis revealed that nicotine increased striatal α4β2 expression, as assessed using [125I]epibatidine. Both METH and nicotine decreased striatal α6β2 expression, as assessed using [125I]α-conotoxin MII. These findings indicate that nicotine protects against METH-induced striatal dopaminergic deficits, perhaps by affecting α4β2 and/or α6β2 expression, and that both age of onset and duration of nicotine exposure affect this protection. PMID:26391161

  11. Radiation-induced taste aversion: effects of radiation exposure level and the exposure-taste interval

    SciTech Connect

    Spector, A.C.; Smith, J.C.; Hollander, G.R.

    1986-05-01

    Radiation-induced taste aversion has been suggested to possibly play a role in the dietary difficulties observed in some radiotherapy patients. In rats, these aversions can still be formed even when the radiation exposure precedes the taste experience by several hours. This study was conducted to examine whether increasing the radiation exposure level could extend the range of the exposure-taste interval that would still support the formation of a taste aversion. Separate groups of rats received either a 100 or 300 R gamma-ray exposure followed 1, 3, 6, or 24 h later by a 10-min saccharin (0.1% w/v) presentation. A control group received a sham exposure followed 1 h later by a 10-min saccharin presentation. Twenty-four hours following the saccharin presentation all rats received a series of twelve 23-h two-bottle preference tests between saccharin and water. The results indicated that the duration of the exposure-taste interval plays an increasingly more important role in determining the initial extent of the aversion as the dose decreases. The course of recovery from taste aversion seems more affected by dose than by the temporal parameters of the conditioning trial.

  12. Exposure to diesel exhaust particulates induces cardiac dysfunction and remodeling

    PubMed Central

    Bradley, Jessica M.; Cryar, Kipp A.; El Hajj, Milad C.; El Hajj, Elia C.

    2013-01-01

    Chronic exposure to diesel exhaust particulates (DEP) increases the risk of cardiovascular disease in urban residents, predisposing them to the development of several cardiovascular stresses, including myocardial infarctions, arrhythmias, thrombosis, and heart failure. DEP contain a high level of polycyclic aromatic hydrocarbons, which activate the aryl hydrocarbon receptor (AHR). We hypothesize that exposure to DEP elicits ventricular remodeling through the activation of the AHR pathway, leading to ventricular dilation and dysfunction. Male Sprague-Dawley rats were exposed by nose-only nebulization to DEP (SRM 2975, 0.2 mg/ml) or vehicle for 20 min/day × 5 wk. DEP exposure resulted in eccentric left ventricular dilation (8% increased left ventricular internal diameter at diastole and 23% decreased left ventricular posterior wall thickness at diastole vs. vehicle), as shown by echocardiograph assessment. Histological analysis using Picrosirius red staining revealed that DEP reduced cardiac interstitial collagen (23% decrease vs. vehicle). Further assessment of cardiac function using a pressure-volume catheter indicated impaired diastolic function (85% increased end-diastolic pressure and 19% decreased Tau vs. vehicle) and contractility (57 and 48% decreased end-systolic pressure-volume relationship and maximum change in pressure over time vs. end-diastolic volume compared with vehicle, respectively) in the DEP-exposed animals. Exposure to DEP significantly increased cardiac expression of AHR (19% increase vs. vehicle). In addition, DEP significantly decreased the cardiac expression of hypoxia inducible factor-1α, the competitive pathway to the AHR, and vascular endothelial growth factor, a downstream mediator of hypoxia inducible factor-1α (26 and 47% decrease vs. vehicle, respectively). These findings indicate that exposure to DEP induced left ventricular dilation by loss of collagen through an AHR-dependent mechanism. PMID:23887904

  13. Prenatal exposure to nitrofen induces Fryns phenotype in mice.

    PubMed

    Acosta, J M; Chai, Y; Meara, J G; Bringas, P; Anderson, K D; Warburton, D

    2001-06-01

    Prenatal exposure to nitrofen is known to cause multiple malformations in mice. The reported malformations include lung hypoplasia, diaphragmatic hernia, cardiovascular defects, skeletal malformations, cleft palate, and renal abnormalities. The authors present detailed findings of craniofacial defects after prenatal exposure to nitrofen, and propose that together with the previously reported malformations, nitrofen exposure induces a Fryns phenotype in mice. Fryns syndrome is a rare human genetic syndrome that is an autosomal recessive disorder characterized by lung hypoplasia, diaphragmatic hernia, craniofacial malformations, skeletal malformations, cardiovascular malformations, and genitourinary malformations. Timed-pregnant Swiss Webster mice were gavage-fed 25 mg of nitrofen on day 8 of gestation. Control animals received olive oil. Osteogenesis and chondrogenesis were studied in fetuses recovered on day 17 after Alcian blue-Alizarin red staining. Approximately 26% of the nitrofen-exposed embryos had severe craniofacial defects, and there was generalized delay in chondrogenesis and osteogenesis throughout the skeleton. No such defects were noted in the control group. The authors propose that prenatal exposure to nitrofen induces a Fryns phenotype in mice, and thus speculate that nitrofen may target similar molecular mechanisms to those that lead to Fryns syndrome.

  14. Environmental Arsenic Exposure and Microbiota in Induced Sputum

    PubMed Central

    White, Allison G.; Watts, George S.; Lu, Zhenqiang; Meza-Montenegro, Maria M.; Lutz, Eric A.; Harber, Philip; Burgess, Jefferey L.

    2014-01-01

    Arsenic exposure from drinking water is associated with adverse respiratory outcomes, but it is unknown whether arsenic affects pulmonary microbiota. This exploratory study assessed the effect of exposure to arsenic in drinking water on bacterial diversity in the respiratory tract of non-smokers. Induced sputum was collected from 10 subjects with moderate mean household water arsenic concentration (21.1 ± 6.4 ppb) and 10 subjects with low household water arsenic (2.4 ± 0.8 ppb). To assess microbiota in sputum, the V6 hypervariable region amplicons of bacterial 16s rRNA genes were sequenced using the Ion Torrent Personal Genome Machine. Microbial community differences between arsenic exposure groups were evaluated using QIIME and Metastats. A total of 3,920,441 sequence reads, ranging from 37,935 to 508,787 per sample for 316 chips after QIIME quality filtering, were taxonomically classified into 142 individual genera and five phyla. Firmicutes (22%), Proteobacteria (17%) and Bacteriodetes (12%) were the main phyla in all samples, with Neisseriaceae (15%), Prevotellaceae (12%) and Veillonellacea (7%) being most common at the genus level. Some genera, including Gemella, Lactobacillales, Streptococcus, Neisseria and Pasteurellaceae were elevated in the moderate arsenic exposure group, while Rothia, Prevotella, Prevotellaceae Fusobacterium and Neisseriaceae were decreased, although none of these differences was statistically significant. Future studies with more participants and a greater range of arsenic exposure are needed to further elucidate the effects of drinking water arsenic consumption on respiratory microbiota. PMID:24566055

  15. Environmental arsenic exposure and microbiota in induced sputum.

    PubMed

    White, Allison G; Watts, George S; Lu, Zhenqiang; Meza-Montenegro, Maria M; Lutz, Eric A; Harber, Philip; Burgess, Jefferey L

    2014-02-21

    Arsenic exposure from drinking water is associated with adverse respiratory outcomes, but it is unknown whether arsenic affects pulmonary microbiota. This exploratory study assessed the effect of exposure to arsenic in drinking water on bacterial diversity in the respiratory tract of non-smokers. Induced sputum was collected from 10 subjects with moderate mean household water arsenic concentration (21.1 ± 6.4 ppb) and 10 subjects with low household water arsenic (2.4 ± 0.8 ppb). To assess microbiota in sputum, the V6 hypervariable region amplicons of bacterial 16s rRNA genes were sequenced using the Ion Torrent Personal Genome Machine. Microbial community differences between arsenic exposure groups were evaluated using QIIME and Metastats. A total of 3,920,441 sequence reads, ranging from 37,935 to 508,787 per sample for 316 chips after QIIME quality filtering, were taxonomically classified into 142 individual genera and five phyla. Firmicutes (22%), Proteobacteria (17%) and Bacteriodetes (12%) were the main phyla in all samples, with Neisseriaceae (15%), Prevotellaceae (12%) and Veillonellacea (7%) being most common at the genus level. Some genera, including Gemella, Lactobacillales, Streptococcus, Neisseria and Pasteurellaceae were elevated in the moderate arsenic exposure group, while Rothia, Prevotella, Prevotellaceae Fusobacterium and Neisseriaceae were decreased, although none of these differences was statistically significant. Future studies with more participants and a greater range of arsenic exposure are needed to further elucidate the effects of drinking water arsenic consumption on respiratory microbiota.

  16. Chronic intermittent hypoxia exposure-induced atherosclerosis: a brief review.

    PubMed

    Song, Dongmei; Fang, Guoqiang; Greenberg, Harly; Liu, Shu Fang

    2015-12-01

    Obstructive sleep apnea (OSA) is highly prevalent in the USA and is recognized as an independent risk factor for atherosclerotic cardiovascular disease. Identification of atherosclerosis risk factor attributable to OSA may provide opportunity to develop preventive measures for cardiovascular risk reduction. Chronic intermittent hypoxia (CIH) is a prominent feature of OSA pathophysiology and may be a major mechanism linking OSA to arteriosclerosis. Animal studies demonstrated that CIH exposure facilitated high-cholesterol diet (HCD)-induced atherosclerosis, accelerated the progression of existing atherosclerosis, and induced atherosclerotic lesions in the absence of other atherosclerosis risk factors, demonstrating that CIH is an independent causal factor of atherosclerosis. Comparative studies revealed major differences between CIH-induced and the classic HCD-induced atherosclerosis. Systemically, CIH was a much weaker inducer of atherosclerosis. CIH and HCD differentially activated inflammatory pathways. Histologically, CIH-induced atherosclerotic plaques had no clear necrotic core, contained a large number of CD31+ endothelial cells, and had mainly elastin deposition, whereas HCD-induced plaques had typical necrotic cores and fibrous caps, contained few endothelial cells, and had mainly collagen deposition. Metabolically, CIH caused mild, but HCD caused more severe dyslipidemia. Mechanistically, CIH did not, but HCD did, cause macrophage foam cell formation. NF-κB p50 gene deletion augmented CIH-induced, but not HCD-induced atherosclerosis. These differences reflect the intrinsic differences between the two types of atherosclerosis in terms of pathological nature and underlying mechanisms and support the notion that CIH-induced atherosclerosis is a new paradigm that differs from the classic HCD-induced atherosclerosis.

  17. Fertilization Induces a Transient Exposure of Phosphatidylserine in Mouse Eggs

    PubMed Central

    Curia, Claudio A.; Ernesto, Juan I.; Stein, Paula; Busso, Dolores; Schultz, Richard M.; Cuasnicu, Patricia S.; Cohen, Débora J.

    2013-01-01

    Phosphatidylserine (PS) is normally localized to the inner leaflet of the plasma membrane and the requirement of PS translocation to the outer leaflet in cellular processes other than apoptosis has been demonstrated recently. In this work we investigated the occurrence of PS mobilization in mouse eggs, which express flippase Atp8a1 and scramblases Plscr1 and 3, as determined by RT-PCR; these enzyme are responsible for PS distribution in cell membranes. We find a dramatic increase in binding of flouresceinated-Annexin-V, which specifically binds to PS, following fertilization or parthenogenetic activation induced by SrCl2 treatment. This increase was not observed when eggs were first treated with BAPTA-AM, indicating that an increase in intracellular Ca2+ concentration was required for PS exposure. Fluorescence was observed over the entire egg surface with the exception of the regions overlying the meiotic spindle and sperm entry site. PS exposure was also observed in activated eggs obtained from CaMKIIγ null females, which are unable to exit metaphase II arrest despite displaying Ca2+ spikes. In contrast, PS exposure was not observed in TPEN-activated eggs, which exit metaphase II arrest in the absence of Ca2+ release. PS exposure was also observed when eggs were activated with ethanol but not with a Ca2+ ionophore, suggesting that the Ca2+ source and concentration are relevant for PS exposure. Last, treatment with cytochalasin D, which disrupts microfilaments, or jasplakinolide, which stabilizes microfilaments, prior to egg activation showed that PS externalization is an actin-dependent process. Thus, the Ca2+ rise during egg activation results in a transient exposure of PS in fertilized eggs that is not associated with apoptosis. PMID:23951277

  18. Early embryonic androgen exposure induces transgenerational epigenetic and metabolic changes.

    PubMed

    Xu, Ning; Chua, Angela K; Jiang, Hong; Liu, Ning-Ai; Goodarzi, Mark O

    2014-08-01

    Androgen excess is a central feature of polycystic ovary syndrome (PCOS), which affects 6% to 10% of young women. Mammals exposed to elevated androgens in utero develop PCOS-like phenotypes in adulthood, suggesting fetal origins of PCOS. We hypothesize that excess androgen exposure during early embryonic development may disturb the epigenome and disrupt metabolism in exposed and unexposed subsequent generations. Zebrafish were used to study the underlying mechanism of fetal origins. Embryos were exposed to androgens (testosterone and dihydrotestosterone) early at 26 to 56 hours post fertilization or late at 21 to 28 days post fertilization. Exposed zebrafish (F0) were grown to adults and crossed to generate unexposed offspring (F1). For both generations, global DNA methylation levels were examined in ovaries using a luminometric methylation assay, and fasting and postprandial blood glucose levels were measured. We found that early but not late androgen exposure induced changes in global methylation and glucose homeostasis in both generations. In general, F0 adult zebrafish exhibited altered global methylation levels in the ovary; F1 zebrafish had global hypomethylation. Fasting blood glucose levels were decreased in F0 but increased in F1; postprandial glucose levels were elevated in both F0 and F1. This androgenized zebrafish study suggests that transient excess androgen exposure during early development can result in transgenerational alterations in the ovarian epigenome and glucose homeostasis. Current data cannot establish a causal relationship between epigenetic changes and altered glucose homeostasis. Whether transgenerational epigenetic alteration induced by prenatal androgen exposure plays a role in the development of PCOS in humans deserves study.

  19. Statin-induced myopathy in the rat: relationship between systemic exposure, muscle exposure and myopathy.

    PubMed

    Sidaway, J; Wang, Y; Marsden, A M; Orton, T C; Westwood, F R; Azuma, C T; Scott, R C

    2009-01-01

    Rare instances of myopathy are associated with all statins, but cerivastatin was withdrawn from clinical use due to a greater incidence of myopathy. The mechanism of statin-induced myopathy with respect to tissue disposition was investigated by measuring the systemic, hepatic, and skeletal muscle exposure of cerivastatin, rosuvastatin, and simvastatin in rats before and after muscle damage. The development of myopathy was not associated with the accumulation of statins in skeletal muscle. For each statin exposure was equivalent in muscles irrespective of their fibre-type sensitivity to myopathy. The low amount of each statin in skeletal muscle relative to the liver does not support a significant role for transporters in the disposition of statins in skeletal muscle. Finally, the concentration of cerivastatin necessary to cause necrosis in skeletal muscle was considerably lower than rosuvastatin or simvastatin, supporting the concept cerivastatin is intrinsically more myotoxic than other statins.

  20. [The advance of model of action in low-dose chronic benzene exposure induced hematotoxicity].

    PubMed

    Gao, Chen; Zhang, Zhengbao; Chen, Liping; Chen, Wen

    2015-09-01

    Benzene is classified as Group 1 carcinogen by IARC. It has been found that benzene induces hematotoxicity even in low dose exposure. The identification of key events during benzene induced hematotoxicty leads to adjustment of occupational exposure limits of benzene. In this review, we focus on the exposure, metabolism, target organs, key epigenetic changes, toxicty effects and end points of low-dose chronic benzene exposure induced hematotoxicity and finally discuss the perspectives on the future study of this area.

  1. Converging concepts: adaptive response, preconditioning, and the Yerkes-Dodson Law are manifestations of hormesis.

    PubMed

    Calabrese, Edward J

    2008-01-01

    The adaptive response in toxicology and environmental mutagenesis, preconditioning in biomedicine and the Yerkes-Dodson Law in psychology have dominating research themes with widespread and significant scientific and societal implications. This paper suggests that these apparently independent biological dose-response phenomena are manifestations of the common and more general biphasic dose-response relationship concept called hormesis. These three types of dose-response, as well as the hormesis concept, may represent the same general type of adaptation, which were discovered independently in different biological disciplines, amongst which there has been little communication. This intellectual isolation, due principally to progressively greater disciplinary specialization, resulted in the evolution of different terminologies for dose-response phenomena with strikingly similar quantitative features. This lack of recognition of converging dose-response concepts across disciplines has important implications since it limits the recognition of a common and basic biological concept while minimizing collaborations by investigators in related areas. The paper concludes that the broadly recognized biological adaptive responses, as described by the concepts of adaptive response, preconditioning and the Yerkes-Dodson Law, are special cases of the more general hormesis dose-response concept.

  2. Abnormal cardiovascular responses induced by localized high power microwave exposure

    SciTech Connect

    Lu, S.-T; Brown, D.O.; Johnson, C.E.; Mathur, S.P. ); Elson, E.C. )

    1992-05-01

    A hypothesis of microwave-induced circulatory under perfusion was tested in ketamine anesthetized rats whose heart rate, mean arterial pressure, pulse pressure, respiration rate, and body temperatures were monitored continuously. Fifty-eight ventral head and neck exposures in a waveguide consisted of sham-exposure and exposure to continuous wave (CW) and pulsed 1.25 GHz microwaves for 5 min. The 0.5 Hz and 16 Hz pulsemodulated microwaves were delivered at 400 kW peak power. The CW microwaves were 2 and 6.4 W. The average specific absorption rate was 4.75 W/kg per watt transmitted in the brain and 17.15 W/kg per watt transmitted in the neck. Respiration rate and mean arterial pressure were not altered. Changes in heart rate and pulse pressure were observed in rats exposed to higher power but not to the lower average power microwaves. Depression of pulse pressure, an indication of a decrease in stroke volume, and increased or decreased heart rate were noted in presence of whole-body hyperthermia. The cardiac output of those animals exposed to higher average power microwaves was considered to be below normal as hypothesized. Decreased cardiac output and normal mean arterial pressure resulted in an increase in the total peripheral resistance which was contrary to the anticipated thermal response of animals.

  3. Amorphous nanosilicas induce consumptive coagulopathy after systemic exposure

    NASA Astrophysics Data System (ADS)

    Nabeshi, Hiromi; Yoshikawa, Tomoaki; Matsuyama, Keigo; Nakazato, Yasutaro; Arimori, Akihiro; Isobe, Masaaki; Tochigi, Saeko; Kondoh, Sayuri; Hirai, Toshiro; Akase, Takanori; Yamashita, Takuya; Yamashita, Kohei; Yoshida, Tokuyuki; Nagano, Kazuya; Abe, Yasuhiro; Yoshioka, Yasuo; Kamada, Haruhiko; Imazawa, Takayoshi; Itoh, Norio; Kondoh, Masuo; Yagi, Kiyohito; Mayumi, Tadanori; Tsunoda, Shin-ichi; Tsutsumi, Yasuo

    2012-02-01

    We previously reported that well-dispersed amorphous nanosilicas with particle size 70 nm (nSP70) penetrate skin and produce systemic exposure after topical application. These findings underscore the need to examine biological effects after systemic exposure to nanosilicas. The present study was designed to examine the biological effects. BALB/c mice were intravenously injected with amorphous nanosilicas of sizes 70, 100, 300, 1000 nm and then assessed for survival, blood biochemistry, and coagulation. As a result, injection of nSP70 caused fatal toxicity, liver damage, and platelet depletion, suggesting that nSP70 caused consumptive coagulopathy. Additionally, nSP70 exerts procoagulant activity in vitro associated with an increase in specific surface area, which increases as diameter reduces. In contrast, nSP70-mediated procoagulant activity was absent in factor XII-deficient plasma. Collectively, we revealed that interaction between nSP70 and intrinsic coagulation factors such as factor XII, were deeply related to nSP70-induced harmful effects. In other words, it is suggested that if interaction between nSP70 and coagulation factors can be suppressed, nSP70-induced harmful effects may be avoided. These results would provide useful information for ensuring the safety of nanomaterials (NMs) and open new frontiers in biological fields by the use of NMs.

  4. Bacterial Exposure Induces and Activates Matrilysin in Mucosal Epithelial Cells

    PubMed Central

    López-Boado, Yolanda S.; Wilson, Carole L.; Hooper, Lora V.; Gordon, Jeffrey I.; Hultgren, Scott J.; Parks, William C.

    2000-01-01

    Matrilysin, a matrix metalloproteinase, is expressed and secreted lumenally by intact mucosal and glandular epithelia throughout the body, suggesting that its regulation and function are shared among tissues. Because matrilysin is produced in Paneth cells of the murine small intestine, where it participates in innate host defense by activation of prodefensins, we speculated that its expression would be influenced by bacterial exposure. Indeed, acute infection (10–90 min) of human colon, bladder, and lung carcinoma cells, primary human tracheal epithelial cells, and human tracheal explants with type 1–piliated Escherichia coli mediated a marked (25–50-fold) and sustained (>24 h) induction of matrilysin production. In addition, bacterial infection resulted in activation of the zymogen form of the enzyme, which was selectively released at the apical surface. Induction of matrilysin was mediated by a soluble, non-LPS bacterial factor and correlated with the release of defensin-like bacteriocidal activity. Bacteria did not induce matrilysin in other cell types, and expression of other metalloproteinases by epithelial cells was not affected by bacteria. Matrilysin was not detected in germ-free mice, but the enzyme was induced after colonization with Bacteroides thetaiotaomicron. These findings indicate that bacterial exposure is a potent and physiologically relevant signal regulating matrilysin expression in epithelial cells. PMID:10725342

  5. Exposure to cold impairs interferon-induced antiviral defense.

    PubMed

    Boonarkart, Chompunuch; Suptawiwat, Ornpreya; Sakorn, Kittima; Puthavathana, Pilaipan; Auewarakul, Prasert

    2017-08-01

    It is commonly believed that exposure to low temperature increases susceptibility to viral infection in the human respiratory tract, but a molecular mechanism supporting this belief has yet to be discovered. In this study, we investigated the effect of low temperature on viral infection and innate defense in cell lines from the human respiratory tract and found that interferon-induced antiviral responses were impaired at low temperatures. Cells maintained at 25°C and 33°C expressed lower levels of myxovirus resistance protein 1 (MxA) and 2'5'-oligoadenylate synthetase 1 (OAS1) mRNAs when compared to cells maintained at 37°C after infection by seasonal influenza viruses. Exogenous β-interferon treatment reduced the viral replication at 37°C, but not at 25°C. Our results suggest that the impairment of interferon-induced antiviral responses by low temperature is one of several mechanisms that could explain an increase in host susceptibility to respiratory viruses after exposure to cold temperature.

  6. ARSENIC EXPOSURE INDUCES THE WARBURG EFFECT IN CULTURED HUMAN CELLS

    PubMed Central

    Zhao, Fei; Severson, Paul; Pacheco, Samantha; Futscher, Bernard W.; Klimecki, Walter T.

    2013-01-01

    Understanding how arsenic exacts its diverse, global disease burden is hampered by a limited understanding of the particular biological pathways that are disrupted by arsenic and underlie pathogenesis. A reductionist view would predict that a small number of basic pathways are generally perturbed by arsenic, and manifest as diverse diseases. Following an initial observation that arsenite-exposed cells in culture acidify their media more rapidly than control cells, the report here shows that low level exposure to arsenite (75 ppb) is sufficient to induce aerobic glycolysis (the Warburg effect) as a generalized phenomenon in cultured human primary cells and cell lines. Expanded studies in one such cell line, the non-malignant pulmonary epithelial line, BEAS-2B, established that the arsenite-induced Warburg effect was associated with increased accumulation of intracellular and extracellular lactate, an increased rate of extracellular acidification, and inhibition by the non-metabolized glucose analog, 2-deoxyglucose. Associated with the induction of aerobic glycolysis was a pathway-wide induction of glycolysis gene expression, as well as protein accumulation of an established glycolysis master-regulator, hypoxia-inducible factor 1α. Arsenite-induced alteration of energy production in human cells represents the type of fundamental perturbation that could extend to many tissue targets and diseases. PMID:23648393

  7. Postnatal irradiation-induced hippocampal neuropathology, cognitive impairment and aging.

    PubMed

    Tang, Feng Ru; Loke, Weng Keong; Khoo, Boo Cheong

    2017-04-01

    Irradiation of the brain in early human life may set abnormal developmental events into motion that last a lifetime, leading to a poor quality of life for affected individuals. While the effect of irradiation at different early developmental stages on the late human life has not been investigated systematically, animal experimental studies suggest that acute postnatal irradiation with ⩾0.1Gy may significantly reduce neurogenesis in the dentate gyrus and endotheliogenesis in cerebral vessels and induce cognitive impairment and aging. Fractionated irradiation also reduces neurogenesis. Furthermore, irradiation induces hippocampal neuronal loss in CA1 and CA3 areas, neuroinflammation and reduces gliogenesis. The hippocampal neurovascular niche and the total number of microvessels are also changed after radiation exposures. Each or combination of these pathological changes may cause cognitive impairment and aging. Interestingly, acute irradiation of aged brain with a certain amount of radiation has also been reported to induce brain hormesis or neurogenesis. At molecular levels, inflammatory cytokines, chemokines, neural growth factors, neurotransmitters, their receptors and signal transduction systems, reactive oxygen species are involved in radiation-induced adverse effect on brain development and functions. Further study at different omics levels after low dose/dose rate irradiation may not only unravel the mechanisms of radiation-induced adverse brain effect or hormesis, but also provide clues for detection or diagnosis of radiation exposure and for therapeutic approaches to effectively prevent radiation-induced cognitive impairment and aging. Investigation focusing on radiation-induced changes of critical brain development events may reveal many previously unknown adverse effects.

  8. Exposure to arousal-inducing sounds facilitates visual search.

    PubMed

    Asutay, Erkin; Västfjäll, Daniel

    2017-09-04

    Exposure to affective stimuli could enhance perception and facilitate attention via increasing alertness, vigilance, and by decreasing attentional thresholds. However, evidence on the impact of affective sounds on perception and attention is scant. Here, a novel aspect of affective facilitation of attention is studied: whether arousal induced by task-irrelevant auditory stimuli could modulate attention in a visual search. In two experiments, participants performed a visual search task with and without auditory-cues that preceded the search. Participants were faster in locating high-salient targets compared to low-salient targets. Critically, search times and search slopes decreased with increasing auditory-induced arousal while searching for low-salient targets. Taken together, these findings suggest that arousal induced by sounds can facilitate attention in a subsequent visual search. This novel finding provides support for the alerting function of the auditory system by showing an auditory-phasic alerting effect in visual attention. The results also indicate that stimulus arousal modulates the alerting effect. Attention and perception are our everyday tools to navigate our surrounding world and the current findings showing that affective sounds could influence visual attention provide evidence that we make use of affective information during perceptual processing.

  9. Parasite Exposure Drives Selective Evolution of Constitutive versus Inducible Defense.

    PubMed

    Westra, Edze R; van Houte, Stineke; Oyesiku-Blakemore, Sam; Makin, Ben; Broniewski, Jenny M; Best, Alex; Bondy-Denomy, Joseph; Davidson, Alan; Boots, Mike; Buckling, Angus

    2015-04-20

    In the face of infectious disease, organisms evolved a range of defense mechanisms, with a clear distinction between those that are constitutive (always active) and those that are inducible (elicited by parasites). Both defense strategies have evolved from each other, but we lack an understanding of the conditions that favor one strategy over the other. While it is hard to generalize about their degree of protection, it is possible to make generalizations about their associated fitness costs, which are commonly detected. By definition, constitutive defenses are always "on," and are therefore associated with a fixed cost, independent of parasite exposure. Inducible defenses, on the other hand, may lack costs in the absence of parasites but become costly when defense is elicited through processes such as immunopathology. Bacteria can evolve constitutive defense against phage by modification/masking of surface receptors, which is often associated with reduced fitness in the absence of phage. Bacteria can also evolve inducible defense using the CRISPR-Cas (clustered regularly interspaced short palindromic repeat, CRISPR associated) immune system, which is typically elicited upon infection. CRISPR-Cas functions by integrating phage sequences into CRISPR loci on the host genome. Upon re-infection, CRISPR transcripts guide cleavage of phage genomes. In nature, both mechanisms are important. Using a general theoretical model and experimental evolution, we tease apart the mechanism that drives their evolution and show that infection risk determines the relative investment in the two arms of defense. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Skin temperature changes induced by strong static magnetic field exposure.

    PubMed

    Ichioka, Shigeru; Minegishi, Masayuki; Iwasaka, Masakazu; Shibata, Masahiro; Nakatsuka, Takashi; Ando, Joji; Ueno, Shoogo

    2003-09-01

    High intensity static magnetic fields, when applied to the whole body of the anesthetized rat, have previously been reported to decrease skin temperature. The hypothesis of the present study was that in diamagnetic water, molecules in the air play significant roles in the mechanism of skin temperature decrease. We used a horizontal cylindrical superconducting magnet. The magnet produced 8 T at its center. A thermistor probe was inserted in a subcutaneous pocket of the anesthetized rats to measure skin temperature. Animals (n=10) were placed in an open plastic holder in which the ambient air was free to move in any direction (group I). Animals (n=10) were placed in a closed holder in which the air circulation toward the direction of weak magnetic field was restricted (group II). Each holder was connected to a hydrometer to measure humidity around the animal in the holder. The data acquisition phase consisted of a 5 min baseline interval, followed by inserting the animal together with the holder into the center of the magnet bore for a 5 min exposure and a 5 min postexposure period outside the bore. In group I, skin temperature and humidity around the animal significantly decreased during exposure, followed by recovery after exposure. In group II, skin temperature and humidity did not decrease during the measurement. The skin temperature decrease was closely related to the decrease in humidity around the body of the animal in the holder, and the changes were completely blocked by restricting the air circulation in the direction of the bore entrance. Possible mechanisms responsible for the decrease in skin temperature may be associated with magnetically induced movement of water vapor at the skin surface, leading to skin temperature decrease. Copyright 2003 Wiley-Liss, Inc.

  11. Immune disorders induced by exposure to pyrethroid insecticides.

    PubMed

    Skolarczyk, Justyna; Pekar, Joanna; Nieradko-Iwanicka, Barbara

    2017-06-08

    Pyrethroids are biocides, which belong to the third generation of insecticides. They are used as biocides, insecticides and medicines. These agents react selectively, because they are less harmful to birds and mammals (due to poor intestinal absorption and rapid detoxification in the body of homeothermic organisms) and they are poisonous for fish and insects. The aim of the article is to present the current state of knowledge on the effects of pyrethroids on the immune system based on the latest scientific research. The mechanism of action of pyrethroids include the delaying closure of voltage- sensitive sodium and chloride channels (including GABA- dependent channels). These compounds are neurotoxic. Studies have shown that they cause numerous immune disorders contributing to lowering of immunity in humans and animals. Exposure to pyrethroids can cause inhibition of proliferation of peripheral blood leukocytes and reducing the concentration of IgG immunolgobulines. They also cause reduced macrophages and decrease in interleukin 2 (IL-2), interleukin 8 (IL-8), interleukin 12p70 (IL-12p70), and interferon γ (IFN-γ). Some of these compounds cause increase of liver weight and increase of bone marrow cellularity, and may induce apoptosis of the thymus. Pyrethroids can cause allergies and asthma. Their immunosuppressive effects can impair host resistance against infections. Exposure to these compounds can also contribute to induction of the cancer, especially in patients with impaired immune function.

  12. Sublethal and hormesis effects of beta-cypermethrin on the biology, life table parameters and reproductive potential of soybean aphid Aphis glycines.

    PubMed

    Qu, Yanyan; Xiao, Da; Liu, Junjie; Chen, Zhou; Song, Lifang; Desneux, Nicolas; Benelli, Giovanni; Gao, Xiwu; Song, Dunlun

    2017-07-06

    Beta-cypermethrin has long been recommended as an effective pesticide to control the soybean aphid, Aphis glycines Matsumura, a serious pest in soybean crops. Besides acute toxicity, it leads to changes in life history traits of A. glycines, notably its reproductive potential. This study has assessed the effects of five sublethal concentrations (0.625, 1.25, 2.5, 5 and 10 µg/L) of beta-cypermethrin on different life history traits of A. glycines. Exposure to these concentrations caused shorter oviposition period and reduced adult longevity. The strongest stimulatory effect on aphid reproduction was achieved when exposed to a higher sublethal beta-cypermethrin concentration (5 µg/L). Net reproduction rate (R 0 ), intrinsic rate of increase (r m ) and finite rate of increase (λ) were significantly higher than that of the control, increasing by 20.58, 4.89 and 2.06%, respectively. We found no significant difference in mean generation time (T) between the treatment of 5 µg/L beta-cypermethrin and the control. However, when the concentration increased to 10 µg/L, the reproduction behavior was restrained and the mean generation time (T) was shortened, resulting in significant decrease in R 0 and T by 16.58 and 3.83%, respectively. In conclusion, a sublethal concentration (5 µg/L) of beta-cypermethrin triggered the strongest hormesis on A.glycines, thus providing valuable knowledge on the sublethal effects of this insecticide on soybean aphids. Hormesis may be one of the mechanisms underlying pest resurgences, and better knowledge would enable a more effective use of insecticides in Integrated Pest Management programs.

  13. Cerebrovascular endothelial dysfunction induced by mercury exposure at low concentrations.

    PubMed

    Wiggers, Giulia Alessandra; Furieri, Lorena Barros; Briones, Ana María; Avendaño, María Soledad; Peçanha, Franck Maciel; Vassallo, Dalton Valentim; Salaices, Mercedes; Alonso, María Jesús

    2016-03-01

    Mercury (Hg) has many harmful vascular effects by increasing oxidative stress, inflammation and vascular/endothelial dysfunction, all of which may contribute to cerebrovascular diseases development. We aimed to explore the effects of chronic low-mercury concentration on vascular function in cerebral arteries and the mechanisms involved. Basilar arteries from control (vehicle-saline solution, im) and mercury chloride (HgCl2)-treated rats for 30 days (first dose 4.6μg/kg, subsequent dose 0.07μg/kg/day, im, to cover daily loss) were used. Vascular reactivity, protein expression, nitric oxide (NO) levels and superoxide anion (O2(-)) production were analyzed. HgCl2 exposure increased serotonin contraction and reduced the endothelium-dependent vasodilatation to bradykinin. After NO synthase inhibition, serotonin responses were enhanced more in control than in mercury-treated rats while bradykinin-induced relaxation was abolished. NO levels were greater in control than Hg-treated rats. Tiron and indomethacin reduced vasoconstriction and increased the bradykinin-induced relaxation only in HgCl2-treated rats. Vascular O2(-) production was greater in mercury-treated when compared to control rats. Protein expressions of endothelial NO synthase, copper/zinc (Cu/Zn), Manganese (Mn) and extracellular-superoxide dismutases were similar in cerebral arteries from both groups. Results suggest that Hg treatment increases cerebrovascular reactivity by reducing endothelial negative modulation and NO bioavailability; this effect seems to be dependent on increased reactive oxygen species and prostanoids generation. These findings show, for the first time, that brain vasculature are also affected by chronic mercury exposure and offer further evidence that even at small concentration, HgCl2 is hazardous and might be an environmental risk factor accounting for cerebral vasospasm development.

  14. Scientific foundations of hormesis. Part 2. Maturation, strengths, limitations, and possible applications in toxicology, pharmacology, and epidemiology.

    PubMed

    Rozman, Karl K; Doull, John

    2003-01-01

    The notion of hormesis has undergone numerous modifications in the course of the 20th century. Because of its unfortunate association with homeopathy, hormesis did not gain acceptance among biomedical professionals. The lack of a plausible mechanism for its occurrence may have contributed much to the rejection of this concept. This treatise outlines the conceptual struggle for an understanding of the widespread occurrence of low dose effects that appear to be opposite to those caused by high doses as also seen in hormesis. An incomplete conceptualization of time as a fundamental variable of effects (in addition to dose) is identified as one of the major reasons why hermetic responses were not observed more frequently than was reported by Calabrese and Baldwin. The definition of hormesis as an (over)compensation response to an inhibitory signal lacks a designation for (over)compensation responses to stimulatory signals in the other direction. Hormoligosis, which was coined by Luckey for all low-dose stimulatory responses of toxins, is suggested as a suitable term for generalizing the latter types of effects. Both types of effects are recognized as originating in a homeostatic overcompensation response that optimizes the ability of an organism to meet challenges beyond the limits of normal (unexercised) adaptation. Thus, repeated biochemical/physiologic/immunological, etc. exercises like physical exercise make an organism more fit and hence both hormetic and hormoligotic effects will have life-prolonging consequences. A more complete generalization was developed by linking hormesis/hormoligosis with the vast literature on Selye's general adaptation syndrome to stress. According to this broader view, stress is just one type of homeostatic exercise making organisms more fit for future biochemical/physiological/immunological, etc.challenges. Therefore, both hormesis and hormoligosis are manifestations of two nonmutational evolutionary principles--homeostasis and

  15. Is the Hygiene Hypothesis an Example of Hormesis?

    PubMed Central

    Bukowski, John A.; Lewis, R. Jeffrey

    2003-01-01

    The “hygiene hypothesis” has been suggested to explain the rising incidence of allergic disorders in developed countries. The postulated mechanism is that infectious and/or microbial agents stimulate the immune system toward Th1 (allergy fighting) rather than Th2 (allergy promoting) response. This paper reviews the evidence related to early life infectious/microbial exposures and subsequent atopic disorders and evaluates whether these data suggest a hormetic effect. Our review indicates an insufficient and contradictory association for bacterial/viral infections, with protective effects being either absent or specific to certain infections and/or populations. Chronic, heavy parasitic burdens appear to confer protection against atopic disorders, but are associated with considerable pathology. Moreover, light parasitic burden may increase allergic responses (i.e., no “low dose” beneficial effect). In contrast, there is consistent evidence that general microbial exposures, particularly gut commensals, may be protective against allergy development, which is consistent with a hormetic effect (i.e., potentially beneficial effects at low doses and detrimental effects at high levels). Conclusion: General microbial exposures in relation to the “hygiene hypothesis” may represent a hormetic effect, although further research with more rigorous study methods (i.e., prospective designs and measurement of exposure timing, dose, route, etc.) are needed. PMID:19330119

  16. Different cell responses induced by exposure to maghemite nanoparticles

    NASA Astrophysics Data System (ADS)

    Luengo, Yurena; Nardecchia, Stefania; Morales, María Puerto; Serrano, M. Concepción

    2013-11-01

    Recent advances in nanotechnology have permitted the development of a wide repertoire of inorganic magnetic nanoparticles (NPs) with extensive promise for biomedical applications. Despite this remarkable potential, many questions still arise concerning the biocompatible nature of NPs when in contact with biological systems. Herein, we have investigated how controlled changes in the physicochemical properties of iron oxide NPs at their surface (i.e., surface charge and hydrodynamic size) affect, first, their interaction with cell media components and, subsequently, cell responses to NP exposure. For that purpose, we have prepared iron oxide NPs with three different coatings (i.e., dimercaptosuccinic acid - DMSA, (3-aminopropyl)triethoxysilane - APS and dextran) and explored the response of two different cell types, murine L929 fibroblasts and human Saos-2 osteoblasts, to their exposure. Interestingly, different cell responses were found depending on the NP concentration, surface charge and cell type. In this sense, neutral NPs, as those coated with dextran, induced negligible cell damage, as their cellular internalization was significantly reduced. In contrast, surface-charged NPs (i.e., those coated with DMSA and APS) caused significant cellular changes in viability, morphology and cell cycle under certain culture conditions, as a result of a more active cellular internalization. These results also revealed a particular cellular ability to detect and remember the original physicochemical properties of the NPs, despite the formation of a protein corona when incubated in culture media. Overall, conclusions from these studies are of crucial interest for future biomedical applications of iron oxide NPs.Recent advances in nanotechnology have permitted the development of a wide repertoire of inorganic magnetic nanoparticles (NPs) with extensive promise for biomedical applications. Despite this remarkable potential, many questions still arise concerning the biocompatible

  17. Acid exposure induces multiplication of Salmonella enterica serovar Typhi.

    PubMed

    Ahirwar, Suneel Kumar; Pratap, Chandra Bhan; Patel, Saurabh Kumar; Shukla, Vijay K; Singh, Indarjeet Gambhir; Mishra, Om Prakash; Kumar, Kailash; Singh, Tej Bali; Nath, Gopal

    2014-12-01

    Salmonella enterica serovar Typhi faces several environmental stresses while going through the stomach (acidic pH) to the small intestine (basic pH) and intracellularly in macrophages (acidic pH) in humans. The acidic pH followed by alkaline pH in the small intestine might be responsible for expression of certain stress-induced genes, resulting in not only better survival but also induction of multiplication and invasion of the bacterium in the small intestine. Based on this hypothesis, we developed a process wherein we exposed the blood, urine, and stool specimens from 90 acute typhoid fever patients and 36 chronic typhoid carriers to acidic pH to see the effect on isolation rate of S. Typhi. About 5 g of freshly passed unpreserved stool, a centrifuged deposit of 15 ml of urine, and 5 ml of blood clot were subjected to 5 ml of Luria-Bertani (LB) broth (pH 3.5) for 20 min, followed by enrichment in bile broth-selenite F broth. When the combined isolation from all 3 specimens, i.e., blood, urine, and stool, after acid exposure was considered, a total of 77.7% of the acute typhoid patients were observed to be positive for the isolation of the S. Typhi serotype, compared to 8.8% by the conventional method. Similarly, 42% (15/36) of chronic carriers yielded positive for S. Typhi growth after acid exposure, compared to 5.5% (2/36) by the conventional method. It therefore can be concluded that acid shock triggers the multiplication of the bacteria, resulting in better isolation rates from blood clot, stool, and urine specimens.

  18. Is the integration of hormesis and essentiality into ecotoxicology now opening Pandora's Box?

    PubMed

    Kefford, Ben J; Zalizniak, Liliana; Warne, Michael St J; Nugegoda, Dayanthi

    2008-02-01

    Hormesis and essentiality are likely real and common effects at the level of the individual. However, the widespread incorporation of stimulatory effects into applications of ecotoxicology requires the acceptance of assumptions, value judgements and possibly lowering of water/sediment quality standards. There is also currently little data appropriate for considering hormetic effects in the ecotoxicological context. Except perhaps in the case of fitting concentration-response curves, it is not clear that incorporation of hormetic and essentiality type responses into ecotoxicology is necessary. Furthermore, its incorporation presents considerable intellectual and practical changes for ecotoxicology and could have unanticipated consequences.

  19. Mice Brain Tissue Injury Induced by Diisononyl Phthalate Exposure and the Protective Application of Vitamin E.

    PubMed

    Peng, Ling

    2015-07-01

    As a widely used plasticizer in plastic industry, the data of diisononyl phthalate (DINP) toxicity due to exposure are insufficient. This work investigated the brain tissue injury induced by DINP exposure. Through oral exposure to DINP, oxidative stress, inflammatory responses, apoptosis, and hippocampus pathological alterations were found in the mice brain. And through the Morris water maze test, cognitive deficits were tested. Our data also showed that these exacerbations were counteracted by vitamin E. These results above indicated that oral exposure of mice to DINP induced brain damage, and oxidative stress, inflammation, and the consequential apoptosis jointly constituted the potential mechanisms of such induced toxicity. © 2015 Wiley Periodicals, Inc.

  20. Structural change of human hair induced by mercury exposure.

    PubMed

    Xing, Xueqing; Du, Rong; Li, Yufeng; Li, Bai; Cai, Quan; Mo, Guang; Gong, Yu; Chen, Zhongjun; Wu, Zhonghua

    2013-10-01

    Mercury is one of the most hazardous pollutants in the environment. In this paper, the structural change of human hair induced by mercury exposure was studied. Human hair samples were, respectively, collected from the normal Beijing area and the Hg-contaminated Wanshan area of the Guizhou Province, China. Inductively coupled plasma mass spectroscopy was used to detect the element contents. A small angle X-ray scattering technique was used to probe the structural change. Three reflections with 8.8, 6.7, and 4.5 nm spacing were compared between the normal and the Hg-contaminated hair samples. The results confirm that the 4.5 nm reflection is from the ordered fibrillar structure of glycosaminoglycan (GAG) in proteoglycan (PG) that composes the matrix around the intermediate filaments. The increase of Ca content makes the regular oriented fibrillar structure of GAG transform to a random oriented one, broadening the angular extent of the reflection with 4.5 nm spacing. However, overdose Hg makes the core proteins where the ordered fibrils of GAG are attached become coiled, which destroys the ordered arrangements of fibrillar GAG in PG, resulting in the disappearance of the reflections with 4.5 nm spacing. The disappearance of the 4.5 nm reflection can be used as a bioindicator of overdose Hg contamination to the human body. A supercoiled-coil model of hair nanoscale structure and a possible mechanism of mercury effect in human hair are proposed in this paper.

  1. Evidence supporting radiation hormesis in atomic bomb survivor cancer mortality data.

    PubMed

    Doss, Mohan

    2012-12-01

    A recent update on the atomic bomb survivor cancer mortality data has concluded that excess relative risk (ERR) for solid cancers increases linearly with dose and that zero dose is the best estimate for the threshold, apparently validating the present use of the linear no threshold (LNT) model for estimating the cancer risk from low dose radiation. A major flaw in the standard ERR formalism for estimating cancer risk from radiation (and other carcinogens) is that it ignores the potential for a large systematic bias in the measured baseline cancer mortality rate, which can have a major effect on the ERR values. Cancer rates are highly variable from year to year and between adjacent regions and so the likelihood of such a bias is high. Calculations show that a correction for such a bias can lower the ERRs in the atomic bomb survivor data to negative values for intermediate doses. This is consistent with the phenomenon of radiation hormesis, providing a rational explanation for the decreased risk of cancer observed at intermediate doses for which there is no explanation based on the LNT model. The recent atomic bomb survivor data provides additional evidence for radiation hormesis in humans.

  2. Hormesis, Cell Death, and Regenerative Medicine for Neurode-Generative Diseases

    PubMed Central

    Wang, Guanghu

    2013-01-01

    Although the adult human brain has a small number of neural stem cells, they are insufficient to repair the damaged brain to achieve significant functional recovery for neurodegenerative diseases and stroke. Stem cell therapy, by either enhancing endogenous neurogenesis, or transplanting stem cells, has been regarded as a promising solution. However, the harsh environment of the diseased brain posts a severe threat to the survival and correct differentiation of those new stem cells. Hormesis (or preconditioning, stress adaptation) is an adaptation mechanism by which cells or organisms are potentiated to survive an otherwise lethal condition, such as the harsh oxidative stress in the stroke brain. Stem cells treated by low levels of chemical, physical, or pharmacological stimuli have been shown to survive better in the neurodegenerative brain. Thus combining hormesis and stem cell therapy might improve the outcome for treatment of these diseases. In addition, since the cell death patterns and their underlying molecular mechanism may vary in different neurodegenerative diseases, even in different progression stages of the same disease, it is essential to design a suitable and optimum hormetic strategy that is tailored to the individual patient. PMID:23930104

  3. The notion of hormesis and the dose-response theory: a unified approach.

    PubMed

    Murado, M A; Vázquez, J A

    2007-02-07

    According to an opinion which is vigorous and insistently defended for approximately one decade, hormesis (the response of a biological entity to an effector, with stimulatory results at low doses and inhibitory results at high doses) radically puts into question the classic theory of dose-response (DR) relationships and demands a profound revision of environmental protection policies. Herein we show that DR theory, with the modifications which we propose, allows the modelling of various kinds of biphasic responses which are phenomenologically similar to hormetic ones and of well-defined origin, as well as responses which have been treated as genuinely hormetic. Our descriptive approach may also represent a useful resource for experimental design, directed towards identifying some of the potentially heterogeneous mechanisms which underlie the hormetic phenomenon. Finally, it also allows to discuss some factors which prevent the use of the notion of hormesis-perhaps useful in a clinical context, under strictly controlled conditions-to make decisions on environmental protection measures.

  4. Hormesis associated with a low dose of methylmercury injected into mallard eggs

    USGS Publications Warehouse

    Heinz, Gary H.; Hoffman, David J.; Klimstra, Jon D.; Stebbins, Katherine R.; Kondrad, Shannon L.; Erwin, Carol A.

    2012-01-01

    We injected mallard (Anas platyrhynchos) eggs with methylmercury chloride at doses of 0, 0.05, 0.1, 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 μg mercury/g egg contents on a wet-weight basis. A case of hormesis seemed to occur because hatching success of eggs injected with 0.05 μg mercury (the lowest dose) was significantly greater (93.3%) than that of controls (72.6%), whereas hatching success decreased at progressively greater doses of mercury. Our finding of hormesis when a low dose of methylmercury was injected into eggs agrees with a similar observation in a study in which a group of female mallards was fed a low dietary concentration of methylmercury and hatching of their eggs was significantly better than that of controls. If methylmercury has a hormetic effect at low concentrations in avian eggs, these low concentrations may be important in a regulatory sense in that they may represent a no-observed adverse effect level (NOAEL).

  5. Detection and assessment of chemical hormesis on the radial growth in vitro of oomycetes and fungal plant pathogens.

    PubMed

    Flores, Francisco J; Garzon, Carla D

    2012-01-01

    Although plant diseases can be caused by bacteria, viruses, and protists, most are caused by fungi and fungus-like oomycetes. Intensive use of fungicides with the same mode of action can lead to selection of resistant strains increasing the risk of unmanageable epidemics. In spite of the integrated use of nonchemical plant disease management strategies, agricultural productivity relies heavily on the use of chemical pesticides and biocides for disease prevention and treatment and sanitation of tools and substrates. Despite the prominent use of fungi in early hormesis studies and the continuous use of yeast as a research model, the relevance of hormesis in agricultural systems has not been investigated by plant pathologists, until recently. A protocol was standardized for detection and assessment of chemical hormesis in fungi and oomycetes using radial growth as endpoint. Biphasic dose-responses were observed in Pythium aphanidermatum exposed to sub-inhibitory doses of ethanol, cyazofamid, and propamocarb, and in Rhizoctonia zeae exposed to ethanol. This report provides an update on chemical hormesis in fungal plant pathogens and a perspective on the potential risks it poses to crop productivity and global food supply.

  6. Early life exposure to air pollution induces adult cardiac dysfunction

    PubMed Central

    Gorr, Matthew W.; Velten, Markus; Nelin, Timothy D.; Youtz, Dane J.; Sun, Qinghua

    2014-01-01

    Exposure to ambient air pollution contributes to the progression of cardiovascular disease, particularly in susceptible populations. The objective of the present study was to determine whether early life exposure to air pollution causes persistent cardiovascular consequences measured at adulthood. Pregnant FVB mice were exposed to filtered (FA) or concentrated ambient particulate matter (PM2.5) during gestation and nursing. Mice were exposed to PM2.5 at an average concentration of 51.69 μg/m3 from the Columbus, OH region for 6 h/day, 7 days/wk in utero until weaning at 3 wk of age. Birth weight was reduced in PM2.5 pups compared with FA (1.36 ± 0.12 g FA, n = 42 mice; 1.30 ± 0.15 g PM2.5, n = 67 P = 0.012). At adulthood, mice exposed to perinatal PM2.5 had reduced left ventricular fractional shortening compared with FA-exposed mice (43.6 ± 2.1% FA, 33.2 ± 1.6% PM2.5, P = 0.001) with greater left ventricular end systolic diameter. Pressure-volume loops showed reduced ejection fraction (79.1 ± 3.5% FA, 35.5 ± 9.5% PM2.5, P = 0.005), increased end-systolic volume (10.4 ± 2.5 μl FA, 39.5 ± 3.8 μl PM2.5, P = 0.001), and reduced dP/dt maximum (11,605 ± 200 μl/s FA, 9,569 ± 800 μl/s PM2.5, P = 0.05) and minimum (−9,203 ± 235 μl/s FA, −7,045 ± 189 μl/s PM2.5, P = 0.0005) in PM2.5-exposed mice. Isolated cardiomyocytes from the hearts of PM2.5-exposed mice had reduced peak shortening (%PS, 8.53 ± 2.82% FA, 6.82 ± 2.04% PM2.5, P = 0.003), slower calcium reuptake (τ, 0.22 ± 0.09 s FA, 0.26 ± 0.07 s PM2.5, P = 0.048), and reduced response to β-adrenergic stimulation compared with cardiomyocytes isolated from mice that were exposed to FA. Histological analyses revealed greater picro-sirius red-positive-stained areas in the PM2.5 vs. FA group, indicative of increased collagen deposition. We concluded that these data demonstrate the detrimental role of early life exposure to ambient particulate air pollution in programming of adult cardiovascular

  7. HIV post exposure prophylaxis induced bicytopenia: a case report

    PubMed Central

    2014-01-01

    Long and short term side effects of antiretroviral drugs are not fully understood yet. Here a case of reversible blood count changes following post exposure prophylaxis with tenofovir/emtricitabin and lopinavir/ritonavir is reported. We propose that antiretroviral drugs used in post exposure prophylaxis may have a significant impact on hematopoiesis. PMID:24506969

  8. Radiation hormesis: its expression in the immune system

    SciTech Connect

    Liu, S.Z.; Liu, W.H.; Sun, J.B.

    1987-05-01

    The effects of low-dose single and continuous whole-body irradiation on immune functions were studied in C57BL/6 mice. Plaque-forming cell reaction of the spleen was found to be stimulated by single doses of x rays in the range of 0.025 to 0.075 Gy and by continuous exposure to gamma rays with a cumulative dose of 0.065 Gy. The reactivity of thymocytes to interleukin 1 showed a dose-dependent depression in the dose range of 0.025 to 0.25 Gy, but there was an increase in cell number in the thymus between doses of 0.025 and 0.10 Gy, resulting in enhancement of reaction of the whole organ. Unscheduled DNA synthesis of spleen cells was stimulated by single irradiation with 0.05 Gy and continuous irradiation with a cumulative dose of 0.13 Gy. The implications of these immunologic changes under low-dose radiation are discussed.

  9. Time in Redox Adaptation Processes: From Evolution to Hormesis

    PubMed Central

    Sthijns, Mireille M. J. P. E.; Weseler, Antje R.; Bast, Aalt; Haenen, Guido R. M. M.

    2016-01-01

    Life on Earth has to adapt to the ever changing environment. For example, due to introduction of oxygen in the atmosphere, an antioxidant network evolved to cope with the exposure to oxygen. The adaptive mechanisms of the antioxidant network, specifically the glutathione (GSH) system, are reviewed with a special focus on the time. The quickest adaptive response to oxidative stress is direct enzyme modification, increasing the GSH levels or activating the GSH-dependent protective enzymes. After several hours, a hormetic response is seen at the transcriptional level by up-regulating Nrf2-mediated expression of enzymes involved in GSH synthesis. In the long run, adaptations occur at the epigenetic and genomic level; for example, the ability to synthesize GSH by phototrophic bacteria. Apparently, in an adaptive hormetic response not only the dose or the compound, but also time, should be considered. This is essential for targeted interventions aimed to prevent diseases by successfully coping with changes in the environment e.g., oxidative stress. PMID:27690013

  10. Commentary on 'resveratrol commonly displays hormesis: occurrence and biomedical significance'.

    PubMed

    Tedesco, Idolo; Russo, Maria; Russo, Gian Luigi

    2010-12-01

    The review by Calabrese et al. describes the hormetic dose responses induced by phytoalexin resveratrol in a wide range of biological models. We agree and support the authors' strategy to present an impressive number of experiments furnished with an exhaustive bibliography to emphasize that 'many effects induced by resveratrol are dependent on dose and that opposite effects occur at low and high doses, being indicative of a hormetic dose response.' We also highly appreciate the holistic view of the hormetic behavior of resveratrol provided by the authors spanning from tumor and non-tumor cell lines to human and parasitic diseases. In our comments, we touched minor points whose discussion would have strengthened the work of Calabrese, such as contradictions on the role of resveratrol in the 'French Paradox,' its effect on aromatase activity, glutamate cysteine ligase expression and glutathione levels. Overall, we encourage colleagues working in this field to read the present review and consider its relevant biological implications. The vision of Calabrese et al. is far too important to be ignored.

  11. Environmental stresses induce transgenerationally inheritable survival advantages via germline-to-soma communication in Caenorhabditis elegans.

    PubMed

    Kishimoto, Saya; Uno, Masaharu; Okabe, Emiko; Nono, Masanori; Nishida, Eisuke

    2017-01-09

    Hormesis is a biological phenomenon, whereby exposure to low levels of toxic agents or conditions increases organismal viability. It thus represents a beneficial aspect of adaptive responses to harmful environmental stimuli. Here we show that hormesis effects induced in the parental generation can be passed on to the descendants in Caenorhabditis elegans. Animals subjected to various stressors during developmental stages exhibit increased resistance to oxidative stress and proteotoxicity. The increased resistance is transmitted to the subsequent generations grown under unstressed conditions through epigenetic alterations. Our analysis reveal that the insulin/insulin-like growth factor (IGF) signalling effector DAF-16/FOXO and the heat-shock factor HSF-1 in the parental somatic cells mediate the formation of epigenetic memory, which is maintained through the histone H3 lysine 4 trimethylase complex in the germline across generations. The elicitation of memory requires the transcription factor SKN-1/Nrf in somatic tissues. We propose that germ-to-soma communication across generations is an essential framework for the transgenerational inheritance of acquired traits, which provides the offspring with survival advantages to deal with environmental perturbation.

  12. Environmental stresses induce transgenerationally inheritable survival advantages via germline-to-soma communication in Caenorhabditis elegans

    PubMed Central

    Kishimoto, Saya; Uno, Masaharu; Okabe, Emiko; Nono, Masanori; Nishida, Eisuke

    2017-01-01

    Hormesis is a biological phenomenon, whereby exposure to low levels of toxic agents or conditions increases organismal viability. It thus represents a beneficial aspect of adaptive responses to harmful environmental stimuli. Here we show that hormesis effects induced in the parental generation can be passed on to the descendants in Caenorhabditis elegans. Animals subjected to various stressors during developmental stages exhibit increased resistance to oxidative stress and proteotoxicity. The increased resistance is transmitted to the subsequent generations grown under unstressed conditions through epigenetic alterations. Our analysis reveal that the insulin/insulin-like growth factor (IGF) signalling effector DAF-16/FOXO and the heat-shock factor HSF-1 in the parental somatic cells mediate the formation of epigenetic memory, which is maintained through the histone H3 lysine 4 trimethylase complex in the germline across generations. The elicitation of memory requires the transcription factor SKN-1/Nrf in somatic tissues. We propose that germ-to-soma communication across generations is an essential framework for the transgenerational inheritance of acquired traits, which provides the offspring with survival advantages to deal with environmental perturbation. PMID:28067237

  13. [Adverse cutaneous reactions induced by exposure to woods].

    PubMed

    Chomiczewska-Skóra, Dorota

    2013-01-01

    Various adverse cutaneous reactions may occur as a result of exposure to wood dust or solid woods. These include allergic contact dermatitis, irritant contact dermatitis and, more rarely, contact urticaria, photoallergic and phototoxic reactions. Also cases of erythema multiforme-like reactions have been reported. Contact dermatitis, both allergic and irritant, is most frequently provoked by exotic woods, e.g. wood of the Dalbergia spp., Machaerium scleroxylon or Tectona grandis. Cutaneous reactions are usually associated with manual or machine woodworking, in occupational setting or as a hobby. As a result of exposure to wood dust, airborne contact dermatitis is often diagnosed. Cases of allergic contact dermatitis due to solid woods of finished articles as jewelry or musical instruments have also been reported. The aim of the paper is to present various adverse skin reactions related to exposure to woods, their causal factors and sources of exposure, based on the review of literature.

  14. Lipid peroxidation induced by maternal cadmium exposure in mouse pups

    SciTech Connect

    Baohui Xu |; Yapin Jin; Zhaoliang Feng; Zhaofa Xu; Matsushita, Toshio

    1993-11-01

    Cadmium as an environmental pollutant has received considerable attention and its toxic effects have been studied extensively in human and adult animals. Moreover, an International Task Group on Metal Accumulation (1973) has established that although it is in a limited quantity cadmium can be transported across placenta and excreted through milk in animals. Likewise, it can pass through placenta in humans. Furthermore, the fact is that women in the cadmium-polluted areas are continuously exposed to cadmium during gestation and lactation. Even if they are removed from the exposure, the body burden of cadmium probably remains high because of the very long biological half-time of cadmium which is estimated to be between 17.6 and 33 years. Thus, it is possible that fetuses and pups may be exposed to cadmium during maternal gestation and lactation. Although placenta affords some protection from cadmium exposure, cadmium exposure prior to day 10-11 when placenta forms may be deleterious. Cadmium exposure during pregnancy and its effects on offsprings, which were mainly focused on litter size, pup survival, pup growth and cadmium contents in pups following maternal cadmium exposure have been reported. Lipid peroxide has been considered as a sensitive toxicological index for environmental pollutants. The inhibited antioxidant enzymes and enhanced lipid peroxidation due to cadmium exposure have been demonstrated both in humans and animals. Therefore, the present study was designed to evaluate the toxic effects of maternal cadmium exposure on mouse pups using both the indices used in the previous studies and determinations of lipid peroxide concentrations in various pup organs. In conclusion, data from the present study indicate that the detection of LPO concentration in selected pup tissues is a sensitive index for evaluating the effects of maternal cadmium exposure on mouse pups. 16 refs., 4 tabs.

  15. Exposure to Fine Airborne Particulate Matters Induces Hepatic Fibrosis in Murine Models

    PubMed Central

    Zheng, Ze; Zhang, Xuebao; Wang, Jiemei; Dandeka, Aditya; Kim, Hyunbae; Qiu, Yining; Xu, Xiaohua; Cui, Yuqi; Wang, Aixia; Chen, Lung Chi; Rajagopalan, Sanjay; Sun, Qinghua; Zhang, Kezhong

    2016-01-01

    Background Hepatic fibrosis, featured by accumulation of excessive extracellular matrix in liver tissues, is associated with metabolic disease and cancer. Inhalation exposure to airborne particulate matter in fine ranges (PM2.5) correlates with pulmonary dysfunction, cardiovascular disease, and metabolic syndrome. In this study, we investigated the effect and mechanism of PM2.5 exposure on hepatic fibrogenesis. Methods Both inhalation exposure of mice and in vitro exposure of specialized cells to PM2.5 were performed to elucidate the effect of PM2.5 exposure on hepatic fibrosis. Histological examinations, gene expression analyses, and genetic animal models were utilized to determine the effect and mechanism by which PM2.5 exposure promotes hepatic fibrosis. Results Inhalation exposure to concentrated ambient PM2.5 induces hepatic fibrosis in mice under the normal chow or high-fat diet. Mice after PM2.5 exposure displayed increased expression of collagens in liver tissues. Exposure to PM2.5 led to activation of the transforming growth factor β (TGFβ)-SMAD3 signaling, suppression of peroxisome proliferator-activated receptor γ (PPARγ), and expression of collagens in hepatic stellate cells. NADPH oxidase plays a critical role in PM2.5-induced liver fibrogenesis. Conclusions Exposure to PM2.5 exerts discernible effects on promoting hepatic fibrogenesis. NADPH oxidase mediates the effects of PM2.5 exposure on promoting hepatic fibrosis. PMID:26220751

  16. Exposure to fine airborne particulate matters induces hepatic fibrosis in murine models.

    PubMed

    Zheng, Ze; Zhang, Xuebao; Wang, Jiemei; Dandekar, Aditya; Kim, Hyunbae; Qiu, Yining; Xu, Xiaohua; Cui, Yuqi; Wang, Aixia; Chen, Lung Chi; Rajagopalan, Sanjay; Sun, Qinghua; Zhang, Kezhong

    2015-12-01

    Hepatic fibrosis, featured by the accumulation of excessive extracellular matrix in liver tissue, is associated with metabolic disease and cancer. Inhalation exposure to airborne particulate matter in fine ranges (PM2.5) correlates with pulmonary dysfunction, cardiovascular disease, and metabolic syndrome. In this study, we investigated the effect and mechanism of PM2.5 exposure on hepatic fibrogenesis. Both inhalation exposure of mice and in vitro exposure of specialized cells to PM2.5 were performed to elucidate the effect of PM2.5 exposure on hepatic fibrosis. Histological examinations, gene expression analyses, and genetic animal models were utilized to determine the effect and mechanism by which PM2.5 exposure promotes hepatic fibrosis. Inhalation exposure to concentrated ambient PM2.5 induces hepatic fibrosis in mice under the normal chow or high-fat diet. Mice after PM2.5 exposure displayed increased expression of collagens in liver tissues. Exposure to PM2.5 led to activation of the transforming growth factor β-SMAD3 signaling, suppression of peroxisome proliferator-activated receptor γ, and expression of collagens in hepatic stellate cells. NADPH oxidase plays a critical role in PM2.5-induced liver fibrogenesis. Exposure to PM2.5 exerts discernible effects on promoting hepatic fibrogenesis. NADPH oxidase mediates the effects of PM2.5 exposure on promoting hepatic fibrosis. Copyright © 2015. Published by Elsevier B.V.

  17. A novel method to assess human population exposure induced by a wireless cellular network.

    PubMed

    Varsier, Nadège; Plets, David; Corre, Yoann; Vermeeren, Günter; Joseph, Wout; Aerts, Sam; Martens, Luc; Wiart, Joe

    2015-09-01

    This paper presents a new metric to evaluate electromagnetic exposure induced by wireless cellular networks. This metric takes into account the exposure induced by base station antennas as well as exposure induced by wireless devices to evaluate average global exposure of the population in a specific geographical area. The paper first explains the concept and gives the formulation of the Exposure Index (EI). Then, the EI computation is illustrated through simple phone call scenarios (indoor office, in train) and a complete macro urban data long-term evolution scenario showing how, based on simulations, radio-planning predictions, realistic population statistics, user traffic data, and specific absorption rate calculations can be combined to assess the index. Bioelectromagnetics. 36:451-463, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  18. OZONE-INDUCED RESPIRATORY SYMPTOMS: EXPOSURE-RESPONSE MODELS AND ASSOCIATION WITH LUNG FUNCTION

    EPA Science Inventory

    Ozone-induced respiratory symptoms are known to be functions of concentration, minute ventilation, and duration of exposure. The purposes of this study were to identify an exposure-response model for symptoms, to determine whether response was related to age, and to assess the re...

  19. OZONE-INDUCED RESPIRATORY SYMPTOMS: EXPOSURE-RESPONSE MODELS AND ASSOCIATION WITH LUNG FUNCTION

    EPA Science Inventory

    Ozone-induced respiratory symptoms are known to be functions of concentration, minute ventilation, and duration of exposure. The purposes of this study were to identify an exposure-response model for symptoms, to determine whether response was related to age, and to assess the re...

  20. A DYNAMIC NONLINEAR MODEL OF OZONE-INDUCED FEV1 RESPONSE UNDER CHANGING EXPOSURE CONDITIONS

    EPA Science Inventory

    A Dynamic Nonlinear Model of Ozone-induced FEV1 Response under Changing Exposure Conditions. 1WF McDonnell, 2PW Stewart, 3MV Smith. 1Human Studies Division, NHEERL, U.S. EPA, RTP, NC. 2University of North Carolina, Chapel Hill, NC. 3ASI, Durham, NC.

    Ozone exposure result...

  1. The influences of diet and exercise on mental health through hormesis.

    PubMed

    Gomez-Pinilla, Fernando

    2008-01-01

    It is likely that the capacity of the brain to remain healthy during aging depends upon its ability to adapt and nurture in response to environmental challenges. In these terms, main principles involved in hormesis can be also applied to understand relationships at a higher level of complexity such as those existing between the CNS and the environment. This review emphasizes the ability of diet, exercise, and other lifestyle adaptations to modulate brain function. Exercise and diet are discussed in relationship to their aptitude to impact systems that sustain synaptic plasticity and mental health, and are therefore important for combating the effects of aging. Mechanisms that interface energy metabolism and synaptic plasticity are discussed, as these are the frameworks for the actions of cellular stress on cognitive function. In particular, neurotrophins are emerging as main factors in the equation that may connect lifestyle factors and mental health.

  2. Invited response to definition of hormesis (EJ Calabrese and LA Baldwin).

    PubMed

    Pickrell, J A; Oehme, F W

    2002-02-01

    Calabrese and Baldwin have proposed the Theory of Hormesis to explain a variety of disparate data. We evaluated the explanation using examples of pulmonary injury, radiation injury to white blood cells and selenium as an essential element, reducer of carcinogenesis and a potential toxicant. Calabrese and Baldwin have fulfilled many of the criteria allowing generalizability of their theory. They have gathered data extensively. These data were logically consistent with their experiences. They needed to examine critically the theory and any theories competing with it. At this point, each theory must be proved, disproved or its limitations clearly stated. It is in this phase that most work is still being accomplished. This examination is important because it provides referents for vigorous outside criticism, the final phase. Calabrese and Baldwin are to be complimented on seeking outside comment. Considerable refinement of the theory has taken place with time.

  3. Chronic exposure to ELF fields may induce depression

    SciTech Connect

    Wilson, B.W.

    1988-01-01

    Exposure to extremely-low-frequency (ELF) electric or magnetic fields has been postulated as a potentially contributing factor in depression. Epidemiologic studies have yielded positive correlations between magnetic- and/or electric-field strengths in local environments and the incidence of depression-related suicide. Chronic exposure to ELF electric or magnetic fields can disrupt normal circadian rhythms in rat pineal serotonin-N-acetyltransferase activity as well as in serotonin and melatonin concentrations. Such disruptions in the circadian rhythmicity of pineal melatonin secretion have been associated with certain depressive disorders in human beings. In the rat, ELF fields may interfere with tonic aspects of neuronal input to the pineal gland, giving rise to what may be termed functional pinealectomy. If long-term exposure to ELF fields causes pineal dysfunction in human beings as it does in the rat, such dysfunction may contribute to the onset of depression or may exacerbate existing depressive disorders. 85 references.

  4. Neutron induced bystander effect among zebrafish embryos

    NASA Astrophysics Data System (ADS)

    Ng, C. Y. P.; Kong, E. Y.; Kobayashi, A.; Suya, N.; Uchihori, Y.; Cheng, S. H.; Konishi, T.; Yu, K. N.

    2015-12-01

    The present paper reported the first-ever observation of neutron induced bystander effect (NIBE) using zebrafish (Danio rerio) embryos as the in vivo model. The neutron exposure in the present work was provided by the Neutron exposure Accelerator System for Biological Effect Experiments (NASBEE) facility at the National Institute of Radiological Sciences (NIRS), Chiba, Japan. Two different strategies were employed to induce NIBE, namely, through directly partnering and through medium transfer. Both results agreed with a neutron-dose window (20-50 mGy) which could induce NIBE. The lower dose limit corresponded to the threshold amount of neutron-induced damages to trigger significant bystander signals, while the upper limit corresponded to the onset of gamma-ray hormesis which could mitigate the neutron-induced damages and thereby suppress the bystander signals. Failures to observe NIBE in previous studies were due to using neutron doses outside the dose-window. Strategies to enhance the chance of observing NIBE included (1) use of a mono-energetic high-energy (e.g., between 100 keV and 2 MeV) neutron source, and (2) use of a neutron source with a small gamma-ray contamination. It appeared that the NASBEE facility used in the present study fulfilled both conditions, and was thus ideal for triggering NIBE.

  5. Metal induced inhalation exposure in urban population: A probabilistic approach

    NASA Astrophysics Data System (ADS)

    Widziewicz, Kamila; Loska, Krzysztof

    2016-03-01

    The paper was aimed at assessing the health risk in the populations of three Silesian cities: Bielsko-Biała, Częstochowa and Katowice exposed to the inhalation intake of cadmium, nickel and arsenic present in airborne particulate matter. In order to establish how the exposure parameters affects risk a probabilistic risk assessment framework was used. The risk model was based on the results of the annual measurements of As, Cd and Ni concentrations in PM2.5 and the sets of data on the concentrations of those elements in PM10 collected by the Voivodship Inspectorate of Environmental Protection over 2012-2013 period. The risk was calculated as an incremental lifetime risk of cancer (ILCR) in particular age groups (infants, children, adults) following Monte Carlo approach. With the aim of depicting the effect the variability of exposure parameters exerts on the risk, the initial parameters of the risk model: metals concentrations, its infiltration into indoor environment, exposure duration, exposure frequency, lung deposition efficiency, daily lung ventilation and body weight were modeled as random variables. The distribution of inhalation cancer risk due to exposure to ambient metals concentrations was LN (1.80 × 10-6 ± 2.89 × 10-6) and LN (6.17 × 10-7 ± 1.08 × 10-6) for PM2.5 and PM10-bound metals respectively and did not exceed the permissible limit of the acceptable risk. The highest probability of contracting cancer was observed for Katowice residents exposed to PM2.5 - LN (2.01 × 10-6 ± 3.24 × 10-6). Across the tested age groups adults were approximately one order of magnitude at higher risk compared to infants. Sensitivity analysis showed that exposure duration (ED) and body weight (BW) were the two variables, which contributed the most to the ILCR.

  6. Look Different: Effect of Radiation Hormesis on the Survival Rate of Immunosuppressed Mice

    PubMed Central

    Alavi, M.; Taeb, S.; Okhovat, M.A.; Atefi, M.; Negahdari, F.

    2016-01-01

    Background: Hormesis is defined as the bio-positive response of something which is bio-negative in high doses. In the present study, the effect of radiation hormesis was evaluated on the survival rate of immunosuppressed BALB/c mice by Cyclosporine A. Material and Methods: We used 75 consanguine, male, BALB/c mice in this experiment. The first group received Technetium-99m and the second group was placed on a sample radioactive soil of Ramsar region (800Bq) for 20 days. The third group was exposed to X-rays and the fourth group was placed on the radioactive soil and then injected Technetium-99m. The last group was the sham irradiated control group. Finally, 30mg Cyclosporine A as the immunosuppressive agent was orally administered to all mice 48 hours after receiving X-rays and Technetium-99m. The mean survival rate of mice in each group was estimated during time. Results: A log rank test was run to determine if there were differences in the survival distribution for different groups and related treatments. According to the results, the survival rate of all pre-irradiated groups was more than the sham irradiated control group (p < .05). The highest survival time was related to the mice which were placed on the radioactive soil of Ramsar region for 20 days and then injected Technetium-99m. Conclusion: This study confirmed the presence of hormetic models and the enhancement of survival rate in immunosuppressed BALB/c mice as a consequence of low-dose irradiation. It is also revealed the positive synergetic radioadaptive response on survival rate of immunosuppressed animals. PMID:27853721

  7. Peri, pre and postnatal morphine exposure: exposure-induced effects and sex differences in the behavioural consequences in rat offspring.

    PubMed

    Timár, Julia; Sobor, Melinda; Király, Kornél P; Gyarmati, Susanna; Riba, Pál; Al-Khrasani, Mahmoud; Fürst, Susanna

    2010-02-01

    This study investigated the behavioural consequences of peri, pre and postnatal morphine (MO) exposure in rats. From gestational day 1 dams were treated with either saline or MO subcutaneously once a day (5 mg/kg on the first 2 days, 10 mg/kg subsequently). Spontaneous locomotor activity in a new environment (habituation) and antinociceptive effects of MO were measured separately in male and female pups after weaning and also in late adolescence or adulthood. The rewarding effect of MO was assessed by conditioned place preference in adult animals. Both exposure-induced and sex differences were observed. A significant delay in habituation to a new environment and decreased sensitivity to the antinociceptive effect of MO were found in male offspring of MO-treated dams. In contrast, the place preference induced by MO was enhanced in the MO-exposed adult animals and this effect was more marked in females. Prenatal exposure to MO resulted in more marked changes than the postnatal exposure through maternal milk. The results indicate that a medium MO dose administered once-daily results in long-term consequences in offspring and may make them more vulnerable to MO abuse in adulthood.

  8. In Utero Estrogen Exposure Increases Antiestrogen Resistance by Inducing EMT

    DTIC Science & Technology

    2015-02-01

    pups were weaned on postnatal day (PND) 21, and continued on the control diet. In utero EE2 exposed rats exhibited significantly earlier vaginal ...seen [1]. 4 Figure 1: Effect on in utero EE2 exposure on sexual maturation in rats. p=0.027 % Vaginal Opening 0 20 40 60 80 100 P o s tn a

  9. Disorders Induced by Direct Occupational Exposure to Noise: Systematic Review

    PubMed Central

    Domingo-Pueyo, Andrea; Sanz-Valero, Javier; Wanden-Berghe, Carmina

    2016-01-01

    Background: To review the available scientific literature about the effects on health by occupational exposure to noise. Materials and Methods: A systematic review of the retrieved scientific literature from the databases MEDLINE (via PubMed), ISI-Web of Knowledge (Institute for Scientific Information), Cochrane Library Plus, SCOPUS, and SciELO (collection of scientific journals) was conducted. The following terms were used as descriptors and were searched in free text: “Noise, Occupational,” “Occupational Exposure,” and “Occupational Disease.” The following limits were considered: “Humans,” “Adult (more than 18 years),” and “Comparative Studies.” Results: A total of 281 references were retrieved, and after applying inclusion/exclusion criteria, 25 articles were selected. Of these selected articles, 19 studies provided information about hearing disturbance, four on cardiovascular disorders, one regarding respiratory alteration, and one on other disorders. Conclusions: It can be interpreted that the exposure to noise causes alterations in humans with different relevant outcomes, and therefore appropriate security measures in the work environment must be employed to minimize such an exposure and thereby to reduce the number of associated disorders. PMID:27762251

  10. Disorders induced by direct occupational exposure to noise: Systematic review.

    PubMed

    Domingo-Pueyo, Andrea; Sanz-Valero, Javier; Wanden-Berghe, Carmina

    2016-01-01

    To review the available scientific literature about the effects on health by occupational exposure to noise. A systematic review of the retrieved scientific literature from the databases MEDLINE (via PubMed), ISI-Web of Knowledge (Institute for Scientific Information), Cochrane Library Plus, SCOPUS, and SciELO (collection of scientific journals) was conducted. The following terms were used as descriptors and were searched in free text: "Noise, Occupational," "Occupational Exposure," and "Occupational Disease." The following limits were considered: "Humans," "Adult (more than 18 years)," and "Comparative Studies." A total of 281 references were retrieved, and after applying inclusion/exclusion criteria, 25 articles were selected. Of these selected articles, 19 studies provided information about hearing disturbance, four on cardiovascular disorders, one regarding respiratory alteration, and one on other disorders. It can be interpreted that the exposure to noise causes alterations in humans with different relevant outcomes, and therefore appropriate security measures in the work environment must be employed to minimize such an exposure and thereby to reduce the number of associated disorders.

  11. Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism.

    PubMed

    Tyler, Christina R; Solomon, Benjamin R; Ulibarri, Adam L; Allan, Andrea M

    2014-09-01

    Several epidemiological studies have reported an association between arsenic exposure and increased rates of psychiatric disorders, including depression, in exposed populations. We have previously demonstrated that developmental exposure to low amounts of arsenic induces depression in adulthood along with several morphological and molecular aberrations, particularly associated with the hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis. The extent and potential reversibility of this toxin-induced damage has not been characterized to date. In this study, we assessed the effects of fluoxetine, a selective serotonin reuptake inhibitor antidepressant, on adult animals exposed to arsenic during development. Perinatal arsenic exposure (PAE) induced depressive-like symptoms in a mild learned helplessness task and in the forced swim task after acute exposure to a predator odor (2,4,5-trimethylthiazoline, TMT). Chronic fluoxetine treatment prevented these behaviors in both tasks in arsenic-exposed animals and ameliorated arsenic-induced blunted stress responses, as measured by corticosterone (CORT) levels before and after TMT exposure. Morphologically, chronic fluoxetine treatment reversed deficits in adult hippocampal neurogenesis (AHN) after PAE, specifically differentiation and survival of neural progenitor cells. Protein expression of BDNF, CREB, the glucocorticoid receptor (GR), and HDAC2 was significantly increased in the dentate gyrus of arsenic animals after fluoxetine treatment. This study demonstrates that damage induced by perinatal arsenic exposure is reversible with chronic fluoxetine treatment resulting in restored resiliency to depression via a neurogenic mechanism.

  12. Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism

    PubMed Central

    Tyler, Christina R.; Solomon, Benjamin R.; Ulibarri, Adam L.; Allan, Andrea M.

    2014-01-01

    Several epidemiological studies have reported an association between arsenic exposure and increased rates of psychiatric disorders, including depression, in exposed populations. We have previously demonstrated that developmental exposure to low amounts of arsenic induces depression in adulthood along with several morphological and molecular aberrations, particularly associated with the hippocampus and the hypothalamic–pituitary–adrenal (HPA) axis. The extent and potential reversibility of this toxin-induced damage has not been characterized to date. In this study, we assessed the effects of fluoxetine, a selective serotonin reuptake inhibitor antidepressant, on adult animals exposed to arsenic during development. Perinatal arsenic exposure (PAE) induced depressive-like symptoms in a mild learned helplessness task and in the forced swim task after acute exposure to a predator odor (2,4,5-trimethylthiazoline, TMT). Chronic fluoxetine treatment prevented these behaviors in both tasks in arsenic-exposed animals and ameliorated arsenic-induced blunted stress responses, as measured by corticosterone (CORT) levels before and after TMT exposure. Morphologically, chronic fluoxetine treatment reversed deficits in adult hippocampal neurogenesis (AHN) after PAE, specifically differentiation and survival of neural progenitor cells. Protein expression of BDNF, CREB, the glucocorticoid receptor (GR), and HDAC2 was significantly increased in the dentate gyrus of arsenic animals after fluoxetine treatment. This study demonstrates that damage induced by perinatal arsenic exposure is reversible with chronic fluoxetine treatment resulting in restored resiliency to depression via a neurogenic mechanism. PMID:24952232

  13. Vanadium exposure-induced neurobehavioral alterations among Chinese workers.

    PubMed

    Li, Hong; Zhou, Dinglun; Zhang, Qin; Feng, Chengyong; Zheng, Wei; He, Keping; Lan, Yajia

    2013-05-01

    Vanadium-containing products are manufactured and widely used in the modern industry. Yet the neurobehavioral toxicity due to occupational exposure to vanadium remained elusive. This cross-sectional study was designed to examine the neurotoxic effects of occupational vanadium exposure. A total of 463 vanadium-exposed workers (exposed group) and 251 non-exposed workers (control group) were recruited from a Steel and Iron Group in Sichuan, China. A WHO-recommended neurobehavioral core test battery (NCTB) and event-related auditory evoked potentials test (P300) were used to assess the neurobehavioral functions of all study subjects. A general linear model was used to compare outcome scores between the two groups while controlling for possible confounders. The exposed group showed a statistically significant neurobehavioral alteration more than the control group in the NCTB tests. The exposed workers also exhibited an increased anger-hostility, depression-dejection and fatigue-inertia on the profile of mood states (p<0.05). Performances in the simple reaction time, digit span, benton visual retention and pursuit aiming were also poorer among exposed workers as compared to unexposed control workers (p<0.05). Some of these poor performances in tests were also significantly related to workers' exposure duration. P300 latencies were longer in the exposed group than in the control (p<0.05). Longer mean reaction times and more counting errors were also found in the exposed workers (p<0.05). Given the findings of our study and the limitations of neurobehavioral workplace testing, we found evidence of altered neurobehavioral outcomes by occupational exposure to vanadium.

  14. Phenanthrene exposure induces cardiac hypertrophy via reducing miR-133a expression by DNA methylation

    PubMed Central

    Huang, Lixing; Xi, Zhihui; Wang, Chonggang; Zhang, Youyu; Yang, Zhibing; Zhang, Shiqi; Chen, Yixin; Zuo, Zhenghong

    2016-01-01

    Growing evidence indicates that there is an emerging link between environmental pollution and cardiac hypertrophy, while the mechanism is unclear. The objective of this study was to examine whether phenanthrene (Phe) could cause cardiac hypertrophy, and elucidate the molecular mechanisms involved. We found that: 1) Phe exposure increased the heart weight and cardiomyocyte size of rats; 2) Phe exposure led to enlarged cell size, and increased protein synthesis in H9C2 cells; 3) Phe exposure induced important markers of cardiac hypertrophy, such as atrial natriuretic peptide, B-type natriuretic peptide, and c-Myc in H9C2 cells and rat hearts; 4) Phe exposure perturbed miR-133a, CdC42 and RhoA, which were key regulators of cardiac hypertrophy, in H9C2 cells and rat hearts; 5) Phe exposure induced DNA methyltransferases (DNMTs) in H9C2 cells and rat hearts; 6) Phe exposure led to methylation of CpG sites within the miR-133a locus and reduced miR-133a expression in H9C2 cells; 7) DNMT inhibition and miR-133a overexpression could both alleviate the enlargement of cell size and perturbation of CdC42 and RhoA caused by Phe exposure. These results indicated that Phe could induce cardiomyocyte hypertrophy in the rat and H9C2 cells. The mechanism might involve reducing miR-133a expression by DNA methylation. PMID:26830171

  15. Allergen exposure induces adipose tissue inflammation and insulin resistance.

    PubMed

    Jung, Chien-Cheng; Tsai, Yau-Sheng; Chang, Chih-Ching; Cheng, Tsun-Jen; Chang, Ching-Wen; Liu, Ping-Yen; Chiu, Yi-Jen; Su, Huey-Jen

    2014-11-01

    This study investigates whether exposure to allergen elicits insulin resistance as a result of adipose tissue inflammation. Male C57BL/6 mice were challenged with ovalbumin (OVA) allergen for 12 weeks, and blood and adipose tissue samples were collected at 24h after the last challenge. Levels of adhesion molecules, fasting insulin, fasting glucose, and adipokines in the blood were analyzed, and fasting homeostasis model assessment was applied to determine insulin resistance (HOMA-IR). The expression of pro- and anti-inflammatory genes in dissected adipose tissues was analyzed by real-time RT-PCR. Our results showed that OVA exposure increased insulin resistance as well as resistin and E-selectin, but reduced adiponectin in the serum. Resistin level was significantly correlated with HOMA-IR. Moreover, in adipose tissues of OVA-challenged mice, the pro-inflammatory M1 genes were more abundant while the anti-inflammatory M2 genes were less than those of PBS-treated mice. The expressional changes of both M1 and M2 genes were significantly associated with serum levels of adiponectin, resistin, and E-selectin. Hematoxylin and eosin (HE) and immunohistochemistry (IHC) stain also showed that there was more obvious inflammation in OVA-challenged mice. In conclusion, the current study suggests the relationship between allergen-elicited adipose tissue inflammation and circulating inflammatory molecules, which are possible mediators for the development of insulin resistance. Therefore, we propose that allergen exposure might be one risk factor for insulin resistance. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Mercury exposure induces proinflammatory enzymes in vascular fibroblasts.

    PubMed

    Millán Longo, Alberto; Montero Saiz, Óscar; Sarró Fuente, Claudia; Aguado Martínez, Andrea; Salaices Sánchez, Mercedes

    2017-09-18

    Previous studies show that mercury exposure increases cardiovascular risk, although the underlying cellular mechanisms have still not been fully studied. The aim of this project is to study, in vascular fibroblasts (VF), the effect of HgCl2 exposure on the expression of enzymes involved in the synthesis of prostanoids and reactive oxygen species (ROS). These molecules have been shown to participate in the inflammatory response associated with cardiovascular diseases. Adventitial VF cultures of Sprague-Dawley rat aortas, shown to be α-actin negative by immunofluorescence, were exposed to HgCl2 (0.05-5μg/mL) for 48h. mRNA and protein levels of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase 1 (mPGES-1), thromboxane A2 synthase (TXAS), NADPH oxidase 1 (NOX-1), and 4 (NOX-4) where analyzed using qRT-PCR and western blot, respectively. NOX activity was determined by chemiluminescence. HgCl2 exposure increased COX-2, mPGES-1, TXAS, and NOX-1 expression and NOX activity, and decreased NOX-4 expression. The increase in NOX-1 and COX-2 expression was abolished by the treatment with inhibitors of COX-2 (10μM celecoxib) and NOX (300μM apocynin, 0.5μM ML-171). 1) HgCl2 increases the expression of pro-inflammatory enzymes involved in ROS and prostanoid synthesis in VF. 2) There is a reciprocal regulation between COX-2 and NOX-1 pathways. 3) These effects can contribute to explain the increase in cardiovascular risk associated to mercury. Copyright © 2017 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

  17. Low G preconditioning reduces liver injury induced by high +Gz exposure in rats

    PubMed Central

    Shi, Bin; Feng, Zhi-Qiang; Li, Wen-Bing; Zhang, Hong-Yi

    2015-01-01

    AIM: To investigate the effect of repeated lower +Gz exposure on liver injury induced by high +Gz exposure in rats. METHODS: Sixty male Wister rats were randomly divided into a blank control group, a low G preconditioning group (LG) (exposed to +4 Gz/5 min per day for 3 d before +10 Gz/5 min exposure), and a +10 Gz/5 min group (10G) (n = 20 in each group). Blood specimens and liver tissue were harvested at 0 h and 6 h after +10 Gz/5 min exposure. Liver function was analyzed by measuring serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, and liver injury was further assessed by histopathological observation. Malondialdehyde (MDA), superoxide dismutase (SOD) and Na+-K+-ATPase were determined in hepatic tissue. RESULTS: The group LG had lower ALT, AST, and MDA values at 0 h after exposure than those in group 10G. SOD values and Na+-K+-ATPase activity in the LG group were higher than in group 10G 0 h post-exposure. Hepatocyte injury was significantly less in group LG than in group 10G on histopathological evaluation. CONCLUSION: It is suggested that repeated low +Gz exposure shows a protective effect on liver injury induced by high +Gz exposure in rats. PMID:26074692

  18. Cognitive deficits induced by 56Fe radiation exposure

    NASA Technical Reports Server (NTRS)

    Shukitt-Hale, B.; Casadesus, G.; Cantuti-Castelvetri, I.; Rabin, B. M.; Joseph, J. A.

    2003-01-01

    Exposing rats to particles of high energy and charge (e.g., 56Fe) disrupts neuronal systems and the behaviors mediated by them; these adverse behavioral and neuronal effects are similar to those seen in aged animals. Because cognition declines with age, and our previous study showed that radiation disrupted Morris water maze spatial learning and memory performance, the present study used an 8-arm radial maze (RAM) to further test the cognitive behavioral consequences of radiation exposure. Control rats or rats exposed to whole-body irradiation with 1.0 Gy of 1 GeV/n high-energy 56Fe particles (delivered at the alternating gradient synchrotron at Brookhaven National Laboratory) were tested nine months following exposure. Radiation adversely affected RAM performance, and the changes seen parallel those of aging. Irradiated animals entered baited arms during the first 4 choices significantly less than did controls, produced their first error sooner, and also tended to make more errors as measured by re-entries into non-baited arms. These results show that irradiation with high-energy particles produces age-like decrements in cognitive behavior that may impair the ability of astronauts to perform critical tasks during long-term space travel beyond the magnetosphere. Published by Elsevier Science Ltd on behalf of COSPAR.

  19. Cognitive deficits induced by 56Fe radiation exposure

    NASA Astrophysics Data System (ADS)

    Shukitt-Hale, B.; Casadesus, G.; Cantuti-Castelvetri, I.; Rabin, B. M.; Joseph, J. A.

    Exposing rats to particles of high energy and charge (e.g., 56Fe) disrupts neuronal systems and the behaviors mediated by them; these adverse behavioral and neuronal effects are similar to those seen in aged animals. Because cognition declines with age, and our previous study showed that radiation disrupted Morris water maze spatial learning and memory performance, the present study used an 8-arm radial maze (RAM) to further test the cognitive behavioral consequences of radiation exposure. Control rats or rats exposed to whole-body irradiation with 1.0 Gy of 1 GeV/n high-energy 56Fe particles (delivered at the alternating gradient synchrotron at Brookhaven National Laboratory) were tested nine months following exposure. Radiation adversely affected RAM performance, and the changes seen parallel those of aging. Irradiated animals entered baited arms during the first 4 choices significantly less than did controls, produced their first error sooner, and also tended to make more errors as measured by re-entries into non-baited arms. These results show that irradiation with high-energy particles produces age-like decrements in cognitive behavior that may impair the ability of astronauts to perform critical tasks during long-term space travel beyond the magnetosphere.

  20. Cognitive deficits induced by 56Fe radiation exposure

    NASA Technical Reports Server (NTRS)

    Shukitt-Hale, B.; Casadesus, G.; Cantuti-Castelvetri, I.; Rabin, B. M.; Joseph, J. A.

    2003-01-01

    Exposing rats to particles of high energy and charge (e.g., 56Fe) disrupts neuronal systems and the behaviors mediated by them; these adverse behavioral and neuronal effects are similar to those seen in aged animals. Because cognition declines with age, and our previous study showed that radiation disrupted Morris water maze spatial learning and memory performance, the present study used an 8-arm radial maze (RAM) to further test the cognitive behavioral consequences of radiation exposure. Control rats or rats exposed to whole-body irradiation with 1.0 Gy of 1 GeV/n high-energy 56Fe particles (delivered at the alternating gradient synchrotron at Brookhaven National Laboratory) were tested nine months following exposure. Radiation adversely affected RAM performance, and the changes seen parallel those of aging. Irradiated animals entered baited arms during the first 4 choices significantly less than did controls, produced their first error sooner, and also tended to make more errors as measured by re-entries into non-baited arms. These results show that irradiation with high-energy particles produces age-like decrements in cognitive behavior that may impair the ability of astronauts to perform critical tasks during long-term space travel beyond the magnetosphere. Published by Elsevier Science Ltd on behalf of COSPAR.

  1. Relationship between exposure duration and sulfur dioxide-induced bronchoconstriction in asthmatic subjects

    SciTech Connect

    Horstman, D.H.; Seal, E.; Folinsbee, L.J.; Ives, P.; Roger, L.J.

    1988-01-01

    The purpose of the study was to determine the shortest duration of exposure to 1.0 ppm sulfur dioxide (SO/sub 2/) sufficient to induce bronchoconstriction significantly greater than that observed with exposure to clean air (CA) in exercising SO/sub 2/ sensitive asthmatics. Asymptomatic, nonmedicated, male asthmatics (n=12) with airway hyperresponsiveness to both methacholine and SO/sub 2/ were exposed in a chamber (20/sup 0/C, 40% relative humidity) for 0.0, 0.5, 1.0, 2.0 and 5.0 min to both CA and 1.0 ppm SO/sub 2/ on separate days (10 exposures). Just prior to each exposure, subjects walked on a treadmill in CA for 5 min at a predetermined speed/elevation to elicit a target ventilation of about 40 L/min. i.e., a brisk pace up a slight incline. After this walk, subjects rapidly entered adjoining exposure chamber containing either CA or SO/sub 2/ and immediately walked at the same speed/elevation for the specified exposure duration. Subjects then rapidly exited the chamber. Postexposure SRaw and symptom ratings increased with increased exposure duration in SO/sub 2/; pstexposure SRaw also was increased with increased exposure duration in CA but to a lesser extent. After adjusting for the CA response, significantly greater SO/sub 2/ induced bronchoconstriction was observed for the 2.0 and 5.0 min exposures as indicated by substantially greater increases in SRaw and substantially higher ratings of respiratory symptoms. The authors conclude that with the above exposure conditions, on average, SO/sub 2/ sensitivie asthamtics exhibit significant brochoconstriction at exposure durations of 2.0 min or more.

  2. Altered Hepatic Transport by Fetal Arsenite Exposure in Diet-Induced Fatty Liver Disease.

    PubMed

    Ditzel, Eric J; Li, Hui; Foy, Caroline E; Perrera, Alec B; Parker, Patricia; Renquist, Benjamin J; Cherrington, Nathan J; Camenisch, Todd D

    2016-07-01

    Non-alcoholic fatty liver disease can result in changes to drug metabolism and disposition potentiating adverse drug reactions. Furthermore, arsenite exposure during development compounds the severity of diet-induced fatty liver disease. This study examines the effects of arsenite potentiated diet-induced fatty liver disease on hepatic transport in male mice. Changes were detected for Mrp2/3/4 hepatic transporter gene expression as well as for Oatp1a4/2b1/1b2. Plasma concentrations of Mrp and Oatp substrates were increased in arsenic exposure groups compared with diet-only controls. In addition, murine embryonic hepatocytes and adult primary hepatocytes show significantly altered transporter expression after exposure to arsenite alone: a previously unreported phenomenon. These data indicate that developmental exposure to arsenite leads to changes in hepatic transport which could increase the risk for ADRs during fatty liver disease.

  3. Social Preference Deficits in Juvenile Zebrafish Induced by Early Chronic Exposure to Sodium Valproate

    PubMed Central

    Liu, Xiuyun; Zhang, Yinglan; Lin, Jia; Xia, Qiaoxi; Guo, Ning; Li, Qiang

    2016-01-01

    Prenatal exposure to sodium valproate (VPA), a widely used anti-epileptic drug, is related to a series of dysfunctions, such as deficits in language and communication. Clinical and animal studies have indicated that the effects of VPA are related to the concentration and to the exposure window, while the neurobehavioral effects of VPA have received limited research attention. In the current study, to analyze the neurobehavioral effects of VPA, zebrafish at 24 h post-fertilization (hpf) were treated with early chronic exposure to 20 μM VPA for 7 h per day for 6 days or with early acute exposure to 100 μM VPA for 7 h. A battery of behavioral screenings was conducted at 1 month of age to investigate social preference, locomotor activity, anxiety, and behavioral response to light change. A social preference deficit was only observed in animals with chronic VPA exposure. Acute VPA exposure induced a change in the locomotor activity, while chronic VPA exposure did not affect locomotor activity. Neither exposure procedure influenced anxiety or the behavioral response to light change. These results suggested that VPA has the potential to affect some behaviors in zebrafish, such as social behavior and the locomotor activity, and that the effects were closely related to the concentration and the exposure window. Additionally, social preference seemed to be independent from other simple behaviors. PMID:27812327

  4. Social Preference Deficits in Juvenile Zebrafish Induced by Early Chronic Exposure to Sodium Valproate.

    PubMed

    Liu, Xiuyun; Zhang, Yinglan; Lin, Jia; Xia, Qiaoxi; Guo, Ning; Li, Qiang

    2016-01-01

    Prenatal exposure to sodium valproate (VPA), a widely used anti-epileptic drug, is related to a series of dysfunctions, such as deficits in language and communication. Clinical and animal studies have indicated that the effects of VPA are related to the concentration and to the exposure window, while the neurobehavioral effects of VPA have received limited research attention. In the current study, to analyze the neurobehavioral effects of VPA, zebrafish at 24 h post-fertilization (hpf) were treated with early chronic exposure to 20 μM VPA for 7 h per day for 6 days or with early acute exposure to 100 μM VPA for 7 h. A battery of behavioral screenings was conducted at 1 month of age to investigate social preference, locomotor activity, anxiety, and behavioral response to light change. A social preference deficit was only observed in animals with chronic VPA exposure. Acute VPA exposure induced a change in the locomotor activity, while chronic VPA exposure did not affect locomotor activity. Neither exposure procedure influenced anxiety or the behavioral response to light change. These results suggested that VPA has the potential to affect some behaviors in zebrafish, such as social behavior and the locomotor activity, and that the effects were closely related to the concentration and the exposure window. Additionally, social preference seemed to be independent from other simple behaviors.

  5. Neonatal exposure to lipopolysaccharide enhances methamphetamine-induced reinstated behavioral sensitization in adult rats

    PubMed Central

    Tien, Lu-Tai; Cai, Zhengwei; Rhodes, Philip G.; Fan, Lir-Wan

    2011-01-01

    Our previous studies have shown that neonatal exposure to lipopolysaccharide (LPS) resulted in long-lasting dopaminergic injury and enhanced methamphetamine (METH)-induced increase of locomotion in the adult male rat. To further investigate the effect of neonatal LPS exposure-induced dopaminergic injury, we used our neonatal rat model of LPS exposure (1 mg/kg, intracerebral injection in postnatal day 5, P5, rats) to examine the METH sensitization as an indicator of drug addiction in the adult rats. On P70, animals began a treatment schedule of 5 daily subcutaneous (s.c.) administration of METH (0.5 mg/kg) or saline (P70-P74) to induce behavioral sensitization. Ninety-six hours after the 5th treatment with METH or saline (P78), animals received a single dose of 0.5 mg/kg METH (s.c.) or saline. Neonatal LPS exposure enhanced the level of development of behavioral sensitization including distance traveled, rearing events and stereotypy to METH administration in both male and female rats. Neonatal LPS exposure also enhanced the reinstated behavioral sensitization in both male and female rats after the administration had ceased for ninety-six hours. However, neonatal LPS exposure induced alteration in the reinstated behaviors sensitization of distance traveled and rearing events to METH administration appears to be greater in male than in female rats. These results indicate that neonatal brain LPS exposure produces a persistent lesion in the dopaminergic system, as indicated by enhanced METH-induced locomotor and stereotyped behavioral sensitization in later life. These findings show that early-life brain inflammation may enhance susceptibility to the development of drug addiction in later life. PMID:21669234

  6. Neonatal exposure to lipopolysaccharide enhances methamphetamine-induced reinstated behavioral sensitization in adult rats.

    PubMed

    Tien, Lu-Tai; Cai, Zhengwei; Rhodes, Philip G; Fan, Lir-Wan

    2011-10-10

    Our previous studies have shown that neonatal exposure to lipopolysaccharide (LPS) resulted in long-lasting dopaminergic injury and enhanced methamphetamine (METH)-induced increase of locomotion in the adult male rat. To further investigate the effect of neonatal LPS exposure-induced dopaminergic injury, we used our neonatal rat model of LPS exposure (1mg/kg, intracerebral injection in postnatal day 5, P5, rats) to examine the METH sensitization as an indicator of drug addiction in the adult rats. On P70, animals began a treatment schedule of 5 daily subcutaneous (s.c.) administration of METH (0.5mg/kg) or saline (P70-P74) to induce behavioral sensitization. Ninety-six hours after the 5th treatment with METH or saline (P78), animals received a single dose of 0.5mg/kg METH (s.c.) or saline. Neonatal LPS exposure enhanced the level of development of behavioral sensitization including distance traveled, rearing events and stereotypy to METH administration in both male and female rats. Neonatal LPS exposure also enhanced the reinstated behavioral sensitization in both male and female rats after the administration had ceased for 96h. However, neonatal LPS exposure induced alteration in the reinstated behaviors sensitization of distance traveled and rearing events to METH administration appears to be greater in male than in female rats. These results indicate that neonatal brain LPS exposure produces a persistent lesion in the dopaminergic system, as indicated by enhanced METH-induced locomotor and stereotyped behavioral sensitization in later life. These findings show that early-life brain inflammation may enhance susceptibility to the development of drug addiction in later life. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. Light-induced melatonin suppression at night after exposure to different wavelength composition of morning light.

    PubMed

    Kozaki, Tomoaki; Kubokawa, Ayaka; Taketomi, Ryunosuke; Hatae, Keisuke

    2016-03-11

    Bright nocturnal light has been shown to suppress melatonin secretion. However, bright light exposure during the day might reduce light-induced melatonin suppression at night. The human circadian system is sensitive to short wavelength light. This study evaluated the preventive effect of different wavelengths of daytime light on light-induced melatonin suppression at night. Twelve male subjects were exposed to various light conditions (dim, white, and bluish white light) between the hours of 09:00 and 10:30 (daytime light conditions). They were then exposed to light (300lx) again between 01:00 and 02:30 (night-time light exposure). Subjects provided saliva samples before (00:55) and after night-time light exposure (02:30). A two-tailed paired t-test yielded significant decrements in melatonin concentrations after night-time light exposure under daytime dim and white light conditions. No significant differences were found in melatonin concentrations between pre- and post-night-time light exposure with bluish-white light. Present findings suggest that daytime blue light exposure has an acute preventive impact on light-induced melatonin suppression in individuals with a general life rhythm (sleep/wake schedule). These findings may be useful for implementing artificial light environments for humans in, for example, hospitals and underground shopping malls to reduce health risks.

  8. Selection of comparison crash types for quasi-induced exposure risk estimation.

    PubMed

    Keall, Michael; Newstead, Stuart

    2009-03-01

    The objective of this study was to find a comparison crash type that best represented exposure on the road and to identify situations where the induced exposure risk estimates were likely to be biased. Counts of crash involvements were compared with distance driven estimates derived from a register of licensed motor vehicles to identify the most appropriate comparison crash type for induced exposure estimation, which is the crash type whose counts are best correlated with vehicle distance driven. The best sets of comparison crashes for disaggregations by driver age and gender and vehicle type were found to be multi-vehicle crashes in which the vehicle was damaged in the rear or multi-vehicle crashes in which the driver was adjudged to be not at fault. Likely bias of induced exposure risk estimates was identified, even for these best sets of comparison crashes, according to vehicle size (with large vehicles underrepresented) and owner age and gender (with young owners and female owners overrepresented). This research identified some important features of crash occurrence useful for making choices of comparison crash types when controlling for exposure. None of the crash types considered as comparison crashes performed perfectly. Even the crash types that seemed to best reflect exposure on the road still appeared to over- or underestimate distance driven according to owner age group, gender, and vehicle size.

  9. Lithium prevents long-term neural and behavioral pathology induced by early alcohol exposure.

    PubMed

    Sadrian, B; Subbanna, S; Wilson, D A; Basavarajappa, B S; Saito, M

    2012-03-29

    Fetal alcohol exposure can cause developmental defects in offspring known as fetal alcohol spectrum disorder (FASD). FASD symptoms range from obvious facial deformities to changes in neuroanatomy and neurophysiology that disrupt normal brain function and behavior. Ethanol exposure at postnatal day 7 in C57BL/6 mice induces neuronal cell death and long-lasting neurobehavioral dysfunction. Previous work has demonstrated that early ethanol exposure impairs spatial memory task performance into adulthood and perturbs local and interregional brain circuit integrity in the olfacto-hippocampal pathway. Here we pursue these findings to examine whether lithium prevents anatomical, neurophysiological, and behavioral pathologies that result from early ethanol exposure. Lithium has neuroprotective properties that have been shown to prevent ethanol-induced apoptosis. Here we show that mice co-treated with lithium on the same day as ethanol exposure exhibit dramatically reduced acute neurodegeneration in the hippocampus and retain hippocampal-dependent spatial memory as adults. Lithium co-treatment also blocked ethanol-induced disruption in synaptic plasticity in slice recordings of hippocampal CA1 in the adult mouse brain. Moreover, long-lasting dysfunctions caused by ethanol in olfacto-hippocampal networks, including sensory-evoked oscillations and resting state coherence, were prevented in mice co-treated with lithium. Together, these results provide behavioral and physiological evidence that lithium is capable of preventing or reducing immediate and long-term deleterious consequences of early ethanol exposure on brain function. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Formaldehyde exposure induces autophagy in testicular tissues of adult male rats.

    PubMed

    Han, Shui-Ping; Zhou, Dang-Xia; Lin, Pu; Qin, Zhen; An, Lu; Zheng, Lie-Rui; Lei, Li

    2015-03-01

    Formaldehyde, a ubiquitous environmental pollutant, has long been suspected of causing adverse male reproductive effects. However, the molecular and cellular mechanisms underlying this phenomenon remain elusive. The overall aim of this study is to clarify the role of autophagy in male reproductive injuries induced by formaldehyde exposure, by which we can further understand the molecular mechanism of spermatogenesis and develop new targets for prevention and treatment of male infertility. In this study, electron microscopy, Western blot, and RT-PCR analysis were used to detect autophagy in testicular tissues. Moreover, testicular weights, histopathology, and morphometry were used to evaluate the reproductive injuries of formaldehyde exposure. We found that formaldehyde exposure-induced autophagy in testicular tissues was dose dependent. Increasing autophagosomes in spermatogenetic cells was observed by electron microscopy in formaldehyde exposure group. In addition, RT-PCR and Western blot analysis showed the transcription levels of the LC3-II, as well as the conversion from LC3-I to LC3-II, an indicator of autophagy, significantly increased in testicular tissue of formaldehyde exposure group in a dose dependent manner when compared with those in control group. Furthermore, the alterations of autophage were basically consistent with the changes in testicular weight and morphologic findings. In summary, formaldehyde exposure triggered autophagy, and autophagy may be a scathing factor responsible for male reproductive impairment induced by formaldehyde. © 2013 Wiley Periodicals, Inc.

  11. Immune heparin-induced thrombocytopenia resulting from preceding exposure to heparin catheter flushes.

    PubMed

    Muslimani, Alaa A; Ricaurte, Basma; Daw, Hamed A

    2007-07-01

    Immune heparin-induced thrombocytopenia (HIT) is a life-threatening adverse effect of heparin. It can result from any type of heparin exposure and by any route of administration; however only a few cases are reported after exposures to small quantities of heparin from catheter flushes. The major clinical problem associated with HIT is thrombosis. Early detection and institution of alternative, non-heparin anticoagulation are important. We report a patient with HIT associated with use of therapeutic-dose unfractionated heparin in whom immune sensitization to heparin was triggered by two 500-unit exposure to UFH associated with intravascular catheter flushing for antineoplastic chemotherapy in a patient with colon adenocarcinoma.

  12. Sub-chronic exposure to second hand smoke induces airspace leukocyte infiltration and decreased lung elastance.

    PubMed

    Hartney, John M; Chu, Hongwei; Pelanda, Roberta; Torres, Raul M

    2012-01-01

    Exposure to second hand tobacco smoke is associated with the development and/or exacerbation of several different pulmonary diseases in humans. To better understand the possible effects of second hand smoke exposure in humans, we sub-chronically (4 weeks) exposed mice to a mixture of mainstream and sidestream tobacco smoke at concentrations similar to second hand smoke exposure in humans. The inflammatory response to smoke exposures was assessed at the end of this time by enumeration of pulmonary leukocyte infiltration together with measurements of lung elastance and pathology. This response was measured in both healthy wild type (C57BL/6) mice as well as mouse mutants deficient in the expression of Arhgef1 (Arhgef1(-/-)) that display constitutive pulmonary inflammation and decreased lung elastance reminiscent of emphysema. The results from this study show that sub-chronic second hand smoke exposure leads to significantly increased numbers of airspace leukocytes in both healthy and mutant animals. While sub-chronic cigarette smoke exposure is not sufficient to induce changes in lung architecture as measured by mean linear intercept, both groups exhibit a significant decrease in lung elastance. Together these data demonstrate that even sub-chronic exposure to second hand smoke is sufficient to induce pulmonary inflammation and decrease lung elastance in both healthy and diseased animals and in the absence of tissue destruction.

  13. Electromagnetic pulse exposure induces overexpression of beta amyloid protein in rats.

    PubMed

    Jiang, Da-peng; Li, Jing; Zhang, Jie; Xu, Sheng-long; Kuang, Fang; Lang, Hai-yang; Wang, Ya-feng; An, Guang-zhou; Li, Jin-hui; Guo, Guo-zhen

    2013-04-01

    With the developing and widely used electromagnetic field (EMF) technology, more and more studies are focusing on the relationship between EMF and Alzheimer's disease (AD). Electromagnetic pulse (EMP) is one type of widely used EMF. This study aimed to clarify whether EMP exposure could induce cognitive and memory impairment, thus finding a possible relationship between EMP and AD. Forty healthy male Sprague Dawley rats were randomly divided into four groups. Animals, respectively, received 100, 1000, and 10,000 pulses EMP (field strength 50 kV/m, repetition rate 100 Hz) exposure and sham exposure when 2 months old. Monthly Morris water maze (MWM) was used to test the changes of cognitive and memory ability. Superoxide dismutase (SOD) activity and glutathione (GSH) content were used as oxidative stress indexes. Expressions of some types of Alzheimer's disease-related proteins were also detected. After exposure, EMP exposure caused clear cognitive and memory impairment compared with sham exposure group (p <0.05). Determination of oxidation indexes showed decreased SOD activity and GSH content in exposure groups compared with sham group. Immunohistochemical (IHC) staining showed increased beta amyloid protein (Aβ) in EMP exposure groups compared with sham group. Western blot experiments showed increased expressions of Aβ oligomer and beta amyloid protein precursor (APP) in EMP exposure groups. Increased expression of microtubule-associated protein 1 light chain 3-II (LC3-II) was also found. The present results showed that EMP exposure can cause long-term impairment in impaired cognition and memory of rats, resulting in AD-like symptoms. This may be induced by enhancing oxidative stress and is related to autophagy dysfunction. Copyright © 2013 IMSS. Published by Elsevier Inc. All rights reserved.

  14. Proposed iso standard determination of occupational noise exposure and estimation of noise-induced hearing impairment

    SciTech Connect

    Von Gierke, H.E.

    1986-01-01

    Research on the relationship between noise exposure and noise-induced hearing loss has been very intense over the last 30 years, and steady progress has been made in spite of many remaining questions and unresolved problems regarding the mechanisms. For the time being, avoidance of excessive noise exposure is the only way to prevent noise-induced hearing loss; this is the reason why governments, industry, workers and their representatives have been looking for scientific exposure criteria and guidelines to prevent hazardous noise exposure as part of comprehensive hearing conservation programs. Although it was clear from the beginning that noise-induced hearing loss in a population with exactly defined noise exposure would exhibit a statistical distribution due to differences in biological susceptibility, the epidemiological statistical data were not available to describe quantitatively the difference between the percentage of people with impaired hearing in a noise-exposed group and the percentage of people in a non-noise-exposed group, i.e., the risk of noise-induced hearing impairment.

  15. Induced tolerance from a sublethal insecticide leads to cross-tolerance to other insecticides.

    PubMed

    Hua, Jessica; Jones, Devin K; Relyea, Rick A

    2014-04-01

    As global pesticide use increases, the ability to rapidly respond to pesticides by increasing tolerance has important implications for the persistence of nontarget organisms. A recent study of larval amphibians discovered that increased tolerance can be induced by an early exposure to low concentrations of a pesticide. Since natural systems are often exposed to a variety of pesticides that vary in mode of action, we need to know whether the induction of increased tolerance to one pesticide confers increased tolerance to other pesticides. Using larval wood frogs (Lithobates sylvaticus), we investigated whether induction of increased tolerance to the insecticide carbaryl (AChE-inhibitor) can induce increased tolerance to other insecticides that have the same mode of action (chlorpyrifos, malathion) or a different mode of action (Na(+)channel-interfering insecticides; permethrin, cypermethrin). We found that embryonic exposure to sublethal concentrations of carbaryl induced higher tolerance to carbaryl and increased cross-tolerance to malathion and cypermethrin but not to chlorpyrifos or permethrin. In one case, the embryonic exposure to carbaryl induced tolerance in a nonlinear pattern (hormesis). These results demonstrate that that the newly discovered phenomenon of induced tolerance also provides induced cross-tolerance that is not restricted to pesticides with the same mode of action.

  16. Synchronous double malignancy: adenocarcinoma of lung and malignant astrocytoma induced by asbestos exposure.

    PubMed

    Kishimoto, T; Hashimoto, H; Ono, T; Okada, K

    1992-01-01

    A 54-year-old male died of cerebellar herniation induced by brain tumor. Radiological examination of this case showed two separate tumorous lesions in the brain and lung. Autopsy proved malignant astrocytoma in the brain and coincidental alveolar cell carcinoma in the lung. He had a history of asbestos exposure for 8 years doing piping work in a shipyard. Furthermore, we detected a large number of asbestos bodies in the lung and one asbestos body in the brain. Therefore, this rare case of double cancer (malignant astrocytoma and lung cancer) might have been induced by asbestos exposure.

  17. Chronic Exposure to Particulate Chromate Induces Premature Centrosome Separation and Centriole Disengagement in Human Lung Cells

    PubMed Central

    Martino, Julieta; Holmes, Amie L.; Xie, Hong; Wise, Sandra S.; Wise, John Pierce

    2015-01-01

    Particulate hexavalent chromium (Cr(VI)) is a well-established human lung carcinogen. Lung tumors are characterized by structural and numerical chromosome instability. Centrosome amplification is a phenotype commonly found in solid tumors, including lung tumors, which strongly correlates with chromosome instability. Human lung cells exposed to Cr(VI) exhibit centrosome amplification but the underlying phenotypes and mechanisms remain unknown. In this study, we further characterize the phenotypes of Cr(VI)-induced centrosome abnormalities. We show that Cr(VI)-induced centrosome amplification correlates with numerical chromosome instability. We also show chronic exposure to particulate Cr(VI) induces centrosomes with supernumerary centrioles and acentriolar centrosomes in human lung cells. Moreover, chronic exposure to particulate Cr(VI) affects the timing of important centriolar events. Specifically, chronic exposure to particulate Cr(VI) causes premature centriole disengagement in S and G2 phase cells. It also induces premature centrosome separation in interphase. Altogether, our data suggest that chronic exposure to particulate Cr(VI) targets the protein linkers that hold centrioles together. These centriolar linkers are important for key events of the centrosome cycle and their premature disruption might underlie Cr(VI)-induced centrosome amplification. PMID:26293554

  18. Arsenite exposure in human lymphoblastoid cell lines induces autophagy and coordinated induction of lysosomal genes.

    PubMed

    Bolt, Alicia M; Douglas, Randi M; Klimecki, Walter T

    2010-11-30

    Chronic exposure to inorganic arsenic is associated with diverse, complex diseases, making the identification of the mechanism underlying arsenic-induced toxicity a challenge. An increasing body of literature from epidemiological and in vitro studies has demonstrated that arsenic is an immunotoxicant, but the mechanism driving arsenic-induced immunotoxicity is not well established. We have previously demonstrated that in human lymphoblastoid cell lines (LCLs), arsenic-induced cell death is strongly associated with the induction of autophagy. In this study we utilized genome-wide gene expression analysis and functional assays to characterize arsenic-induced effects in seven LCLs that were exposed to an environmentally relevant, minimally cytotoxic, concentration of arsenite (0.75 μM) over an eight-day time course. Arsenic exposure resulted in inhibition of cellular growth and induction of autophagy (measured by expansion of acidic vesicles) over the eight-day exposure duration. Gene expression analysis revealed that arsenic exposure increased global lysosomal gene expression, which was associated with increased functional activity of the lysosome protease, cathepsin D. The arsenic-induced expansion of the lysosomal compartment in LCL represents a novel target that may offer insight into the immunotoxic effects of arsenic.

  19. Repeated Ketamine Exposure Induces an Enduring Resilient Phenotype in Adolescent and Adult Rats

    PubMed Central

    Parise, Eric M.; Alcantara, Lyonna F.; Warren, Brandon L.; Wright, Katherine N.; Hadad, Roey; Sial, Omar K.; Kroeck, Kyle G.; Iñiguez, Sergio D.; Bolaños-Guzmán, Carlos A.

    2013-01-01

    Background Major Depressive Disorder (MDD) afflicts up to 10% of adolescents. However, nearly 50% of those afflicted are considered non-responsive to available treatments. Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist has shown potential as a rapid-acting and long-lasting treatment for MDD in adults. Thus, the effectiveness and functional consequences of ketamine exposure during adolescence were explored. Methods Adolescent male rats (postnatal day [PD] 35) received two ketamine (0, 5, 10 or 20 mg/kg) injections, 4 hours apart, after exposure to day 1 of the forced swim test (FST). The next day, rats were re-exposed to the FST to assess ketamine-induced antidepressant-like responses. Separate groups were exposed to chronic unpredictable stress (CUS) to confirm findings from the FST. After these initial experiments, adolescent naïve rats were exposed to either 1 or 15 consecutive days (PD35–49) of ketamine (20 mg/kg) twice/daily. Ketamine's influence on behavioral reactivity to rewarding (i.e., sucrose preference) and aversive (i.e., elevated plus-maze, FST) circumstances was then assessed 2 months after treatment. To control for age-dependent effects, adult rats (PD75–89) were exposed to identical experimental conditions. Results Ketamine (20 mg/kg) reversed the CUS-induced depression-like behaviors in the FST. Repeated ketamine exposure resulted in anxiolytic- and antidepressant-like responses 2 months after drug exposure. None of the ketamine doses used were capable of inducing drug-seeking behaviors as measured by place preference conditioning. Conclusions Repeated ketamine exposure induces enduring resilient-like responses regardless of age of exposure. These findings point to ketamine, and its repeated exposure, as a potentially useful antidepressant during adolescence. PMID:23790225

  20. Repeated ketamine exposure induces an enduring resilient phenotype in adolescent and adult rats.

    PubMed

    Parise, Eric M; Alcantara, Lyonna F; Warren, Brandon L; Wright, Katherine N; Hadad, Roey; Sial, Omar K; Kroeck, Kyle G; Iñiguez, Sergio D; Bolaños-Guzmán, Carlos A

    2013-11-15

    Major depressive disorder afflicts up to 10% of adolescents. However, nearly 50% of those afflicted are considered nonresponsive to available treatments. Ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist has shown potential as a rapid-acting and long-lasting treatment for major depressive disorder in adults. Thus, the effectiveness and functional consequences of ketamine exposure during adolescence were explored. Adolescent male rats (postnatal day [PD] 35) received two ketamine (0, 5, 10, or 20 mg/kg) injections, 4 hours apart, after exposure to day 1 of the forced swim test (FST). The next day, rats were reexposed to the FST to assess ketamine-induced antidepressant-like responses. Separate groups were exposed to chronic unpredictable stress to confirm findings from the FST. After these initial experiments, adolescent naive rats were exposed to either 1 or 15 consecutive days (PD35-49) of ketamine (20 mg/kg) twice daily. Ketamine's influence on behavioral reactivity to rewarding (i.e., sucrose preference) and aversive (i.e., elevated plus-maze, FST) circumstances was then assessed 2 months after treatment. To control for age-dependent effects, adult rats (PD75-89) were exposed to identical experimental conditions. Ketamine (20 mg/kg) reversed the chronic unpredictable stress-induced depression-like behaviors in the FST. Repeated ketamine exposure resulted in anxiolytic- and antidepressant-like responses 2 months after drug exposure. None of the ketamine doses used were capable of inducing drug-seeking behaviors as measured by place preference conditioning. Repeated ketamine exposure induces enduring resilient-like responses regardless of age of exposure. These findings point to ketamine, and its repeated exposure, as a potentially useful antidepressant during adolescence. © 2013 Society of Biological Psychiatry.

  1. Exercise Prevents Memory Impairment Induced by Arsenic Exposure in Mice: Implication of Hippocampal BDNF and CREB

    PubMed Central

    Yu, Zi-Jiang; Yu, Yan; Xiao, Chao-Lun; Kang, Chao-Sheng; Ge, Guo; Linghu, Yan; Zhu, Jun-De; Li, Yu-Mei; Li, Qiang-Ming; Luo, Shi-Peng; Yang, Dang; Li, Lin; Zhang, Wen-Yan; Tian, Guang

    2015-01-01

    High concentrations of arsenic, which can be occasionally found in drinking water, have been recognized as a global health problem. Exposure to arsenic can disrupt spatial memory; however, the underlying mechanism remains unclear. In the present study, we tested whether exercise could interfere with the effect of arsenic exposure on the long-term memory (LTM) of object recognition in mice. Arsenic (0, 1, 3, and 10 mg/ kg, i.g.) was administered daily for 12 weeks. We found that arsenic at dosages of 1, 3, and 10 mg/kg decreased body weight and increased the arsenic content in the brain. The object recognition LTM (tested 24 h after training) was disrupted by 3 mg/ kg and 10 mg/ kg, but not 1 mg/ kg arsenic exposure. Swimming exercise also prevented LTM impairment induced by 3 mg/ kg, but not with 10 mg/ kg, of arsenic exposure. The expression of brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP-response element binding protein (pCREB) in the CA1 and dentate gyrus areas (DG) of the dorsal hippocampus were decreased by 3 mg/ kg and 10 mg/ kg, but not by 1 mg/ kg, of arsenic exposure. The decrease in BDNF and pCREB in the CA1 and DG induced by 3 mg/ kg, but not 10 mg/ kg, of arsenic exposure were prevented by swimming exercise. Arsenic exposure did not affect the total CREB expression in the CA1 or DG. Taken together, these results indicated that swimming exercise prevented the impairment of object recognition LTM induced by arsenic exposure, which may be mediated by BDNF and CREB in the dorsal hippocampus. PMID:26368803

  2. Exercise Prevents Memory Impairment Induced by Arsenic Exposure in Mice: Implication of Hippocampal BDNF and CREB.

    PubMed

    Sun, Bao-Fei; Wang, Qing-Qing; Yu, Zi-Jiang; Yu, Yan; Xiao, Chao-Lun; Kang, Chao-Sheng; Ge, Guo; Linghu, Yan; Zhu, Jun-De; Li, Yu-Mei; Li, Qiang-Ming; Luo, Shi-Peng; Yang, Dang; Li, Lin; Zhang, Wen-Yan; Tian, Guang

    2015-01-01

    High concentrations of arsenic, which can be occasionally found in drinking water, have been recognized as a global health problem. Exposure to arsenic can disrupt spatial memory; however, the underlying mechanism remains unclear. In the present study, we tested whether exercise could interfere with the effect of arsenic exposure on the long-term memory (LTM) of object recognition in mice. Arsenic (0, 1, 3, and 10 mg/ kg, i.g.) was administered daily for 12 weeks. We found that arsenic at dosages of 1, 3, and 10 mg/kg decreased body weight and increased the arsenic content in the brain. The object recognition LTM (tested 24 h after training) was disrupted by 3 mg/ kg and 10 mg/ kg, but not 1 mg/ kg arsenic exposure. Swimming exercise also prevented LTM impairment induced by 3 mg/ kg, but not with 10 mg/ kg, of arsenic exposure. The expression of brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP-response element binding protein (pCREB) in the CA1 and dentate gyrus areas (DG) of the dorsal hippocampus were decreased by 3 mg/ kg and 10 mg/ kg, but not by 1 mg/ kg, of arsenic exposure. The decrease in BDNF and pCREB in the CA1 and DG induced by 3 mg/ kg, but not 10 mg/ kg, of arsenic exposure were prevented by swimming exercise. Arsenic exposure did not affect the total CREB expression in the CA1 or DG. Taken together, these results indicated that swimming exercise prevented the impairment of object recognition LTM induced by arsenic exposure, which may be mediated by BDNF and CREB in the dorsal hippocampus.

  3. The Concept of Hormesis in Cancer Therapy – Is Less More?

    PubMed Central

    Akle, Charles A; Mudan, Satvinder; Grange, John

    2015-01-01

    There has, in recent years, been a paradigm shift in our understanding of the role of the immune system in the development of cancers. Immune dysregulation, manifesting as chronic inflammation, not only facilitates the growth and spread of tumors but prevents the host from mounting effective immune defenses against it. Many attempts are being made to develop novel immunotherapeutic strategies, but there is growing evidence that a radical reevaluation of the mode of action of chemotherapeutic agents and ionizing radiation is required in the light of advances in immunology. Based on the concept of hormesis – defined as the presence of different modes of action of therapeutic modalities at different doses – a ‘repositioning’ of chemotherapy and radiotherapy may be required in all aspects of cancer management. In the case of chemotherapy, this may involve a change from the maximum tolerated dose concept to low dose intermittent (‘metronomic’) therapy, whilst in radiation therapy, highly accurate stereotactic targeting enables ablative, antigen-releasing (immunogenic) doses of radiation to be delivered to the tumor with sparing of surrounding normal tissues. Coupled with emerging immunotherapeutic procedures, the future of cancer treatment may well lie in repositioned chemotherapy, radiotherapy, and more localized debulking surgery. PMID:26180685

  4. Cellular Stress Responses, The Hormesis Paradigm, and Vitagenes: Novel Targets for Therapeutic Intervention in Neurodegenerative Disorders

    PubMed Central

    Cornelius, Carolin; Dinkova-Kostova, Albena T.; Calabrese, Edward J.; Mattson, Mark P.

    2010-01-01

    Abstract Despite the capacity of chaperones and other homeostatic components to restore folding equilibrium, cells appear poorly adapted for chronic oxidative stress that increases in cancer and in metabolic and neurodegenerative diseases. Modulation of endogenous cellular defense mechanisms represents an innovative approach to therapeutic intervention in diseases causing chronic tissue damage, such as in neurodegeneration. This article introduces the concept of hormesis and its applications to the field of neuroprotection. It is argued that the hormetic dose response provides the central underpinning of neuroprotective responses, providing a framework for explaining the common quantitative features of their dose–response relationships, their mechanistic foundations, and their relationship to the concept of biological plasticity, as well as providing a key insight for improving the accuracy of the therapeutic dose of pharmaceutical agents within the highly heterogeneous human population. This article describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways, including sirtuin and Nrf2 and related pathways that integrate adaptive stress responses in the prevention of neurodegenerative diseases. Particular attention is given to the emerging role of nitric oxide, carbon monoxide, and hydrogen sulfide gases in hormetic-based neuroprotection and their relationship to membrane radical dynamics and mitochondrial redox signaling. Antioxid. Redox Signal. 13, 1763–1811. PMID:20446769

  5. Commentary: Hormesis can be used in enhancing plant productivity and health; but not as previously envisaged.

    PubMed

    Gressel, Jonathan; Dodds, John

    2013-12-01

    Sub-toxic doses of many toxicants have positive, beneficial effects on productivity, or stress resistance (hormesis). Transcriptomic, proteomic, and metabolomic responses to a disparate variety hormetic agents, coupled with bioinformatic analyses, can be used to identify consensus genes, their controlling elements, and their metabolites related to stimulation of growth and/or health. This information can then be used as a method for generating healthier and higher yielding crops using transgenic or other biotechnological techniques. The same bioinformatic information can be used to develop knowledge-based, transcriptomic, proteomic and metabolomic high throughput pre-screens using young plants to identify hormetic chemicals that are potentially useful for enhancement of crop health and yield. Such pre-screens preclude the need to use whole plants through maturity. While the hormetic effectors themselves have to date been of limited direct utility, it is clear that they can be used to help pinpoint genes and chemicals that are potentially useful. This is superior to the presently used random screening or even "educated guess" screening of genes and chemicals.

  6. Hormesis--implications for risk assessment caloric intake (body weight) as an exemplar.

    PubMed

    Turturro, A; Hass, B; Hart, R W

    1998-08-01

    Hormesis can be considered as a parameter which has a non-monotonic relationship with some endpoint. Since caloric intake is such a parameter, and the impact of this parameter on risk assessment has been fairly well characterized, it can provide clues as to how to integrate the information from a hormetic parameter into risk assessments for toxicants. Based on the work with caloric intake, one could: (a) define a biomarker for hormetic effect; (b) integrate specific information on when in the animals lifespan the parameter is active to influence parameters such as survival; (c) evaluate component effects of the overall hormetic response; and (d) address the consequences of a non-monotonic relationship between the hormetic parameter and endpoints critical for risk assessment. These impacts on risk assessments have been characterized for chronic tests, but are also true for short-term tests. A priority is the characterization of the dose-response curves for hormetic parameters. This quantification will be critical in utilizing them in risk assessment. With this information, one could better quantitatively address the changes one expects to result from the hormetic parameter, and limit the uncertainty and variability which occurs in toxicity testing.

  7. Toxicology of cupric salts in honeybees. I. Hormesis effects of organic derivatives on lethality parameters.

    PubMed

    Bounias, M; Navone-Nectoux, M; Popeskovic, D S

    1995-07-01

    Feeding bees with organic cupric salts provides long-term control of the parasite Varroa jacobsoni. A set of new algebraic parameters (M. Bounias C.R. Acad. Sci. 310(3), 65-70, 1990) completely describing the population lethality function has been calculated following chronic administration of cupric gluconate, aspartate, and isoleucinate, with or without dietary pollen. Mortality curves allowed the calculation of LT50 (time for 50% lethality) as well as Hill coefficients (h) of the curves and the LD50 as a function of time. The tangent at the inflexion point of the sigmoidal time/mortality curves (delta i) gave the maximum mortality acceleration as an additional parameter. No toxicity (i.e., no decrease of TL50 vs doses and no LD50 values) was found for cupric gluconate and isoleucinate with pollen, whereas increases in LT50 and decreases in delta indicated hormesis effects. Doses decreasing by half-time LT50, h, or delta were used as objective lethality indexes for comparisons of toxicity in the other cases. Routine acute toxicity at high dosage was also compared with phosalone and lindane effects 24 hr after treatment.

  8. Commentary on resveratrol and hormesis: resveratrol--a hormetic marvel in waiting?

    PubMed

    Marques, Francine Z; Morris, Brian J

    2010-12-01

    Hormesis is a phenomenon in which adaptive responses to low doses of otherwise-harmful factors (also called mild stressors) make cells and organisms more robust. In their review, Calabrese et al. provide evidence for resveratrol acting hormetically in different types of human cell lines. The effects of resveratrol represent a 'two-edged sword' in that it has contrasting effects at low and high doses in healthy and cancerogenous cells. What demarcates a low and a high dose needs to be clarified. Concentrations tested in cell cultures, moreover, may not be relevant to whole organisms. And data from animal models need not apply to humans. Co-morbidities should also be considered. More research is needed to understand the action of resveratrol on all cell types and conditions, and the optimum therapeutic concentration that applies to each of these. Future research needs to determine the dynamics of the effects of resveratrol in different subcellular compartments and the interactions of these. In addition, the interactions between resveratrol, environmental factors, other compounds and medications, diseases and the genetic background of the individual will need to be appreciated in order to gain a complete understanding of the hormetic response of resveratrol.

  9. Language exposure induced neuroplasticity in the bilingual brain: a follow-up fMRI study.

    PubMed

    Tu, Liu; Wang, Junjing; Abutalebi, Jubin; Jiang, Bo; Pan, Ximin; Li, Meng; Gao, Wei; Yang, Yuchen; Liang, Bishan; Lu, Zhi; Huang, Ruiwang

    2015-03-01

    Although several studies have shown that language exposure crucially influence the cerebral representation of bilinguals, the effects of short-term change of language exposure in daily life upon language control areas in bilinguals are less known. To explore this issue, we employed follow-up fMRI to investigate whether differential exposure induces neuroplastic changes in the language control network in high-proficient Cantonese (L1)-Mandarin (L2) early bilinguals. The same 10 subjects underwent twice BOLD-fMRI scans while performing a silent narration task which corresponded to two different language exposure conditions, CON-1 (L1/L2 usage percentage, 50%:50%) and CON-2 (L1/L2 usage percentage, 90%:10%). We report a strong effect of language exposure in areas related to language control for the less exposed language. Interestingly, these significant effects were present after only a 30-day period of differential language exposure. In detail, we reached the following results: (1) the interaction effect of language and language exposure condition was found significantly in the left pars opercularis (BA 44) and marginally in the left MFG (BA 9); (2) in CON-2, increases of activation values in L2 were found significantly in bilateral BA 46 and BA 9, in the left BA44, and marginally in the left caudate; and (3) in CON-2, we found a significant negative correlation between language exposure to L2 and the BOLD activation value specifically in the left ACC. These findings strongly support the hypothesis that even short periods of differential exposure to a given language may induce significant neuroplastic changes in areas responsible for language control. The language which a bilingual is less exposed to and is also less used will be in need of increased mental control as shown by the increased activity of language control areas.

  10. Evolution of color vision loss induced by occupational exposure to chemicals.

    PubMed

    Gobba, F; Cavalleri, A

    2000-10-01

    The evolution of occupationally induced color vision loss was studied in workers exposed to various chemicals. Exposure was evaluated by biological monitoring or personal air samplers, and color vision using the Lanthony D-15 desaturated panel (D-15 d). The effect of short-term interruption of exposure was studied in 39 Styrene (St) exposed workers: at a first examination a dose-related color vision loss was disclosed; a re-test performed after one month's interruption of exposure did not show any improvement of the effect. The evolution during longer periods was studied in another group of 30 St workers. Exposure and color vision were evaluated, then a follow-up was done 12 months later: the exposure was unmodified or slightly decreased in 20 subjects, and D-15 d outcomes remained unchanged, while St levels had increased and color vision loss progressed in the other 10. Similar results were obtained in 33 PCE exposed dry-cleaners: no change in color perception was observed in 14 workers whose exposure decreased, while in the other 19 a rise in PCE levels was followed by a significant color vision worsening. In 21 Hg exposed workers whose mean urinary excretion of Hg was threefold the BEI proposed by ACGIH, a dose-related impairment in color perception was observed. 12 months after a marked reduction of exposure, an almost complete recovery of the impairment was observed. Our data show that an increase in exposure can induce a worsening in color vision loss. A short interruption in exposure did not reduce the effect. A more prolonged reduction of dose reversed color vision loss in Hg exposed workers, while in solvent-exposed individuals the progression deserves further evaluation. D-15 d proved a useful test for studies on the evolution of color perception in workers exposed to eye-toxic chemicals.

  11. Novel Pharmacological Approaches for Treatment of Neurotoxicity Induced by Chronic Exposure to Depleted Uranium

    DTIC Science & Technology

    2009-09-01

    an anti- oxidant agent and/or an NMDA receptor antagonist will reduce neurotoxicity resulting from chronic exposure to DU. This hypothesis is based...DU-induced oxidative stress. As prescribed by the Statement of Work, efforts continued in year 2 on Tasks 1 (drug therapies to reverse DU-induced...SUBJECT TERMS depleted uranium, glutamate release, military disease, hippocampus, oxidative stress, neuroprotectant drugs 16. SECURITY

  12. Time to Reject the Linear-No Threshold Hypothesis and Accept Thresholds and Hormesis: A Petition to the U.S. Nuclear Regulatory Commission.

    PubMed

    Marcus, Carol S

    2015-07-01

    On February 9, 2015, I submitted a petition to the U.S. Nuclear Regulatory Commission (NRC) to reject the linear-no threshold (LNT) hypothesis and ALARA as the bases for radiation safety regulation in the United States, using instead threshold and hormesis evidence. In this article, I will briefly review the history of LNT and its use by regulators, the lack of evidence supporting LNT, and the large body of evidence supporting thresholds and hormesis. Physician acceptance of cancer risk from low dose radiation based upon federal regulatory claims is unfortunate and needs to be reevaluated. This is dangerous to patients and impedes good medical care. A link to my petition is available: http://radiationeffects.org/wp-content/uploads/2015/03/Hormesis-Petition-to-NRC-02-09-15.pdf, and support by individual physicians once the public comment period begins would be extremely important.

  13. Mechanisms of particle-induced pulmonary inflammation in a mouse model: exposure to wood dust.

    PubMed

    Määttä, Juha; Lehto, Maili; Leino, Marina; Tillander, Sari; Haapakoski, Rita; Majuri, Marja-Leena; Wolff, Henrik; Rautio, Sari; Welling, Irma; Husgafvel-Pursiainen, Kirsti; Savolainen, Kai; Alenius, Harri

    2006-09-01

    Repeated airway exposure to wood dust has long been known to cause adverse respiratory effects such as asthma and chronic bronchitis and impairment of lung function. However, the mechanisms underlying the inflammatory responses of the airways after wood dust exposure are poorly known. We used a mouse model to elucidate the mechanisms of particle-induced inflammatory responses to fine wood dust particles. BALB/c mice were exposed to intranasally administered fine (more than 99% of the particles had a particle size of < or = 5 microm, with virtually identical size distribution) birch or oak dusts twice a week for 3 weeks. PBS, LPS, and titanium dioxide were used as controls. Intranasal instillation of birch or oak dusts elicited influx of inflammatory cells to the lungs in mice. Enhancement of lymphocytes and neutrophils was seen after oak dust exposure, whereas eosinophil infiltration was higher after birch dust exposure. Infiltration of inflammatory cells was associated with an increase in the mRNA levels of several cytokines, chemokines, and chemokine receptors in lung tissue. Oak dust appeared to be a more potent inducer of these inflammatory mediators than birch dust. The results from our in vivo mouse model show that repeated airway exposure to wood dust can elicit lung inflammation, which is accompanied by induction of several proinflammatory cytokines and chemokines. Oak and birch dusts exhibited quantitative and qualitative differences in the elicitation of pulmonary inflammation, suggesting that the inflammatory responses induced by the wood species may rise via different cellular mechanisms.

  14. Severe malformations of eelpout (Zoarces viviparus) fry are induced by maternal estrogenic exposure during early embryogenesis.

    PubMed

    Morthorst, Jane E; Korsgaard, Bodil; Bjerregaard, Poul

    2016-02-01

    Pregnant eelpout were exposed via the water to known endocrine disrupting compounds (EDCs) to clarify if EDCs could be causing the increased eelpout fry malformation frequencies observed in coastal areas receiving high anthropogenic input. The presence of a teratogenic window for estrogen-induced malformations was also investigated by starting the exposure at different times during eelpout pregnancy. Both 17α-ethinylestradiol (EE2) (17.8 ng/L) and pyrene (0.5 μg/L) significantly increased fry malformation frequency whereas 4-t-octylphenol (4-t-OP) up to 14.3 μg/L did not. Vitellogenin was significantly induced by EE2 (5.7 and 17.8 ng/L) but not by 4-t-OP and pyrene. A critical period for estrogen-induced fry malformations was identified and closed between 14 and 22 days post fertilization (dpf). Exposure to 17β-estradiol (E2) between 0 and 14 dpf caused severe malformations and severity increased the closer exposure start was to fertilization, whereas malformations were absent by exposure starting later than 14 dpf. Data on ovarian fluid volume and larval length supported the suggested teratogenic window. Larval mortality also increased when exposure started right after fertilization.

  15. Acute exposure of apigenin induces hepatotoxicity in Swiss mice.

    PubMed

    Singh, Prabhat; Mishra, Shrawan Kumar; Noel, Sanjeev; Sharma, Sharad; Rath, Srikanta Kumar

    2012-01-01

    Apigenin, a dietary flavonoid, is reported to have several therapeutic effects in different diseases including cancer. Toxicity of Apigenin is however, least explored, and reports are scanty in literature. This warrants dose-specific evaluation of toxicity in vivo. In the present study, Apigenin was administered intraperitoneally to Swiss mice at doses of 25, 50, 100 and 200 mg/kg. Serum levels of alanine amino transferase (ALT), aspartate amino transferase (AST) and alkaline phosphatase (ALP) were measured along with the examination of liver histology, reactive oxygen species (ROS) in blood, lipid peroxidation (LPO), glutathione level, superoxide dismutase activity, catalase activity, glutathione S-transferase activity and gene expression in liver tissue. Increase in ALT, AST, ALP, ROS, ratio of oxidized to reduced glutathione (GSSG/GSH) and LPO, altered enzyme activities along with damaged histoarchitecture in the liver of 100 or 200 mg/kg Apigenin treated animals were found. Microarray analysis revealed the differential expression of genes that correspond to different biologically relevant pathways including oxidative stress and apoptosis. In conclusion, these results suggested the oxidative stress induced liver damage which may be due to the regulation of multiple genes by Apigenin at higher doses in Swiss mice.

  16. Piracetam prevents memory deficit induced by postnatal propofol exposure in mice.

    PubMed

    Wang, Yuan-Lin; Li, Feng; Chen, Xin

    2016-05-15

    Postnatal propofol exposure impairs hippocampal synaptic development and memory. However, the effective agent to alleviate the impairments was not verified. In this study, piracetam, a positive allosteric modulator of AMPA receptor was administered following a seven-day propofol regime. Two months after propofol administration, hippocampal long-term potentiation (LTP) and long-term memory decreased, while intraperitoneal injection of piracetam at doses of 100mg/kg and 50mg/kg following last propofol exposure reversed the impairments of memory and LTP. Mechanically, piracetam reversed propofol exposure-induced decrease of BDNF and phosphorylation of mTor. Similar as piracetam, BDNF supplementary also ameliorated propofol-induced abnormalities of synaptic plasticity-related protein expressions, hippocampal LTP and long-term memory. These results suggest that piracetam prevents detrimental effects of propofol, likely via activating BDNF synthesis. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Exposure of Metarhizium acridum mycelium to light induces tolerance to UV-B radiation.

    PubMed

    Brancini, Guilherme T P; Rangel, Drauzio E N; Braga, Gilberto Ú L

    2016-03-01

    Metarhizium acridum is an entomopathogenic fungus commonly used as a bioinsecticide. The conidium is the fungal stage normally employed as field inoculum in biological control programs and must survive under field conditions such as high ultraviolet-B (UV-B) exposure. Light, which is an important stimulus for many fungi, has been shown to induce the production of M. robertsii conidia with increased stress tolerance. Here we show that a two-hour exposure to white or blue/UV-A light of fast-growing mycelium induces tolerance to subsequent UV-B irradiation. Red light, however, does not have the same effect. In addition, we established that this induction can take place with as little as 1 min of white-light exposure. This brief illumination scheme could be relevant in future studies of M. acridum photobiology and for the production of UV-B resistant mycelium used in mycelium-based formulations for biological control.

  18. Current densities in a pregnant woman model induced by simultaneous ELF electric and magnetic field exposure

    NASA Astrophysics Data System (ADS)

    Cech, R.; Leitgeb, N.; Pediaditis, M.

    2008-01-01

    The pregnant woman model SILVY was studied to ascertain to what extent the electric current densities induced by 50 Hz homogeneous electric and magnetic fields increase in the case of simultaneous exposure. By vectorial addition of the electric current densities, it could be shown that under worst case conditions the basic restrictions recommended by ICNIRP (International Commission on Non-Ionizing Radiation Protection) guidelines are exceeded within the central nervous system (CNS) of the mother, whereas in sole field exposure they are not. However, within the foetus the induced current densities do not comply with basic restrictions, either from single reference-level electric fields or from simultaneous exposure to electric and magnetic fields. Basic limits were considerably exceeded.

  19. Low level ozone exposure induces airways inflammation and modifies cell surface phenotypes in healthy humans

    EPA Science Inventory

    Background: The effects of low level ozone exposure (0.08 ppm) on pulmonary function in healthy young adults are well known, however much less is known about the inflammatory and immuno-modulatory effects oflow level ozone in the airways. Techniques such as induced sputum and flo...

  20. THE EFFECTS OF HEAT SHOCK PROTEIN 70 (HSP70) AND EXPOSURE PROTOCOL ON ARSENITE INDUCED GENOTOXICITY

    EPA Science Inventory

    The Effects of Heat Shock Protein 70 (Hsp70) and Exposure Protocol on Arsenite Induced Genotoxicity

    Barnes, J.A.1,2, Collins, B.W.2, Dix, D.J.3 and Allen J.W2.
    1National Research Council, 2Environmental Carcinogenesis Division, 3Reproductive Toxicology Division, Office...

  1. Effect of low-level NO/sub 2/ chronic exposure on elastase-induced emphysema

    SciTech Connect

    Lafuma, C.; Harf, A.; Lange, F.; Bozzi, L.; Poncy, J.L.; Bignon, J.

    1987-06-01

    The effect of chronic exposure to 2 ppm nitrogen dioxide (NO/sub 2/) for 8 hr a day, 5 days a week, for 8 weeks was assessed in normal and emphysematous hamsters by measuring (1) lung morphometry (mean linear intercept (Lm) and internal surface area (ISA)), (2) lung mechanics (lung volume, compliance and coefficient of static deflation, pressure-volume curve fitted to an exponential equation), and (3) serum elastolytic activity and protease inhibitor capacity. Emphysema was induced by a single intratracheal injection of 6 IU porcine pancreatic elastase. Four groups of animals were used: control, NO/sub 2/-exposed, elastase-treated, and NO/sub 2/-exposed postelastase. Results show that NO/sub 2/ exposure alone induced mild emphysematous lesions whose degree of severity was of the same order as that of the lesions induced by 6 IU elastase. Exposure to 2 ppm NO/sub 2/ enhanced elastase-induced emphysema. By contrast, study of lung mechanics revealed no difference between the control and NO/sub 2/-exposed groups or between the elastase-treated animals exposed to NO/sub 2/ and those not so exposed. Lastly, results suggest that chronic exposure to 2 ppm NO/sub 2/ may cause individuals with inherited or acquired emphysematous lesions to develop more severe emphysema.

  2. Environmental Enrichment Ameliorates Neonatal Sevoflurane Exposure-Induced Cognitive and Synaptic Plasticity Impairments.

    PubMed

    Ji, Mu-huo; Wang, Xing-ming; Sun, Xiao-ru; Zhang, Hui; Ju, Ling-sha; Qiu, Li-li; Yang, Jiao-jiao; Jia, Min; Wu, Jing; Yang, Jianjun

    2015-11-01

    Early exposure to sevoflurane, an inhalation anesthetic, induces neurodegeneration in the developing brain and subsequent long-term neurobehavioral abnormalities. Here, we investigated whether an enriched environment could mitigate neonatal sevoflurane exposure-induced long-term cognitive and synaptic plasticity impairments. Male C57BL/6 mice were exposed to 3 % sevoflurane 2 h daily for 3 days from postnatal day 6 (P6) to P8. The exposed mice were randomly allocated to an enriched environment for 2 h daily between P8 and P42 or to a standard environment. Their behavior and cognition were assessed using open field (P35) and fear conditioning tests (P41-P42). Hematoxylin-eosin staining was used to study morphological changes in pyramidal neurons of hippocampal CA1 and CA3 regions. Synaptic plasticity alternations were assessed using western blotting, Golgi staining, and electrophysiological recording. We found that sevoflurane-exposed mice housed in a standard environment exhibited a reduced freezing response in the contextual test, decreased number of dendritic spines on pyramidal neurons and synaptic plasticity-related proteins in the hippocampus, and impaired long-term potentiation. However, in an enriched environment, some of these abnormities induced by repeated sevoflurane exposure. In conclusion, neonatal sevoflurane exposure-induced cognitive and synaptic plasticity impairments are ameliorated by an enriched environment.

  3. Low level ozone exposure induces airways inflammation and modifies cell surface phenotypes in healthy humans

    EPA Science Inventory

    Background: The effects of low level ozone exposure (0.08 ppm) on pulmonary function in healthy young adults are well known, however much less is known about the inflammatory and immuno-modulatory effects oflow level ozone in the airways. Techniques such as induced sputum and flo...

  4. AIR PARTICULATE POLLUTION EXPOSURE INDUCES SYSTEMIC OXIDATIVE STRESS IN HEALTHY MICE

    EPA Science Inventory

    Air particulate pollution exposure induces systemic oxidative stress in healthy mice

    Elizabeth S Roberts1 and Kevin L Dreher2. 1 College or Veterinary Medicine, NC State University, Raleigh, NC , 2US Environmental Protection Agency, NHEERL, RTP, NC

    Epidemiological s...

  5. Biomarkers of asbestos-induced lung injury: the influence of fiber characteristics and exposure methodology

    EPA Science Inventory

    ATS 2013 Biomarkers of asbestos-induced lung injury: the influence of fiber characteristics and exposure methodology Urmila P Kodavanti, Debora Andrews, Mette C Schaldweiler, Jaime M Cyphert, Darol E Dodd, and Stephen H Gavett NHEERL, U.S. EPA, Research Triangle Park, NC; NIEH...

  6. THE EFFECTS OF HEAT SHOCK PROTEIN 70 (HSP70) AND EXPOSURE PROTOCOL ON ARSENITE INDUCED GENOTOXICITY

    EPA Science Inventory

    The Effects of Heat Shock Protein 70 (Hsp70) and Exposure Protocol on Arsenite Induced Genotoxicity

    Barnes, J.A.1,2, Collins, B.W.2, Dix, D.J.3 and Allen J.W2.
    1National Research Council, 2Environmental Carcinogenesis Division, 3Reproductive Toxicology Division, Office...

  7. Biomarkers of asbestos-induced lung injury: the influence of fiber characteristics and exposure methodology

    EPA Science Inventory

    ATS 2013 Biomarkers of asbestos-induced lung injury: the influence of fiber characteristics and exposure methodology Urmila P Kodavanti, Debora Andrews, Mette C Schaldweiler, Jaime M Cyphert, Darol E Dodd, and Stephen H Gavett NHEERL, U.S. EPA, Research Triangle Park, NC; NIEH...

  8. AIR PARTICULATE POLLUTION EXPOSURE INDUCES SYSTEMIC OXIDATIVE STRESS IN HEALTHY MICE

    EPA Science Inventory

    Air particulate pollution exposure induces systemic oxidative stress in healthy mice

    Elizabeth S Roberts1 and Kevin L Dreher2. 1 College or Veterinary Medicine, NC State University, Raleigh, NC , 2US Environmental Protection Agency, NHEERL, RTP, NC

    Epidemiological s...

  9. Repeat organic dust exposure-induced monocyte inflammation is associated with protein kinase C activity.

    PubMed

    Poole, Jill A; Wyatt, Todd A; Von Essen, Susanna G; Hervert, John; Parks, Conrad; Mathisen, Tracy; Romberger, Debra J

    2007-08-01

    Organic dust exposure results in an inflammatory response that attenuates over time, but repetitive exposures can result in chronic respiratory diseases. Mechanisms underlying this modulated response are not clear. This study investigated the effects of repeat versus single organic dust exposure-induced inflammatory mediators and protein kinase C (PKC) activity in monocytes. Settled organic dust was obtained from swine confinement facilities. Promonocytic THP-1 cells and human peripheral blood monocytes were pretreated with or without dust extract and then restimulated. Culture supernatants were evaluated for TNF-alpha, IL-6, CXCL8, and IL-10. Responses were compared with endotoxin-depleted dust, LPS, and peptidoglycan. PKC isoform (alpha, delta, epsilon, zeta) activation was evaluated by direct kinase activity. PKC isoform inhibitors' effects on TNF-alpha secretion were studied. Single exposure to organic dust stimulated monocyte secretion of TNF-alpha, IL-6, CXCL8, and IL-10 compared with unstimulated cells. TNF-alpha and IL-6 were diminished in pretreated cells restimulated with dust. Secretion of CXCL8 and IL-10 remained persistently elevated. TNF-alpha responses were retained after marked depletion of endotoxin. Dust exposure induced significant PKC alpha, delta, epsilon, and zeta activation, peaking at 30 to 60 minutes. PKC isoform activation was attenuated in repeat exposed cells. Inhibition of PKCalpha and PKCepsilon reduced dust-induced TNF-alpha secretion. Repeat organic dust exposure modulated inflammatory mediator production in monocytes independent of endotoxin. The inability of PKC to be reactivated may account for this observation. Targeting PKC and specific mediators associated with repetitive organic dust exposure may result in novel therapeutic strategies.

  10. Differential Immunotoxicity Induced by Two Different Windows of Developmental Trichloroethylene Exposure

    PubMed Central

    Gilbert, Kathleen M.; Woodruff, William; Blossom, Sarah J.

    2014-01-01

    Developmental exposure to environmental toxicants may induce immune system alterations that contribute to adult stage autoimmune disease. We have shown that continuous exposure of MRL+/+ mice to trichloroethylene (TCE) from gestational day (GD) 0 to postnatal day (PND) 49 alters several aspects of CD4+ T cell function. This window of exposure corresponds to conception-adolescence/young adulthood in humans. More narrowly defining the window of TCE developmental exposure causes immunotoxicity that would establish the stage at which avoidance and/or intervention would be most effective. The current study divided continuous TCE exposure into two separate windows, namely, gestation only (GD0 to birth (PND0)) and early-life only (PND0-PND49). The mice were examined for specific alterations in CD4+ T cell function at PND49. One potentially long-lasting effect of developmental exposure, alterations in retrotransposon expression indicative of epigenetic alterations, was found in peripheral CD4+ T cells from both sets of developmentally exposed mice. Interestingly, certain other effects, such as alterations in thymus cellularity, were only found in mice exposed to TCE during gestation. In contrast, expansion of memory/activation cell subset of peripheral CD4+ T cells were only found in mice exposed to TCE during early life. Different windows of developmental TCE exposure can have different functional consequences. PMID:24696780

  11. Differential immunotoxicity induced by two different windows of developmental trichloroethylene exposure.

    PubMed

    Gilbert, Kathleen M; Woodruff, William; Blossom, Sarah J

    2014-01-01

    Developmental exposure to environmental toxicants may induce immune system alterations that contribute to adult stage autoimmune disease. We have shown that continuous exposure of MRL+/+ mice to trichloroethylene (TCE) from gestational day (GD) 0 to postnatal day (PND) 49 alters several aspects of CD4(+) T cell function. This window of exposure corresponds to conception-adolescence/young adulthood in humans. More narrowly defining the window of TCE developmental exposure causes immunotoxicity that would establish the stage at which avoidance and/or intervention would be most effective. The current study divided continuous TCE exposure into two separate windows, namely, gestation only (GD0 to birth (PND0)) and early-life only (PND0-PND49). The mice were examined for specific alterations in CD4(+) T cell function at PND49. One potentially long-lasting effect of developmental exposure, alterations in retrotransposon expression indicative of epigenetic alterations, was found in peripheral CD4(+) T cells from both sets of developmentally exposed mice. Interestingly, certain other effects, such as alterations in thymus cellularity, were only found in mice exposed to TCE during gestation. In contrast, expansion of memory/activation cell subset of peripheral CD4(+) T cells were only found in mice exposed to TCE during early life. Different windows of developmental TCE exposure can have different functional consequences.

  12. Low-dose cadmium exposure induces peribronchiolar fibrosis through site-specific phosphorylation of vimentin.

    PubMed

    Li, Fu Jun; Surolia, Ranu; Li, Huashi; Wang, Zheng; Liu, Gang; Liu, Rui-Ming; Mirov, Sergey B; Athar, Mohammad; Thannickal, Victor J; Antony, Veena B

    2017-07-01

    Exposure to cadmium (Cd) has been associated with development of chronic obstructive lung disease (COPD). The mechanisms and signaling pathways whereby Cd causes pathological peribronchiolar fibrosis, airway remodeling, and subsequent airflow obstruction remain unclear. We aimed to evaluate whether low-dose Cd exposure induces vimentin phosphorylation and Yes-associated protein 1 (YAP1) activation leading to peribronchiolar fibrosis and subsequent airway remodeling. Our data demonstrate that Cd induces myofibroblast differentiation and extracellular matrix (ECM) deposition around small (<2 mm in diameter) airways. Upon Cd exposure, α-smooth muscle actin (α-SMA) expression and the production of ECM proteins, including fibronectin and collagen-1, are markedly induced in primary human lung fibroblasts. Cd induces Smad2/3 activation and the translocation of both Smad2/3 and Yes-associated protein 1 (YAP1) into the nucleus. In parallel, Cd induces AKT and cdc2 phosphorylation and downstream vimentin phosphorylation at Ser(39) and Ser(55), respectively. AKT and cdc2 inhibitors block Cd-induced vimentin fragmentation and secretion in association with inhibition of α-SMA expression, ECM deposition, and collagen secretion. Furthermore, vimentin silencing abrogates Cd-induced α-SMA expression and decreases ECM production. Vimentin-deficient mice are protected from Cd-induced peribronchiolar fibrosis and remodeling. These findings identify two specific sites on vimentin that are phosphorylated by Cd and highlight the functional significance of vimentin phosphorylation in YAP1/Smad3 signaling that mediates Cd-induced peribronchiolar fibrosis and airway remodeling. Copyright © 2017 the American Physiological Society.

  13. Lung injury via oxidative stress in mice induced by inhalation exposure to rocket kerosene.

    PubMed

    Xu, Bingxin; Li, Chenglin; Wang, Jianying; Wu, Jihua; Si, Shaoyan; Liu, Zhiguo; Li, Jianzhong; Zhang, Jianzhong; Cui, Yan

    2015-01-01

    Rocket kerosene (RK) is a new rocket propellant. Toxicity occurs if a high level of RK is inhaled. To study the toxicity of RK in lung and the mechanisms of RK-induced lung jury, a total of 72 male ICR mice (1.5 months, adult) were randomly assigned to the RK exposure group (RKEG) and normal control group (NCG). Mice were whole-body exposed to room air or aerosol of 18000 mg/m3 RK for 4 hours. Histopathological analysis was performed to evaluate the pulmonary lesions. Oxidative stress was assessed by assay of MDA, SOD, GSH-PX and TAOC. Inflammatory response was estimated by detecting inflammatory cell counts, TNF-α and IL-6 protein levels in serum. The results showed that after 2 to 6 hours of RK exposure, pulmonary vascular dilatation, congestion and edematous widening of the alveolar septum were noted. After 12 to 24 hours post-exposure, diffuse hemorrhage in alveolar space were found, along with the progressive pulmonary vascular dilatation and edematous widening of alveolar septum. During 3 to 7 days of RK-exposure, inflammatory cells were scattered in the lung tissue. The pathological alterations of the lung were alleviated after 14 days post-exposure, and showed significant improvement after 21 days post-exposure. After 30 days of RK exposure, the pathological changes in the lung tissue were nearly recovered except the local thickening of the alveolar wall. Compared with NCG, RK inhalation produced a significant increase of MDA levels and a significant decrease of SOD, GSH-Px and TAOC activity in the lung after 2 hours post-exposure (P<0.05). There were significant increases of TNF-α and IL-6 protein levels in serum of mice in RKEG after 2, 6 and 12 hours and 1, 4 and 7 days post-exposure compared with NCG (P<0.05). TNF-α protein levels had a sharp increase after 4 days of exposure. IL-6 protein level was increased at early phase of experiment and then gradually decreased along with the prolonged course of exposure. Considering that the RK-induced lung

  14. Lung injury via oxidative stress in mice induced by inhalation exposure to rocket kerosene

    PubMed Central

    Xu, Bingxin; Li, Chenglin; Wang, Jianying; Wu, Jihua; Si, Shaoyan; Liu, Zhiguo; Li, Jianzhong; Zhang, Jianzhong; Cui, Yan

    2015-01-01

    Rocket kerosene (RK) is a new rocket propellant. Toxicity occurs if a high level of RK is inhaled. To study the toxicity of RK in lung and the mechanisms of RK-induced lung jury, a total of 72 male ICR mice (1.5 months, adult) were randomly assigned to the RK exposure group (RKEG) and normal control group (NCG). Mice were whole-body exposed to room air or aerosol of 18000 mg/m3 RK for 4 hours. Histopathological analysis was performed to evaluate the pulmonary lesions. Oxidative stress was assessed by assay of MDA, SOD, GSH-PX and TAOC. Inflammatory response was estimated by detecting inflammatory cell counts, TNF-α and IL-6 protein levels in serum. The results showed that after 2 to 6 hours of RK exposure, pulmonary vascular dilatation, congestion and edematous widening of the alveolar septum were noted. After 12 to 24 hours post-exposure, diffuse hemorrhage in alveolar space were found, along with the progressive pulmonary vascular dilatation and edematous widening of alveolar septum. During 3 to 7 days of RK-exposure, inflammatory cells were scattered in the lung tissue. The pathological alterations of the lung were alleviated after 14 days post-exposure, and showed significant improvement after 21 days post-exposure. After 30 days of RK exposure, the pathological changes in the lung tissue were nearly recovered except the local thickening of the alveolar wall. Compared with NCG, RK inhalation produced a significant increase of MDA levels and a significant decrease of SOD, GSH-Px and TAOC activity in the lung after 2 hours post-exposure (P < 0.05). There were significant increases of TNF-α and IL-6 protein levels in serum of mice in RKEG after 2, 6 and 12 hours and 1, 4 and 7 days post-exposure compared with NCG (P < 0.05). TNF-α protein levels had a sharp increase after 4 days of exposure. IL-6 protein level was increased at early phase of experiment and then gradually decreased along with the prolonged course of exposure. Considering that the RK-induced lung

  15. The Shift of ERG B-Wave Induced by Hours' Dark Exposure in Rodents.

    PubMed

    Li, Dake; Fang, Qi; Yu, Hongbo

    2016-01-01

    Dark adaptation can induce a rapid functional shift in the retina, and after that, the retinal function is believed to remain stable during the continuous dark exposure. However, we found that electroretinograms (ERG) b-waves gradually shifted during 24 hours' dark exposure in rodents. Detailed experiments were designed to explore this non-classical dark adaptation. In vivo ERG recording in adult and developing rodents after light manipulations. We revealed a five-fold decrease in ERG b-waves in adult rats that were dark exposed for 24 hours. The ERG b-waves significantly increased within the first hour's dark exposure, but after that decreased continuously and finally attained steady state after 1 day's dark exposure. After 3 repetitive, 10 minutes' light exposure, the dark exposed rats fully recovered. This recovery effect was eye-specific, and light exposure to one eye could not restore the ERGs in the non-exposed eye. The prolonged dark exposure-induced functional shift was also reflected in the down-regulation on the amplitude of intensity-ERG response curve, but the dynamic range of the responsive light intensity remained largely stable. Furthermore, the ERG b-wave shifts occurred in and beyond classical critical period, and in both rats and mice. Importantly, when ERG b-wave greatly shifted, the amplitude of ERG a-wave did not change significantly after the prolonged dark exposure. This rapid age-independent ERG change demonstrates a generally existing functional shift in the retina, which is at the entry level of visual system.

  16. The Shift of ERG B-Wave Induced by Hours' Dark Exposure in Rodents

    PubMed Central

    Li, Dake; Fang, Qi; Yu, Hongbo

    2016-01-01

    Purpose Dark adaptation can induce a rapid functional shift in the retina, and after that, the retinal function is believed to remain stable during the continuous dark exposure. However, we found that electroretinograms (ERG) b-waves gradually shifted during 24 hours’ dark exposure in rodents. Detailed experiments were designed to explore this non-classical dark adaptation. Methods In vivo ERG recording in adult and developing rodents after light manipulations. Results We revealed a five-fold decrease in ERG b-waves in adult rats that were dark exposed for 24 hours. The ERG b-waves significantly increased within the first hour’s dark exposure, but after that decreased continuously and finally attained steady state after 1 day’s dark exposure. After 3 repetitive, 10 minutes’ light exposure, the dark exposed rats fully recovered. This recovery effect was eye-specific, and light exposure to one eye could not restore the ERGs in the non-exposed eye. The prolonged dark exposure-induced functional shift was also reflected in the down-regulation on the amplitude of intensity-ERG response curve, but the dynamic range of the responsive light intensity remained largely stable. Furthermore, the ERG b-wave shifts occurred in and beyond classical critical period, and in both rats and mice. Importantly, when ERG b-wave greatly shifted, the amplitude of ERG a-wave did not change significantly after the prolonged dark exposure. Conclusions This rapid age-independent ERG change demonstrates a generally existing functional shift in the retina, which is at the entry level of visual system. PMID:27517462

  17. Resistin deficiency in mice has no effect on pulmonary responses induced by acute ozone exposure

    PubMed Central

    Razvi, Shehla S.; Richards, Jeremy B.; Malik, Farhan; Cromar, Kevin R.; Price, Roger E.; Bell, Cynthia S.; Weng, Tingting; Atkins, Constance L.; Spencer, Chantal Y.; Cockerill, Katherine J.; Alexander, Amy L.; Blackburn, Michael R.; Alcorn, Joseph L.; Haque, Ikram U.

    2015-01-01

    Acute exposure to ozone (O3), an air pollutant, causes pulmonary inflammation, airway epithelial desquamation, and airway hyperresponsiveness (AHR). Pro-inflammatory cytokines—including IL-6 and ligands of chemokine (C-X-C motif) receptor 2 [keratinocyte chemoattractant (KC) and macrophage inflammatory protein (MIP)-2], TNF receptor 1 and 2 (TNF), and type I IL-1 receptor (IL-1α and IL-1β)—promote these sequelae. Human resistin, a pleiotropic hormone and cytokine, induces expression of IL-1α, IL-1β, IL-6, IL-8 (the human ortholog of murine KC and MIP-2), and TNF. Functional differences exist between human and murine resistin; yet given the aforementioned observations, we hypothesized that murine resistin promotes O3-induced lung pathology by inducing expression of the same inflammatory cytokines as human resistin. Consequently, we examined indexes of O3-induced lung pathology in wild-type and resistin-deficient mice following acute exposure to either filtered room air or O3. In wild-type mice, O3 increased bronchoalveolar lavage fluid (BALF) resistin. Furthermore, O3 increased lung tissue or BALF IL-1α, IL-6, KC, TNF, macrophages, neutrophils, and epithelial cells in wild-type and resistin-deficient mice. With the exception of KC, which was significantly greater in resistin-deficient compared with wild-type mice, no genotype-related differences in the other indexes existed following O3 exposure. O3 caused AHR to acetyl-β-methylcholine chloride (methacholine) in wild-type and resistin-deficient mice. However, genotype-related differences in airway responsiveness to methacholine were nonexistent subsequent to O3 exposure. Taken together, these data demonstrate that murine resistin is increased in the lungs of wild-type mice following acute O3 exposure but does not promote O3-induced lung pathology. PMID:26386120

  18. Resistin deficiency in mice has no effect on pulmonary responses induced by acute ozone exposure.

    PubMed

    Razvi, Shehla S; Richards, Jeremy B; Malik, Farhan; Cromar, Kevin R; Price, Roger E; Bell, Cynthia S; Weng, Tingting; Atkins, Constance L; Spencer, Chantal Y; Cockerill, Katherine J; Alexander, Amy L; Blackburn, Michael R; Alcorn, Joseph L; Haque, Ikram U; Johnston, Richard A

    2015-11-15

    Acute exposure to ozone (O3), an air pollutant, causes pulmonary inflammation, airway epithelial desquamation, and airway hyperresponsiveness (AHR). Pro-inflammatory cytokines-including IL-6 and ligands of chemokine (C-X-C motif) receptor 2 [keratinocyte chemoattractant (KC) and macrophage inflammatory protein (MIP)-2], TNF receptor 1 and 2 (TNF), and type I IL-1 receptor (IL-1α and IL-1β)-promote these sequelae. Human resistin, a pleiotropic hormone and cytokine, induces expression of IL-1α, IL-1β, IL-6, IL-8 (the human ortholog of murine KC and MIP-2), and TNF. Functional differences exist between human and murine resistin; yet given the aforementioned observations, we hypothesized that murine resistin promotes O3-induced lung pathology by inducing expression of the same inflammatory cytokines as human resistin. Consequently, we examined indexes of O3-induced lung pathology in wild-type and resistin-deficient mice following acute exposure to either filtered room air or O3. In wild-type mice, O3 increased bronchoalveolar lavage fluid (BALF) resistin. Furthermore, O3 increased lung tissue or BALF IL-1α, IL-6, KC, TNF, macrophages, neutrophils, and epithelial cells in wild-type and resistin-deficient mice. With the exception of KC, which was significantly greater in resistin-deficient compared with wild-type mice, no genotype-related differences in the other indexes existed following O3 exposure. O3 caused AHR to acetyl-β-methylcholine chloride (methacholine) in wild-type and resistin-deficient mice. However, genotype-related differences in airway responsiveness to methacholine were nonexistent subsequent to O3 exposure. Taken together, these data demonstrate that murine resistin is increased in the lungs of wild-type mice following acute O3 exposure but does not promote O3-induced lung pathology. Copyright © 2015 the American Physiological Society.

  19. Airway Exposure to E-Cigarette Vapors Impairs Autophagy and Induces Aggresome Formation.

    PubMed

    Shivalingappa, Prashanth Chandramani; Hole, Rachel; Westphal, Colin Van; Vij, Neeraj

    2015-10-27

    Electronic cigarettes (e-cigarettes) are proposed to be a safer alternative to tobacco cigarettes. Hence, we evaluated if e-cigarette vapors (eCV) impair cellular proteostasis similar to cigarette smoke exposure. First, we evaluated the impact of eCV exposure (2.5 or 7.5 mg) on Beas2b cells that showed significant increase in accumulation of total polyubiquitinated proteins (Ub, insoluble fractions) with time-dependent decrease in proteasomal activities from 1 h (p < 0.05), 3 h (p < 0.001) to 6 h (p < 0.001) of eCV exposure compared to room air control. We verified that even minimal eCV exposure (1 h) induces valosin-containing protein (VCP; p < 0.001), sequestosome-1/p62 (aberrant autophagy marker; p < 0.05), and aggresome formation (total poly-Ub-accumulation; p < 0.001) using immunoblotting (IB), fluorescence microscopy, and immunoprecipitation (IP). The inhibition of protein synthesis by 6 h of cycloheximide (50 μg/ml) treatment significantly (p < 0.01) alleviates eCV-induced (1 h) aggresome bodies. We also observed that eCV (1 h)-induced protein aggregation can activate oxidative stress, apoptosis (caspase-3/7), and senescence (p < 0.01) compared to room air controls. We verified using an autophagy inducer carbamazepine (20 μM, 6 h) or cysteamine (250 μM; 6 h, antioxidant) that eCV-induced changes in oxidative stress, poly-ub-accumulation, proteasomal activity, autophagy, apoptosis, and/or senescence could be controlled by autophagy induction. We further confirmed the role of acute eCV exposure on autophagy impairment in murine lungs (C57BL/6 and CD1) by IB (Ub, p62, VCP) and IP (VCP, p62), similar to in-vitro experiments. In this study, we report for the first time that eCV exposure induces proteostasis/autophagy impairment leading to oxidative stress, apoptosis, and senescence that can be ameliorated by an autophagy inducer. eCV-induced autophagy impairment and aggresome formation suggest their

  20. Airway Exposure to E-Cigarette Vapors Impairs Autophagy and Induces Aggresome Formation

    PubMed Central

    Shivalingappa, Prashanth Chandramani; Hole, Rachel; Van Westphal, Colin

    2016-01-01

    Abstract Aims: Electronic cigarettes (e-cigarettes) are proposed to be a safer alternative to tobacco cigarettes. Hence, we evaluated if e-cigarette vapors (eCV) impair cellular proteostasis similar to cigarette smoke exposure. Results: First, we evaluated the impact of eCV exposure (2.5 or 7.5 mg) on Beas2b cells that showed significant increase in accumulation of total polyubiquitinated proteins (Ub, insoluble fractions) with time-dependent decrease in proteasomal activities from 1 h (p < 0.05), 3 h (p < 0.001) to 6 h (p < 0.001) of eCV exposure compared to room air control. We verified that even minimal eCV exposure (1 h) induces valosin-containing protein (VCP; p < 0.001), sequestosome-1/p62 (aberrant autophagy marker; p < 0.05), and aggresome formation (total poly-Ub-accumulation; p < 0.001) using immunoblotting (IB), fluorescence microscopy, and immunoprecipitation (IP). The inhibition of protein synthesis by 6 h of cycloheximide (50 μg/ml) treatment significantly (p < 0.01) alleviates eCV-induced (1 h) aggresome bodies. We also observed that eCV (1 h)-induced protein aggregation can activate oxidative stress, apoptosis (caspase-3/7), and senescence (p < 0.01) compared to room air controls. We verified using an autophagy inducer carbamazepine (20 μM, 6 h) or cysteamine (250 μM; 6 h, antioxidant) that eCV-induced changes in oxidative stress, poly-ub-accumulation, proteasomal activity, autophagy, apoptosis, and/or senescence could be controlled by autophagy induction. We further confirmed the role of acute eCV exposure on autophagy impairment in murine lungs (C57BL/6 and CD1) by IB (Ub, p62, VCP) and IP (VCP, p62), similar to in-vitro experiments. Innovation: In this study, we report for the first time that eCV exposure induces proteostasis/autophagy impairment leading to oxidative stress, apoptosis, and senescence that can be ameliorated by an autophagy inducer. Conclusion: eCV-induced autophagy

  1. Inhalation exposure to ethylene induces eosinophilic rhinitis and nasal epithelial remodeling in Fischer 344 rats.

    PubMed

    Brandenberger, Christina; Hotchkiss, Jon A; Krieger, Shannon M; Pottenger, Lynn H; Harkema, Jack R

    2015-11-05

    This study investigated the time- and concentration-dependent effects of inhaled ethylene on eosinophilic rhinitis and nasal epithelial remodeling in Fisher 344 rats exposed to 0, 10, 50, 300, or 10,000 ppm ethylene, 6 h/day, 5 days/week for up to 4 weeks. Morphometric quantitation of eosinophilic inflammation and mucous cell metaplasia/hyperplasia (MCM) and nasal mucosal gene expression were evaluated at anatomic sites previously shown to undergo ethylene-induced epithelial remodeling. Serum levels of total IgE, IgG1 and IgG2a were measured to determine if ethylene exposure increased the expression of Th2-associated (IgE and IgG1) relative to Th1-associated (IgG2a) antibody isotypes. Rats exposed to 0 or 10,000 ppm for 1, 3, 5, 10, or 20 days were analyzed to assess the temporal pattern of ethylene-induced alterations in nasal epithelial cell proliferation, morphology and gene expression. Rats exposed to 0, 10, 50, 300, and 10,000 ppm ethylene for 20 days were analyzed to assess concentration-dependent effects on lesion development. Additional rats exposed 4 weeks to 0, 300, or 10,000 ppm ethylene were held for 13 weeks post-exposure to examine the persistence of ethylene-induced mucosal alterations. The data indicate that cell death and reparative cell proliferation were not a part of the pathogenesis of ethylene-induced nasal lesions. Enhanced gene expression of Th2 cytokines (e.g., IL-5, IL-13) and chitinase (YM1/2) in the nasal mucosa was much greater than that of Th1 cytokines (e.g., IFNγ) after ethylene exposure. A significant increase in MCM was measured after 5 days of exposure to 10,000 ppm ethylene and after 20 days of exposure 10 ppm ethylene. Ethylene-induced MCM was reversible after cessation of exposure. No increase in total serum IgE, IgG1 or IgG2a was measured in any ethylene-exposed group. These data do not support involvement of an immune-mediated allergic mechanism in the pathogenesis of ethylene-induced nasal lesions in rats. Repeated

  2. The temporary threshold shift of vibratory sensation induced by composite-band vibration exposure.

    PubMed

    Nishiyama, K; Taoda, K; Yamashita, H; Watanabe, S

    1996-01-01

    Eight healthy subjects were exposed to three 1/3 octave-band vibrations (63, 200, and 500 Hz) by hand clasping a vibrated handle in a soundproof and thermoregulated room. The vibratory sensation threshold at 125 Hz was measured before and after the vibration exposure at an exposed fingertip. According to a preceding study, we first determined the relationship between the acceleration of the vibration and the temporary threshold shift of vibratory sensation immediately after the vibratory exposure (TTSv,0) induced by 1/3 octave-band vibration. We then measured TTSv after the exposure to a composite vibration composed of two 1/3 octave-band vibrations that might induce an equal magnitude of TTSv,0 on the basis of the above relationship. The TTSv,0 induced by the composite vibration was not larger than the TTSv,0 induced by the component vibrations. This result suggests that the component of the vibration inducing the largest TTSv,0 determines the TTSv,0 by broad-band random vibration.

  3. Perfluorooctanoic acid exposure for 28 days affects glucose homeostasis and induces insulin hypersensitivity in mice.

    PubMed

    Yan, Shengmin; Zhang, Hongxia; Zheng, Fei; Sheng, Nan; Guo, Xuejiang; Dai, Jiayin

    2015-06-12

    Perfluoroalkyl acids (PFAAs) are widely used in many applications due to their unique physical and chemical characteristics. Because of the increasing prevalence of metabolic syndromes, including obesity, dyslipidemia and insulin resistance, concern has arisen about the roles of environmental pollutants in such diseases. Earlier epidemiologic studies showed a potential association between perfluorooctanoic acid (PFOA) and glucose metabolism, but how PFOA influences glucose homeostasis is still unknown. Here, we report on the modulation of the phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K-AKT) signaling pathway in the livers of mice after 28 d of exposure to PFOA. Compared with normal mice, PFOA exposure significantly decreased the expression of the phosphatase and tensin homologue (PTEN) protein and affected the PI3K-AKT signaling pathway in the liver. Tolerance tests further indicated that PFOA exposure induced higher insulin sensitivity and glucose tolerance in mice. Biochemical analysis revealed that PFOA exposure reduced hepatic glycogen synthesis, which might be attributed to gluconeogenesis inhibition. The levels of several circulating proteins were altered after PFOA exposure, including proteins potentially related to diabetes and liver disease. Our results suggest that PFOA affected glucose metabolism and induced insulin hypersensitivity in mice.

  4. Perfluorooctanoic acid exposure for 28 days affects glucose homeostasis and induces insulin hypersensitivity in mice

    PubMed Central

    Yan, Shengmin; Zhang, Hongxia; Zheng, Fei; Sheng, Nan; Guo, Xuejiang; Dai, Jiayin

    2015-01-01

    Perfluoroalkyl acids (PFAAs) are widely used in many applications due to their unique physical and chemical characteristics. Because of the increasing prevalence of metabolic syndromes, including obesity, dyslipidemia and insulin resistance, concern has arisen about the roles of environmental pollutants in such diseases. Earlier epidemiologic studies showed a potential association between perfluorooctanoic acid (PFOA) and glucose metabolism, but how PFOA influences glucose homeostasis is still unknown. Here, we report on the modulation of the phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K-AKT) signaling pathway in the livers of mice after 28 d of exposure to PFOA. Compared with normal mice, PFOA exposure significantly decreased the expression of the phosphatase and tensin homologue (PTEN) protein and affected the PI3K-AKT signaling pathway in the liver. Tolerance tests further indicated that PFOA exposure induced higher insulin sensitivity and glucose tolerance in mice. Biochemical analysis revealed that PFOA exposure reduced hepatic glycogen synthesis, which might be attributed to gluconeogenesis inhibition. The levels of several circulating proteins were altered after PFOA exposure, including proteins potentially related to diabetes and liver disease. Our results suggest that PFOA affected glucose metabolism and induced insulin hypersensitivity in mice. PMID:26066376

  5. Perfluorooctanoic acid exposure for 28 days affects glucose homeostasis and induces insulin hypersensitivity in mice

    NASA Astrophysics Data System (ADS)

    Yan, Shengmin; Zhang, Hongxia; Zheng, Fei; Sheng, Nan; Guo, Xuejiang; Dai, Jiayin

    2015-06-01

    Perfluoroalkyl acids (PFAAs) are widely used in many applications due to their unique physical and chemical characteristics. Because of the increasing prevalence of metabolic syndromes, including obesity, dyslipidemia and insulin resistance, concern has arisen about the roles of environmental pollutants in such diseases. Earlier epidemiologic studies showed a potential association between perfluorooctanoic acid (PFOA) and glucose metabolism, but how PFOA influences glucose homeostasis is still unknown. Here, we report on the modulation of the phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K-AKT) signaling pathway in the livers of mice after 28 d of exposure to PFOA. Compared with normal mice, PFOA exposure significantly decreased the expression of the phosphatase and tensin homologue (PTEN) protein and affected the PI3K-AKT signaling pathway in the liver. Tolerance tests further indicated that PFOA exposure induced higher insulin sensitivity and glucose tolerance in mice. Biochemical analysis revealed that PFOA exposure reduced hepatic glycogen synthesis, which might be attributed to gluconeogenesis inhibition. The levels of several circulating proteins were altered after PFOA exposure, including proteins potentially related to diabetes and liver disease. Our results suggest that PFOA affected glucose metabolism and induced insulin hypersensitivity in mice.

  6. Transmitted mutational events induced in mouse germ cells following acrylamide or glycidamide exposure.

    PubMed

    Favor, Jack; Shelby, Michael D

    2005-02-07

    An increase in the germ line mutation rate in humans will result in an increase in the incidence of genetically determined diseases in subsequent generations. Thus, it is important to identify those agents that are mutagenic in mammalian germ cells. Acrylamide is water soluble, absorbed and distributed in the body, chemically reactive with nucleophilic sites, and there are known sources of human exposure. Here we review all seven published studies that assessed the effectiveness of acrylamide or its active metabolite, glycidamide, in inducing transmitted reciprocal translocations or gene mutations in the mouse. Major conclusions were (a) acrylamide is mutagenic in spermatozoa and spermatid stages of the male germ line; (b) in these spermatogenic stages acrylamide is mainly or exclusively a clastogen; (c) per unit dose, i.p. exposure is more effective than dermal exposure; and (d) per unit dose, glycidamide is more effective than acrylamide. Since stem cell spermatogonia persist and may accumulate mutations throughout the reproductive life of males, assessment of induced mutations in this germ cell stage is critical for the assessment of genetic risk associated with exposure to a mutagen. The two specific-locus mutation experiments which studied the stem cell spermatogonial stage yielded conflicting results. This discrepancy should be resolved. Finally, it is noted that no experiments have studied the mutagenic potential of acrylamide to increase the frequency of transmitted mutational events following exposure in the female germ line.

  7. Effects of acute low-level microwaves on pentobarbital-induced hypothermia depend on exposure orientation

    SciTech Connect

    Lai, H.; Horita, A.; Chou, C.K.; Guy, A.W.

    1984-01-01

    Two series of experiments were performed to study the effects of acute exposure (45 min) to 2,450-MHz circularly polarized, pulsed microwaves (1 mW/cm2, 2-mus pulses, 500 pps, specific absorption rate (SAR) 0.6 W/kg) on the actions of pentobarbital in the rat. In the first experiment, rats were irradiated with microwaves and then immediately injected with pentobarbital. Microwave exposure did not significantly affect the extent of the pentobarbital-induced fall in colonic temperature. However, the rate of recovery from the hypothermia was significantly slower in the microwave-irradiated rats and they also took a significantly longer time to regain their righting reflex. In a second experiment, rats were first anesthetized with pentobarbital and then exposed to microwaves with their heads either pointing toward the source of microwaves (anterior exposure) or pointing away (posterior exposure). Microwave radiation significantly retarded the pentobarbital-induced fall in colonic temperature regardless of the orientation of exposure. However, the recovery from hypothermia was significantly faster in posterior-exposed animals compared to those of the anterior-exposed and sham-irradiated animals. Furthermore, the posterior-exposed rats took a significantly shorter time to regain their righting reflex than both the anterior-exposed and sham-irradiated animals.

  8. Chronic cocaine exposure induces putamen glutamate and glutamine metabolite abnormalities in squirrel monkeys

    PubMed Central

    Liu, Xiaoxu; Jensen, J. Eric; Gillis, Timothy E.; Zuo, Chun S.; Prescot, Andrew P.; Brimson, Melanie; Cayetano, Kenroy; Renshaw, Perry F.

    2011-01-01

    Rationale Chronic cocaine exposure has been associated with progressive brain structural and functional changes. Clarifying mechanisms underlying cocaine’s progressive brain effects may help in the development of effective cocaine abuse treatments. Objectives We used a controlled squirrel monkey model of chronic cocaine exposure (45 mg/kg/week for 9 months) combined with ultra-high magnetic field (9.4 T) proton magnetic resonance spectroscopy to prospectively measure putamen metabolite changes. Methods Proton metabolites were measured with a STEAM sequence, quantified with LCModel using a simulated basis set, and expressed as metabolite/total creatine (tCr) ratios. Results We found cocaine-induced time-dependent changes in putamen glutamate/tCr and glutamine/tCr metabolite ratios suggestive of altered glutamate compartmentalization, neurotransmission, and metabolism. By contrast, saline-treated monkeys exhibited no metabolite changes over time. The time course of cocaine-induced metabolite abnormalities we detected is consistent with the apparent time course of glutamate abnormalities identified in a cross-sectional study in human cocaine users, as well as with microdialysis findings in rodent models of repeated cocaine exposure. Conclusions Together, these findings suggests that this squirrel monkey model may be useful for characterizing glutamatergic changes associated with cocaine exposure and for determining efficacies of treatments designed to mitigate cocaine-induced glutamatergic system dysfunction. PMID:21494788

  9. Neonatal exposure to monosodium glutamate induces morphological alterations in suprachiasmatic nucleus of adult rat.

    PubMed

    Rojas-Castañeda, Julio César; Vigueras-Villaseñor, Rosa María; Chávez-Saldaña, Margarita; Rojas, Patricia; Gutiérrez-Pérez, Oscar; Rojas, Carolina; Arteaga-Silva, Marcela

    2016-02-01

    Neonatal exposure to monosodium glutamate (MSG) induces circadian disorders in several physiological and behavioural processes regulated by the suprachiasmatic nucleus (SCN). The objective of this study was to evaluate the effects of neonatal exposure to MSG on locomotor activity, and on morphology, cellular density and expression of proteins, as evaluated by optical density (OD), of vasopressin (VP)-, vasoactive intestinal polypeptide (VIP)- and glial fibrillary acidic protein (GFAP)-immunoreactive cells in the SCN. Male Wistar rats were used: the MSG group was subcutaneously treated from 3 to 10 days of age with 3.5 mg/g/day. Locomotor activity was evaluated at 90 days of age using 'open-field' test, and the brains were processed for immunohistochemical studies. MSG exposure induced a significant decrease in locomotor activity. VP- and VIP-immunoreactive neuronal densities showed a significant decrease, while the somatic OD showed an increase. Major axes and somatic area were significantly increased in VIP neurons. The cellular and optical densities of GFAP-immunoreactive sections of SCN were significantly increased. These results demonstrated that newborn exposure to MSG induced morphological alterations in SCN cells, an alteration that could be the basis for behavioural disorders observed in the animals.

  10. Exposure to endocrine disruptor induces transgenerational epigenetic deregulation of microRNAs in primordial germ cells.

    PubMed

    Brieño-Enríquez, Miguel A; García-López, Jesús; Cárdenas, David B; Guibert, Sylvain; Cleroux, Elouan; Děd, Lukas; Hourcade, Juan de Dios; Pěknicová, Jana; Weber, Michael; Del Mazo, Jesús

    2015-01-01

    In mammals, germ cell differentiation is initiated in the Primordial Germ Cells (PGCs) during fetal development. Prenatal exposure to environmental toxicants such as endocrine disruptors may alter PGC differentiation, development of the male germline and induce transgenerational epigenetic disorders. The anti-androgenic compound vinclozolin represents a paradigmatic example of molecule causing transgenerational effects on germ cells. We performed prenatal exposure to vinclozolin in mice and analyzed the phenotypic and molecular changes in three successive generations. A reduction in the number of embryonic PGCs and increased rate of apoptotic cells along with decrease of fertility rate in adult males were observed in F1 to F3 generations. Blimp1 is a crucial regulator of PGC differentiation. We show that prenatal exposure to vinclozolin deregulates specific microRNAs in PGCs, such as miR-23b and miR-21, inducing disequilibrium in the Lin28/let-7/Blimp1 pathway in three successive generations of males. As determined by global maps of cytosine methylation, we found no evidence for prominent changes in DNA methylation in PGCs or mature sperm. Our data suggest that embryonic exposure to environmental endocrine disruptors induces transgenerational epigenetic deregulation of expression of microRNAs affecting key regulatory pathways of germ cells differentiation.

  11. Bisphenol A exposure at an environmentally relevant dose induces meiotic abnormalities in adult male rats.

    PubMed

    Liu, Chuan; Duan, Weixia; Zhang, Lei; Xu, Shangcheng; Li, Renyan; Chen, Chunhai; He, Mindi; Lu, Yonghui; Wu, Hongjuan; Yu, Zhengping; Zhou, Zhou

    2014-01-01

    Whether environmental exposure to bisphenol A (BPA) may induce reproductive disorders is still controversial but certain studies have reported that BPA may cause meiotic abnormalities in C. elegans and female mice. However, little is known about the effect of BPA on meiosis in adult males. To determine whether BPA exposure at an environmentally relevant dose could induce meiotic abnormalities in adult male rats, we exposed 9-week-old male Wistar rats to BPA by gavage at 20 μg/kg body weight (bw)/day for 60 consecutive days. We found that BPA significantly increased the proportion of stage VII seminiferous epithelium and decreased the proportion of stage VIII. Consequently, spermiation was inhibited and spermatogenesis was disrupted. Further investigation revealed that BPA exposure delayed meiosis initiation in the early meiotic stage and induced the accumulation of chromosomal abnormalities and meiotic DNA double-strand breaks (DSBs) in the late meiotic stage. The latter event subsequently activated the phosphatidylinositol 3-kinase-related protein kinase (ATM). Our results suggest that long-term exposure to BPA may lead to continuous meiotic abnormalities and ultimately put mammalian reproductive health at risk.

  12. Nicotine ameliorates schizophrenia-like cognitive deficits induced by maternal LPS exposure: a study in rats

    PubMed Central

    Waterhouse, Uta; Roper, Vic E.; Brennan, Katharine A.

    2016-01-01

    ABSTRACT Maternal exposure to infectious agents is a predisposing factor for schizophrenia with associated cognitive deficits in offspring. A high incidence of smoking in these individuals in adulthood might be, at least in part, due to the cognitive-enhancing effects of nicotine. Here, we have used prenatal exposure to maternal lipopolysaccharide (LPS, bacterial endotoxin) at different time points as a model for cognitive deficits in schizophrenia to determine whether nicotine reverses any associated impairments. Pregnant rats were treated subcutaneously with LPS (0.5 mg/kg) at one of three neurodevelopmental time periods [gestation days (GD) 10-11, 15-16, 18-19]. Cognitive assessment in male offspring commenced in early adulthood [postnatal day (PND) 60] and included: prepulse inhibition (PPI), latent inhibition (LI) and delayed non-matching to sample (DNMTS). Following PND 100, daily nicotine injections (0.6 mg/kg, subcutaneously) were administered, and animals were re-tested in the same tasks (PND 110). Only maternal LPS exposure early during fetal neurodevelopment (GD 10-11) resulted in deficits in all tests compared to animals that had been prenatally exposed to saline at the same gestational time point. Repeated nicotine treatment led to global (PPI) and selective (LI) improvements in performance. Early but not later prenatal LPS exposure induced consistent deficits in cognitive tests with relevance for schizophrenia. Nicotine reversed the LPS-induced deficits in selective attention (LI) and induced a global enhancement of sensorimotor gating (PPI). PMID:27483346

  13. Zebrafish retinal defects induced by ethanol exposure are rescued by retinoic acid and folic acid supplement

    PubMed Central

    Muralidharan, Pooja; Sarmah, Swapnalee; Marrs, James A.

    2014-01-01

    Fetal Alcohol Spectrum Disorder (FASD) is caused by prenatal alcohol exposure, producing craniofacial, sensory, motor, and cognitive defects. FASD is highly prevalent in low socioeconomic populations, which are frequently accompanied by malnutrition. FASD-associated ocular pathologies include microphthalmia, optic nerve hypoplasia, and cataracts. The present study characterizes specific retinal tissue defects, identifies ethanol-sensitive stages during retinal development, and dissects the effect of nutrient supplements, such as retinoic acid (RA) and folic acid (FA) on ethanol-induced retinal defects. Exposure to pathophysiological concentrations of ethanol (during midblastula transition through somitogenesis; 2–24 hours post fertilization [hpf]) altered critical transcription factor expression involved in retinal cell differentiation, and produced severe retinal ganglion cell, photoreceptor, and Müller glial differentiation defects. Ethanol exposure did not alter retinal cell differentiation induction, but increased retinal cell death and proliferation. RA and FA nutrient co-supplementation rescued retinal photoreceptor and ganglion cell differentiation defects. Ethanol exposure during retinal morphogenesis stages (16–24 hpf) produced retinal defects like those seen with ethanol exposure between 2–24 hpf. Significantly, during an ethanol-sensitive time window (16–24 hpf), RA co-supplementation moderately rescued these defects, whereas FA co-supplementation showed significant rescue of optic nerve and photoreceptor differentiation defects. Interestingly, RA, but not FA, supplementation after ethanol exposure could reverse ethanol-induced optic nerve and photoreceptor differentiation defects. Our results indicate that various ethanol-sensitive events underlie FASD-associated retinal defects. Nutrient supplements like retinoids and folate were effective in alleviating ethanol-induced retinal defects. PMID:25541501

  14. Zebrafish retinal defects induced by ethanol exposure are rescued by retinoic acid and folic acid supplement.

    PubMed

    Muralidharan, Pooja; Sarmah, Swapnalee; Marrs, James A

    2015-03-01

    Fetal Alcohol Spectrum Disorder (FASD) is caused by prenatal alcohol exposure, producing craniofacial, sensory, motor, and cognitive defects. FASD is highly prevalent in low socioeconomic populations, which are frequently accompanied by malnutrition. FASD-associated ocular pathologies include microphthalmia, optic nerve hypoplasia, and cataracts. The present study characterizes specific retinal tissue defects, identifies ethanol-sensitive stages during retinal development, and dissects the effect of nutrient supplements, such as retinoic acid (RA) and folic acid (FA) on ethanol-induced retinal defects. Exposure to pathophysiological concentrations of ethanol (during midblastula transition through somitogenesis; 2-24 h post fertilization [hpf]) altered critical transcription factor expression involved in retinal cell differentiation, and produced severe retinal ganglion cell, photoreceptor, and Müller glial differentiation defects. Ethanol exposure did not alter retinal cell differentiation induction, but increased retinal cell death and proliferation. RA and FA nutrient co-supplementation rescued retinal photoreceptor and ganglion cell differentiation defects. Ethanol exposure during retinal morphogenesis stages (16-24 hpf) produced retinal defects like those seen with ethanol exposure between 2 and 24 hpf. Significantly, during an ethanol-sensitive time window (16-24 hpf), RA co-supplementation moderately rescued these defects, whereas FA co-supplementation showed significant rescue of optic nerve and photoreceptor differentiation defects. Interestingly, RA, but not FA, supplementation after ethanol exposure could reverse ethanol-induced optic nerve and photoreceptor differentiation defects. Our results indicate that various ethanol-sensitive events underlie FASD-associated retinal defects. Nutrient supplements like retinoids and folate were effective in alleviating ethanol-induced retinal defects.

  15. Perinatal alcohol exposure in rat induces long-term depression of respiration after episodic hypoxia.

    PubMed

    Kervern, Myriam; Dubois, Christophe; Naassila, Mickael; Daoust, Martine; Pierrefiche, Olivier

    2009-04-01

    Little is known about the effects of alcohol exposure during pregnancy, which is responsible for fetal alcohol syndrome and the respiratory network functions, especially respiratory network plasticity (e.g., long-term facilitation) elicited after repeated short-lasting hypoxic episodes. The mechanism of induction of respiratory long-term facilitation involves 5-HT(2A/2C) receptors, which also participate in the response to hypoxia. Because fetal alcohol exposure is known to reduce serotonin centrally, and synaptic plasticity in the hippocampus, we hypothesized that alcohol exposure during gestation might impair respiratory long-term facilitation after hypoxic episodes. To analyze the effects of prenatal and postnatal alcohol exposure on respiratory long-term facilitation in 5- to 7-day-old rats. Respiratory frequency and amplitude were measured in vivo and in an in vitro rhythmic medullary slice before and after three hypoxia episodes or three applications of a 5-HT(2A/2C) receptor agonist in vitro. 5-HT(2A/2C) receptor mRNA was measured from the slice. Alcohol exposure impaired respiratory long-term facilitation and induced long-term depression of respiration in both in vivo and in vitro models. Alcohol altered 5-HT(2A/2C) mRNA expression, although 5-HT(2A/2C) agonist efficacy was not altered in increasing rhythmic activity in slices. However, a higher concentration of 5-HT(2A/2C) agonist was necessary to induce transient facilitation in slices from ethanol-exposed animals, suggesting disturbances in induction and maintenance mechanisms of respiratory long-term facilitation. Respiratory facilitation after repeated hypoxia was converted to long-term depression in rats treated with alcohol in utero. Alcohol exposure during pregnancy may therefore induce long-term maladaptive behavior of the respiratory system in neonates.

  16. Repeated exposure of human fibroblasts to UVR induces secretion of stem cell factor and senescence.

    PubMed

    Shin, J; Kim, J-H; Kim, E K

    2012-12-01

    Some of chronic hyperpigmentary diseases, such as melasma, induced by multiple factors including chronic sunlight exposure, can recur even after chemical epidermal removal. Dermal factors may be involved in the pathogenesis of melasma. Changes in dermal fibroblasts resulting from chronic sun exposure might cause melanocytes to synthesize melanin in the epidermis. This study aimed at determining the effects of repetitive ultraviolet (UV) radiation on cultured fibroblasts and the secretion of melanogenic factors. Cultured human fibroblasts were exposed to ultraviolet A (UVA) or ultraviolet B (UVB) for five consecutive days. After each irradiation, the supernatant medium was isolated from each dish and measured for levels of stem cell factor (SCF) and hepatocyte growth factor using an ELISA kit assay. To assess the effect of the keratinocyte-derived factors on fibroblast-secretion of SCF and hepatocyte growth factor, we added supernatants of the UV-irradiated keratinocytes to the non-irradiated fibroblasts. Finally, the irradiated fibroblasts were stained with senescence associated-β-galactosidase to assess their senescent change. Fibroblasts irradiated with UVA or UVB for five consecutive days, secreted SCF at levels that increased with repeated UVA or UVB exposure. Conditioned culture medium from UV-irradiated keratinocytes also induced SCF release from fibroblasts, depending on the number of UV exposures. UVA- or UVB-irradiated fibroblasts stained positive for senescence associated-β-galactosidase, and the staining intensity increased with repeated exposure. These results suggest that fibroblast senescence and increased SCF secretion after repeated UV irradiation may be related to the pathogenesis of recurring hyperpigmentation disorders induced by chronic sun exposure. © 2011 The Authors. Journal of the European Academy of Dermatology and Venereology © 2011 European Academy of Dermatology and Venereology.

  17. Chronic Water-Pipe Smoke Exposure Induces Injurious Effects to Reproductive System in Male Mice

    PubMed Central

    Ali, Badreldin H.; Al Balushi, Khalid A.; Ashique, Mohammed; Shalaby, Asem; Al Kindi, Mohammed A.; Adham, Sirin A.; Karaca, Turan; Beegam, Sumaya; Yuvaraju, Priya; Nemmar, Abderrahim

    2017-01-01

    There is a global increase in the popularity of water-pipe tobacco smoking including in Europe and North America. Nevertheless, little is known about the male reproductive effects of water-pipe smoke (WPS), especially after long-term exposure. Here, we assessed effects of WPS exposure (30 min/day) in male mice for 6 months. Control mice were exposed to air-only for the same period of time. Twenty-four hours after the last exposure, testicular histopathology, and markers of inflammation and oxidative stress, and the tyrosine–protein kinase vascular endothelial growth factor receptor 1 (VEGFR1) were assessed in testicular homogenates. Moreover, plasma testosterone, estradiol, and luteinizing hormone (LH) concentrations were also measured. Chronic WPS exposure induced a significant decrease of testosterone and estradiol, and a slight but significant increase of LH. Glutathione reductase, catalase, and ascorbic acid were significantly decreased following WPS exposure. Plasma concentration of leptin was significantly decreased by WPS exposure, whereas that of tumor necrosis factor α and interleukin 6 was significantly increased. Histopathological analysis of the testes revealed the presence of a marked reduction in the diameter of the seminiferous tubules with reduced spermatogenesis. Transmission electron microscopy examination showed irregular thickening and wrinkling of the basement membranes with abnormal shapes and structures of the spermatozoa. VEGFR1 was overexpressed in the testis of the mice exposed to WPS and was not detected in the control. The urine concentration of cotinine, the predominant metabolite of nicotine, was significantly increased in the WPS-exposed group compared with the control group. We conclude that chronic exposure to WPS induces damaging effects to the reproductive system in male mice. If this can be confirmed in humans, it would be an additional concern to an already serious public health problem, especially with the increased use of

  18. Chronic Water-Pipe Smoke Exposure Induces Injurious Effects to Reproductive System in Male Mice.

    PubMed

    Ali, Badreldin H; Al Balushi, Khalid A; Ashique, Mohammed; Shalaby, Asem; Al Kindi, Mohammed A; Adham, Sirin A; Karaca, Turan; Beegam, Sumaya; Yuvaraju, Priya; Nemmar, Abderrahim

    2017-01-01

    There is a global increase in the popularity of water-pipe tobacco smoking including in Europe and North America. Nevertheless, little is known about the male reproductive effects of water-pipe smoke (WPS), especially after long-term exposure. Here, we assessed effects of WPS exposure (30 min/day) in male mice for 6 months. Control mice were exposed to air-only for the same period of time. Twenty-four hours after the last exposure, testicular histopathology, and markers of inflammation and oxidative stress, and the tyrosine-protein kinase vascular endothelial growth factor receptor 1 (VEGFR1) were assessed in testicular homogenates. Moreover, plasma testosterone, estradiol, and luteinizing hormone (LH) concentrations were also measured. Chronic WPS exposure induced a significant decrease of testosterone and estradiol, and a slight but significant increase of LH. Glutathione reductase, catalase, and ascorbic acid were significantly decreased following WPS exposure. Plasma concentration of leptin was significantly decreased by WPS exposure, whereas that of tumor necrosis factor α and interleukin 6 was significantly increased. Histopathological analysis of the testes revealed the presence of a marked reduction in the diameter of the seminiferous tubules with reduced spermatogenesis. Transmission electron microscopy examination showed irregular thickening and wrinkling of the basement membranes with abnormal shapes and structures of the spermatozoa. VEGFR1 was overexpressed in the testis of the mice exposed to WPS and was not detected in the control. The urine concentration of cotinine, the predominant metabolite of nicotine, was significantly increased in the WPS-exposed group compared with the control group. We conclude that chronic exposure to WPS induces damaging effects to the reproductive system in male mice. If this can be confirmed in humans, it would be an additional concern to an already serious public health problem, especially with the increased use of WPS

  19. Exposure to mercuric chloride induces developmental damage, oxidative stress and immunotoxicity in zebrafish embryos-larvae.

    PubMed

    Zhang, Qun-Fang; Li, Ying-Wen; Liu, Zhi-Hao; Chen, Qi-Liang

    2016-12-01

    Mercury (Hg) is a widespread environmental pollutant that can produce severe negative effects on fish even at very low concentrations. However, the mechanisms underlying inorganic Hg-induced oxidative stress and immunotoxicity in the early development stage of fish still need to be clarified. In the present study, zebrafish (Danio rerio) embryos were exposed to different concentrations of Hg(2+) (0, 1, 4 and 16μg/L; added as mercuric chloride, HgCl2) from 2h post-fertilization (hpf) to 168hpf. Developmental parameters and total Hg accumulation were monitored during the exposure period, and antioxidant status and the mRNA expression of genes related to the innate immune system were examined at 168hpf. The results showed that increasing Hg(2+) concentration and time significantly increased total Hg accumulation in zebrafish embryos-larvae. Exposure to 16μg/L Hg(2+) caused developmental damage, including increased mortality and malformation, decreased body length, and delayed hatching period. Meanwhile, HgCl2 exposure (especially in the 16μg/L Hg(2+) group) induced oxidative stress affecting antioxidant enzyme (CAT, GST and GPX) activities, endogenous GSH and MDA contents, as well as the mRNA levels of genes (cat1, sod1, gstr, gpx1a, nrf2, keap1, hsp70 and mt) encoding antioxidant proteins. Moreover, the transcription levels of several representative genes (il-1β, il-8, il-10, tnfα2, lyz and c3) involved in innate immunity were up-regulated by HgCl2 exposure, suggesting that inorganic Hg had the potential to induce immunotoxicity. Taken together, the present study provides evidence that waterborne HgCl2 exposure can induce developmental impairment, oxidative stress and immunotoxicity in the early development stage of fish, which brings insights into the toxicity mechanisms of inorganic Hg in fish.

  20. Exposure to Fine Particulate Air Pollution Causes Vascular Insulin Resistance by Inducing Pulmonary Oxidative Stress

    PubMed Central

    Haberzettl, Petra; O’Toole, Timothy E.; Bhatnagar, Aruni; Conklin, Daniel J.

    2016-01-01

    Background: Epidemiological evidence suggests that exposure to ambient air fine particulate matter (PM2.5) increases the risk of developing type 2 diabetes and cardiovascular disease. However, the mechanisms underlying these effects of PM2.5 remain unclear. Objectives: We tested the hypothesis that PM2.5 exposure decreases vascular insulin sensitivity by inducing pulmonary oxidative stress. Methods: Mice fed control (10–13% kcal fat) and high-fat (60% kcal fat, HFD) diets, treated with 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) or mice overexpressing lung-specific extracellular superoxide dismutase (ecSOD) were exposed to HEPA-filtered air or to concentrated PM2.5 (CAP) for 9 or 30 days, and changes in systemic and organ-specific insulin sensitivity and inflammation were measured. Results: In control diet–fed mice, exposure to CAP for 30 days decreased insulin-stimulated Akt phosphorylation in lung, heart, and aorta but not in skeletal muscle, adipose tissue, and liver and did not affect adiposity or systemic glucose tolerance. In HFD-fed mice, 30-day CAP exposure suppressed insulin-stimulated endothelial nitric oxide synthase (eNOS) phosphorylation in skeletal muscle and increased adipose tissue inflammation and systemic glucose intolerance. In control diet–fed mice, a 9-day CAP exposure was sufficient to suppress insulin-stimulated Akt and eNOS phosphorylation and to decrease IκBα (inhibitor of the transcription factor NF-κB levels in the aorta. Treatment with the antioxidant TEMPOL or lung-specific overexpression of ecSOD prevented CAP-induced vascular insulin resistance and inflammation. Conclusions: Short-term exposure to PM2.5 induces vascular insulin resistance and inflammation triggered by a mechanism involving pulmonary oxidative stress. Suppression of vascular insulin signaling by PM2.5 may accelerate the progression to systemic insulin resistance, particularly in the context of diet-induced obesity. Citation: Haberzettl P, O

  1. Exposure to Fine Particulate Air Pollution Causes Vascular Insulin Resistance by Inducing Pulmonary Oxidative Stress.

    PubMed

    Haberzettl, Petra; O'Toole, Timothy E; Bhatnagar, Aruni; Conklin, Daniel J

    2016-12-01

    Epidemiological evidence suggests that exposure to ambient air fine particulate matter (PM2.5) increases the risk of developing type 2 diabetes and cardiovascular disease. However, the mechanisms underlying these effects of PM2.5 remain unclear. We tested the hypothesis that PM2.5 exposure decreases vascular insulin sensitivity by inducing pulmonary oxidative stress. Mice fed control (10-13% kcal fat) and high-fat (60% kcal fat, HFD) diets, treated with 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) or mice overexpressing lung-specific extracellular superoxide dismutase (ecSOD) were exposed to HEPA-filtered air or to concentrated PM2.5 (CAP) for 9 or 30 days, and changes in systemic and organ-specific insulin sensitivity and inflammation were measured. In control diet-fed mice, exposure to CAP for 30 days decreased insulin-stimulated Akt phosphorylation in lung, heart, and aorta but not in skeletal muscle, adipose tissue, and liver and did not affect adiposity or systemic glucose tolerance. In HFD-fed mice, 30-day CAP exposure suppressed insulin-stimulated endothelial nitric oxide synthase (eNOS) phosphorylation in skeletal muscle and increased adipose tissue inflammation and systemic glucose intolerance. In control diet-fed mice, a 9-day CAP exposure was sufficient to suppress insulin-stimulated Akt and eNOS phosphorylation and to decrease IκBα (inhibitor of the transcription factor NF-κB levels in the aorta. Treatment with the antioxidant TEMPOL or lung-specific overexpression of ecSOD prevented CAP-induced vascular insulin resistance and inflammation. Short-term exposure to PM2.5 induces vascular insulin resistance and inflammation triggered by a mechanism involving pulmonary oxidative stress. Suppression of vascular insulin signaling by PM2.5 may accelerate the progression to systemic insulin resistance, particularly in the context of diet-induced obesity. Citation: Haberzettl P, O'Toole TE, Bhatnagar A, Conklin DJ. 2016. Exposure to fine

  2. Acute Exposure to Ozone Exacerbates Acetaminophen-Induced Liver Injury in Mice

    PubMed Central

    Ibrahim Aibo, Daher; Birmingham, Neil P.; Lewandowski, Ryan; Maddox, Jane F.; Roth, Robert A.; Ganey, Patricia E.; Wagner, James G.; Harkema, Jack R.

    2010-01-01

    Ozone (O3), an oxidant air pollutant in photochemical smog, principally targets epithelial cells lining the respiratory tract. However, changes in gene expression have also been reported in livers of O3-exposed mice. The principal aim of the present study was to determine if acute exposure to environmentally relevant concentrations of O3 could cause exacerbation of drug-induced liver injury in mice. Overdose with acetaminophen (APAP) is the most common cause of drug-induced liver injury in developed countries. In the present study, we examined the hepatic effects of acute O3 exposure in mice pretreated with a hepatotoxic dose of APAP. C57BL/6 male mice were fasted overnight and then given APAP (300 mg/kg ip) or saline vehicle (0 mg/kg APAP). Two hours later, mice were exposed to 0, 0.25, or 0.5 ppm O3 for 6 h and then sacrificed 9 or 32 h after APAP administration (1 or 24 h after O3 exposure, respectively). Animals euthanized at 32 h were given 5-bromo-2-deoxyuridine 2 h before sacrifice to identify hepatocytes undergoing reparative DNA synthesis. Saline-treated mice exposed to either air or O3 had no liver injury. All APAP-treated mice developed marked centrilobular hepatocellular necrosis that increased in severity with time after APAP exposure. O3 exposure increased the severity of APAP-induced liver injury as indicated by an increase in necrotic hepatic tissue and plasma alanine aminotransferase activity. O3 also caused an increase in neutrophil accumulation in livers of APAP-treated animals. APAP induced a 10-fold increase in the number of bromodeoxyuridine-labeled hepatocytes that was markedly attenuated by O3 exposure. Gene expression analysis 9 h after APAP revealed differential expression of genes involved in inflammation, oxidative stress, and cellular regeneration in mice treated with APAP and O3 compared to APAP or O3 alone, providing some indications of the mechanisms behind the APAP and O3 potentiation. These results suggest that acute exposure to

  3. Tumor necrosis factor-α induced protein 6 attenuates acute lung injury following paraquat exposure.

    PubMed

    Xu, Jiajun; Zhen, Jiantao; Zhu, Jingfa; Lin, Qingming

    2016-01-01

    Paraquat exposure commonly occurs in the developing countries and the mortality rate is high. However, there is currently no consensus on the efficacy of treatment for paraquat exposure. The study was aimed to explore the effects of tumor necrosis factor-α (TNF-α) induced protein 6 (TSG-6) on acute lung injury (ALI) following paraquat exposure in rats. Male Sprague-Dawley (SD) rats were randomly divided into the sham group (n = 8), the paraquat group (n = 8), and the paraquat TSG-6-treated group (n = 8). Rats were administered with 50 mg/kg of paraquat intraperitoneally. At 1 h after exposure, rats were treated with 30 μg of recombinant human TSG-6 (rhTSG-6) intraperitoneally. After 6 h of exposure, ALI scores were evaluated by histology and the expression of pro-inflammatory cytokines in lung was assayed using real-time RT-PCR. ALI scores were significantly lower in the paraquat TSG-6-treated group, compared with the paraquat group (p < 0.05). The expression of interleukin (IL)-1β, IL-6, and TNF-α mRNA was significantly lower in the paraquat TSG-6-treated group, compared with the paraquat group (p < 0.01, respectively). Administration of rhTSG-6 attenuates ALI following paraquat exposure by suppressing inflammatory response.

  4. Continuous and cyclic thermal exposure induced degradation in boron reinforced 6061 aluminum composites

    NASA Technical Reports Server (NTRS)

    Olsen, G. C.; Tompkins, S. S.

    1977-01-01

    Boron reinforced 6061 aluminum (B/Al) composite was continuously exposed at 728 K for up to 240 hours and cyclically exposed between 293 K and 728 K for up to 6000 three-minute cycles. Room temperature tensile strengths were measured and the specimens were metallographically examined. The data suggest that, in addition to AlB2 formation, magnesium in the matrix diffused to the reaction layer and formed (Al,Mg)B2. This formation could weaken the matrix and embrittle the reaction layer. Continuous exposure degraded the strength of the B/Al specimens about 28% in 240 hours. However, the fracture mode, one indicative of high strength interfaces, did not change. The strength degradation was attributed to crack initiation in the brittle reaction layer causing stress concentrations in the fibers. Cyclic exposure degraded the strength of the B/Al about 34% in 6000 cycles. The fracture mode of the cyclic exposure specimens showed transition toward a mode characteristic of low interfacial strength. The lower interfacial strengths were attributed to stress fields induced by differential thermal expansion. Cyclic exposure degraded the strength of the B/Al specimens more than continuous exposure for similar cumulative exposure times.

  5. Digital music exposure reliably induces temporary threshold shift (TTS) in normal hearing human subjects

    PubMed Central

    Le Prell, C. G.; Dell, S.; Hensley, B.; Hall, J. W.; Campbell, K. C. M.; Antonelli, P. J.; Green, G. E.; Miller, J. M.; Guire, K.

    2012-01-01

    Objectives One of the challenges for evaluating new otoprotective agents for potential benefit in human populations is availability of an established clinical paradigm with real world relevance. These studies were explicitly designed to develop a real-world digital music exposure that reliably induces temporary threshold shift (TTS) in normal hearing human subjects. Design Thirty-three subjects participated in studies that measured effects of digital music player use on hearing. Subjects selected either rock or pop music, which was then presented at 93–95 (n=10), 98–100 (n=11), or 100–102 (n=12) dBA in-ear exposure level for a period of four hours. Audiograms and distortion product otoacoustic emissions (DPOAEs) were measured prior to and after music exposure. Post-music tests were initiated 15 min, 1 hr 15 min, 2 hr 15 min, and 3 hr 15 min after the exposure ended. Additional tests were conducted the following day and one week later. Results Changes in thresholds after the lowest level exposure were difficult to distinguish from test-retest variability; however, TTS was reliably detected after higher levels of sound exposure. Changes in audiometric thresholds had a “notch” configuration, with the largest changes observed at 4 kHz (mean=6.3±3.9dB; range=0–13 dB). Recovery was largely complete within the first 4 hours post-exposure, and all subjects showed complete recovery of both thresholds and DPOAE measures when tested 1-week post-exposure. Conclusions These data provide insight into the variability of TTS induced by music player use in a healthy, normal-hearing, young adult population, with music playlist, level, and duration carefully controlled. These data confirm the likelihood of temporary changes in auditory function following digital music player use. Such data are essential for the development of a human clinical trial protocol that provides a highly powered design for evaluating novel therapeutics in human clinical trials. Care must be

  6. Hormetic effect induced by depleted uranium in zebrafish embryos.

    PubMed

    Ng, C Y P; Cheng, S H; Yu, K N

    2016-06-01

    The present work studied the hormetic effect induced by uranium (U) in embryos of zebrafish (Danio rerio) using apoptosis as the biological endpoint. Hormetic effect is characterized by biphasic dose-response relationships showing a low-dose stimulation and a high-dose inhibition. Embryos were dechorionated at 4h post fertilization (hpf), and were then exposed to 10 or 100μg/l depleted uranium (DU) in uranyl acetate solutions from 5 to 6 hpf. For exposures to 10μg/l DU, the amounts of apoptotic signals in the embryos were significantly increased at 20 hpf but were significantly decreased at 24 hpf, which demonstrated the presence of U-induced hormesis. For exposures to 100μg/l DU, the amounts of apoptotic signals in the embryos were significantly increased at 20, 24 and 30 hpf. Hormetic effect was not shown but its occurrence between 30 and 48 hpf could not be ruled out. In conclusion, hormetic effect could be induced in zebrafish embryos in a concentration- and time-dependent manner.

  7. Photosensitized rose Bengal-induced phototoxicity on human melanoma cell line under natural sunlight exposure.

    PubMed

    Srivastav, Ajeet K; Mujtaba, Syed Faiz; Dwivedi, Ashish; Amar, Saroj K; Goyal, Shruti; Verma, Ankit; Kushwaha, Hari N; Chaturvedi, Rajnish K; Ray, Ratan Singh

    2016-03-01

    Rose Bengal (RB) is an anionic water-soluble xanthene dye, which used for many years to assess eye cornea and conjunctiva damage. RB showed strong absorption maxima (λmax) under visible light followed by UV-B and UV-A. RB under sunlight exposure showed a time-dependent photodegradation. Our results show that photosensitized RB generates (1)O2 via Type-II photodynamic pathway and induced DNA damage under sunlight/UV-R exposure. 2'dGuO degradation, micronuclei formation, and single- and double-strand breakage were the outcome of photogenotoxicity caused by RB. Quenching studies with NaN3 advocate the involvement of (1)O2 in RB photogenotoxicity. RB induced linoleic acid photoperoxidation, which was parallel to (1)O2-mediated DNA damage. Oxidative stress in A375 cell line (human melanoma cell line) was detected through DCF-DA assay. Photosensitized RB decreased maximum cellular viability under sunlight followed by UV-B and UV-A exposures. Apoptosis was detected as a pattern of cell death through the increased of caspase-3 activity, decreased mitochondrial membrane potential, and PS translocation through inner to outer plasma membrane. Increased cytosolic levels of Bax also advocate the apoptotic cell death. We propose a p53-mediated apoptosis via increased expression of Bax gene and protein. Thus, the exact mechanism behind RB phototoxicity was the involvement of (1)O2, which induced oxidative stress-mediated DNA and membrane damage, finally apoptotic cell death under natural sunlight exposure. The study suggests that after the use of RB, sunlight exposure may avoid to prevent from its harmful effects.

  8. Exposure to 915 MHz radiation induces micronuclei in Vicia faba root tips.

    PubMed

    Gustavino, Bianca; Carboni, Giovanni; Petrillo, Roberto; Paoluzzi, Giovanni; Santovetti, Emanuele; Rizzoni, Marco

    2016-03-01

    The increasing use of mobile phones and wireless networks raised a great debate about the real carcinogenic potential of radiofrequency-electromagnetic field (RF-EMF) exposure associated with these devices. Conflicting results are reported by the great majority of in vivo and in vitro studies on the capability of RF-EMF exposure to induce DNA damage and mutations in mammalian systems. Aimed at understanding whether less ambiguous responses to RF-EMF exposure might be evidenced in plant systems with respect to mammalian ones, in the present work the mutagenic effect of RF-EMF has been studied through the micronucleus (MN) test in secondary roots of Vicia faba seedlings exposed to mobile phone transmission in controlled conditions, inside a transverse electro magnetic (TEM) cell. Exposure of roots was carried out for 72h using a continuous wave (CW) of 915 MHz radiation at three values of equivalent plane wave power densities (23, 35 and 46W/m(2)). The specific absorption rate (SAR) was measured with a calorimetric method and the corresponding values were found to fall in the range of 0.4-1.5W/kg. Results of three independent experiments show the induction of a significant increase of MN frequency after exposure, ranging from a 2.3-fold increase above the sham value, at the lowest SAR level, up to a 7-fold increase at the highest SAR. These findings are in agreement with the limited number of data on cytogenetic effects detected in other plant systems exposed to mobile phone RF-EMF frequencies and clearly show the capability of radiofrequency exposure to induce DNA damage in this eukaryotic cell system.

  9. Exposure to metal oxide nanoparticles administered at occupationally relevant doses induces pulmonary effects in mice.

    PubMed

    Présumé, Mirlande; Simon-Deckers, Angélique; Tomkiewicz-Raulet, Céline; Le Grand, Béatrice; Tran Van Nhieu, Jeanne; Beaune, Gregory; Duruphty, Olivier; Doucet, Jean; Coumoul, Xavier; Pairon, Jean-Claude; Boczkowski, Jorge; Lanone, Sophie; Andujar, Pascal

    2016-12-01

    In spite of the great promises that the development of nanotechnologies can offer, concerns regarding potential adverse health effects of occupational exposure to nanoparticle (NP) is raised. We recently identified metal oxide NP in lung tissue sections of welders, located inside macrophages infiltrated in fibrous regions. This suggests a role of these NP in the lung alterations observed in welders. We therefore designed a study aimed to investigate the pulmonary effects, in mice, of repeated exposure to NP administered at occupationally relevant doses. We therefore chose four metal oxide NPs representative of those found in the welder's lungs: Fe2O3, Fe3O4, MnFe2O4 and CrOOH. These NPs were administered weekly for up to 3 months at two different doses: 5 μg, chosen as occupationally relevant to welding activity, and 50 μg, chosen as occupationally relevant to the context of an NP-manufacturing facility. Our results show that 3 month-repeated exposures to 5 μg NP induced limited pulmonary effects, characterized by the development of a mild peribronchiolar fibrosis observed for MnFe2O4 and CrOOH NP only. This fibrotic event was further extended in terms of intensity and localization after the repeated administration of 50 μg NP: all but Fe2O3 NP induced the development of peribronchiolar, perivascular and alveolar fibrosis, together with an interstitial inflammation. Our data demonstrate for the first time a potential risk for respiratory health posed by repeated exposure to NP at occupationally relevant doses. Given these results, the development of occupational exposure limits (OELs) specifically dedicated to NP exposure might therefore be an important issue to address.

  10. Perinatal DDT Exposure Induces Hypertension and Cardiac Hypertrophy in Adult Mice

    PubMed Central

    La Merrill, Michele A.; Sethi, Sunjay; Benard, Ludovic; Moshier, Erin; Haraldsson, Borje; Buettner, Christoph

    2016-01-01

    Background: Dichlorodiphenyltrichloroethane (DDT) was used extensively to control malaria, typhus, body lice, and bubonic plague worldwide, until countries began restricting its use in the 1970s. However, the use of DDT to control vector-borne diseases continues in developing countries. Prenatal DDT exposure is associated with elevated blood pressure in humans. Objective: We hypothesized that perinatal DDT exposure causes hypertension in adult mice. Methods: DDT was administered to C57BL/6J dams from gestational day 11.5 to postnatal day 5. Blood pressure (BP) and myocardial wall thickness were measured in male and female adult offspring. Adult mice were treated with an angiotensin converting enzyme (ACE) inhibitor, captopril, to evaluate sensitivity to amelioration of DDT-associated hypertension by ACE inhibition. We further assessed the influence of DDT exposure on the expression of mRNAs that regulate BP through renal ion transport. Results: Adult mice perinatally exposed to DDT exhibited chronically increased systolic BP, increased myocardial wall thickness, and elevated expression of mRNAs of several renal ion transporters. Captopril completely reversed hypertension in mice perinatally exposed to DDT. Conclusions: These data demonstrate that perinatal exposure to DDT causes hypertension and cardiac hypertrophy in adult offspring. A key mechanism underpinning this hypertension is an overactivated renin angiotensin system because ACE inhibition reverses the hypertension induced by perinatal DDT exposure. Citation: La Merrill M, Sethi S, Benard L, Moshier E, Haraldsson B, Buettner C. 2016. Perinatal DDT exposure induces hypertension and cardiac hypertrophy in adult mice. Environ Health Perspect 124:1722–1727; http://dx.doi.org/10.1289/EHP164 PMID:27325568

  11. Nicotine exposure induces bronchial epithelial cell apoptosis and senescence via ROS mediated autophagy-impairment.

    PubMed

    Bodas, Manish; Van Westphal, Colin; Carpenter-Thompson, Rhett; K Mohanty, Dillip; Vij, Neeraj

    2016-08-01

    Waterpipe smoking and e-cigarette vaping, the non-combustible sources of inhaled nicotine exposure are increasingly becoming popular and marketed as safer alternative to cigarette smoking. Hence, this study was designed to investigate the impact of inhaled nicotine exposure on disease causing COPD-emphysema mechanisms. For in vitro studies, human bronchial epithelial cells (Beas2b) were treated with waterpipe smoke extract (WPSE, 5%), nicotine (5mM), and/or cysteamine (250μM, an autophagy inducer and anti-oxidant drug), for 6hrs. We observed significantly (p<0.05) increased ubiquitinated protein-accumulation in the insoluble protein fractions of Beas2b cells treated with WPSE or nicotine that could be rescued by cysteamine treatment, suggesting aggresome-formation and autophagy-impairment. Moreover, our data also demonstrate that both WPSE and nicotine exposure significantly (p<0.05) elevates Ub-LC3β co-localization to aggresome-bodies while inducing Ub-p62 co-expression/accumulation, verifying autophagy-impairment. We also found that WPSE and nicotine exposure impacts Beas2b cell viability by significantly (p<0.05) inducing cellular apoptosis/senescence via ROS-activation, as it could be controlled by cysteamine, which is known to have an anti-oxidant property. For murine studies, C57BL/6 mice were administered with inhaled nicotine (intranasal, 500μg/mouse/day for 5 days), as an experimental model of non-combustible nicotine exposure. The inhaled nicotine exposure mediated oxidative-stress induces autophagy-impairment in the murine lungs as seen by significant (p<0.05, n=4) increase in the expression levels of nitrotyrosine protein-adduct (oxidative-stress marker, soluble-fraction) and Ub/p62/VCP (impaired-autophagy marker, insoluble-fraction). Overall, our data shows that nicotine, a common component of WPS, e-cigarette vapor and cigarette smoke, induces bronchial epithelial cell apoptosis and senescence via ROS mediated autophagy-impairment as a potential

  12. Microwave-induced post-exposure hyperthermia: Involvement of endogenous opioids and serotonin

    SciTech Connect

    Lai, H.; Chou, C.K.; Guy, A.W.; Horita, A.

    1984-08-01

    Acute exposure to pulsed microwaves (2450 MHz, 1 mW/ cm/sup 2/, SAR 0.6 W/kg, 2-..mu..s pulses, 500 pulses/s) induces a transient post-exposure hyperthermia in the rat. The hyperthermia was attenuated by treatment with either the narcotic antagonist naltrexone or one of the serotonin antagonists cinanserin, cyproheptadine, or metergoline. It was not affected, however, by treatment with the peripheral serotonin antagonist xylamidine nor the dopamine antagonist haloperidol. It thus appears that both endogenous opioids and central serotonin are involved. It is proposed that pulsed microwaves activate endogenous opioid systems, and that they in turn activate a serotonergic mechanism that induces the rise in body temperature.

  13. [Nervous system disorders induced by occupational exposure to arsenic and its inorganic compounds: a literature review].

    PubMed

    Sińczuk-Walczak, Halina

    2009-01-01

    This paper presents a review of the effect of arsenic (As) and its inorganic compounds on the nervous system. In humans, inhalation exposure mostly occurs in occupational conditions. In the occupational environment, the most extensive exposure to this element is observed in the copper industry. Chronic As poisoning is manifested by skin and mucous membrane lesions, impairment of the nervous system in the form of disorders of psychic functions and polyneuropathies, retrobulbar neuritis, disorders of peripheral circulation and the risk for Raynaud's syndrome. Arsenic-induced polyneuropathy is usually a very serious and chronic disease. A complete recovery is observed in only 15-20% of patients. As-induced encephalopathy is an irreversible process.

  14. Charge trapping in aligned single-walled carbon nanotube arrays induced by ionizing radiation exposure

    SciTech Connect

    Esqueda, Ivan S.; Cress, Cory D.; Che, Yuchi; Cao, Yu; Zhou, Chongwu

    2014-02-07

    The effects of near-interfacial trapping induced by ionizing radiation exposure of aligned single-walled carbon nanotube (SWCNT) arrays are investigated via measurements of gate hysteresis in the transfer characteristics of aligned SWCNT field-effect transistors. Gate hysteresis is attributed to charge injection (i.e., trapping) from the SWCNTs into radiation-induced traps in regions near the SWCNT/dielectric interface. Self-consistent calculations of surface-potential, carrier density, and trapped charge are used to describe hysteresis as a function of ionizing radiation exposure. Hysteresis width (h) and its dependence on gate sweep range are investigated analytically. The effects of non-uniform trap energy distributions on the relationship between hysteresis, gate sweep range, and total ionizing dose are demonstrated with simulations and verified experimentally.

  15. Ethanol exposure induces a delay in the reacquisition of function during head regeneration in Schmidtea mediterranea.

    PubMed

    Lowe, Jesse R; Mahool, Tyler D; Staehle, Mary M

    2015-01-01

    Prenatal exposure to ethanol affects neurodevelopmental processes, leading to a variety of physical and cognitive impairments collectively termed Fetal Alcohol Spectrum Disorders (FASD). The molecular level ethanol-induced alterations that underlie FASD are poorly understood and are difficult to study in mammals. Ethanol exposure has been shown to affect regulation and differentiation of embryonic stem cells in vitro, suggesting that in vivo effects such as FASD could arise from similar alterations of stem cells. In this study, we hypothesize that ethanol exposure affects head regeneration and neuroregeneration in the Schmidtea mediterranea planarian. S. mediterranea freshwater flatworms have remarkable regenerative abilities arising from an abundant population of pluripotent adult somatic stem cells known as neoblasts. Here, we evaluated the mobility-normalized photophobic behavior of ethanol-exposed planaria as an indicator of cognitive function in intact and head-regenerating worms. Our studies show that exposure to 1% ethanol induces a delay in the reacquisition of behavior during head regeneration that cannot be attributed to the effect of ethanol on intact worms. This suggests that the S. mediterranea planarian could provide insight into conserved neurodevelopmental processes that are affected by ethanol and that lead to FASD in humans.

  16. Short-term, low-dose cadmium exposure induces hyperpermeability in human renal glomerular endothelial cells.

    PubMed

    Li, Liqun; Dong, Fengyun; Xu, Dongmei; Du, Linna; Yan, Suhua; Hu, Hesheng; Lobe, Corrinne G; Yi, Fan; Kapron, Carolyn M; Liu, Ju

    2016-02-01

    The kidney is the principal organ targeted by exposure to cadmium (Cd), a well-known toxic metal. Even at a low level, Cd damages glomerular filtration. However, little is known about the effects of Cd on the glomerular endothelium, which performs the filtration function and directly interacts with Cd in blood plasma. In this study, we cultured human renal glomerular endothelial cells (HRGECs) in the presence of serum with treatment of a short term (1 h) and low concentration (1 μm) of Cd, which mimics the pattern of glomerular endothelium exposure to Cd in vivo. We found that this short-term, low-dose Cd exposure does not induce cytotoxicity, but increases permeability in HRGECs monolayers and redistributes adherens junction proteins vascular endothelial-cadherin and β-catenin. Though short-term, low-dose Cd exposure activates all three major mitogen activated protein kinases, only the inhibitor of p38 mitogen activated protein kinase partially prevents Cd-induced hyperpermeability in HRGECs. Our data indicate that the presence of Cd in blood circulation might directly disrupt the glomerular endothelial cell barrier and contribute to the development of clinical symptoms of glomerular diseases. Copyright © 2015 John Wiley & Sons, Ltd.

  17. Increased concanavalin A-induced suppressor cell activity in humans with occupational lead exposure

    SciTech Connect

    Cohen, N.; Modai, D.; Golik, A.; Weissgarten, J.; Peller, S.; Katz, A.; Averbukh, Z.; Shaked, U.

    1989-02-01

    E-rosette-forming cells (E-RFC), mitogen-induced blast transformation, OKT4+, OKT8+ cells, and their ratio were found to be normal in 10 subjects chronically exposed to lead with blood levels of 40-51 micrograms%. However, concanavalin A (Con A)-induced suppressor cell activity (SCA) in these subjects was significantly greater than in normal matched controls. The clinical relevance of this observation is not clear, but it may have some bearing on the various immunologic defects described in lead exposure.

  18. Application of an induced field sensor for assessment of electromagnetic exposure from compact fluorescent lamps.

    PubMed

    Nadakuduti, Jagadish; Douglas, Mark; Capstick, Myles; Kühn, Sven; Kuster, Niels

    2012-02-01

    The development of scientifically sound instrumentation, methods, and procedures for the electromagnetic exposure assessment of compact fluorescent lamps (CFLs) is investigated. The incident and induced fields from 11 CFLs have been measured in the 10 kHz-1 MHz range, and they are compared with the levels for incandescent and light emitting diode (LED) bulbs. Commercially available equipment was used to measure the incident fields, while a novel sensor was built to assess the induced fields in humans. Incident electric field levels significantly exceed the International Commission on Non-Ionizing Radiation Protection (ICNIRP) reference levels at close distances for some sources, while the induced fields are within the ICNIRP basic restrictions. This demonstrates the importance of assessing the induced fields rather than the incident fields for these sources. Maximum current densities for CFLs are comparable to the limits (in the range of 9% to 56%), demonstrating the need for measurements to establish compliance. For the frequency range investigated, the induced fields were found to be considerably higher for CFLs than for incandescent light bulbs, while the exposure from the two LED bulbs was low. The proposed instrumentation and methods offer several advantages over an existing measurement standard, and the measurement uncertainty is significantly better than the assessment of electric and magnetic fields at close distances. Copyright © 2011 Wiley Periodicals, Inc.

  19. Vitamin E Reversed Apoptosis of Cardiomyocytes Induced by Exposure to High Dose Formaldehyde During Mice Pregnancy.

    PubMed

    Wu, Dongyuan; Jiang, Zhirong; Gong, Bing; Dou, Yue; Song, Mingxuan; Song, Xiaoxia; Tian, Yu

    2017-09-30

    In this study, we investigated the protection effect of Vitamin E (Vit E) on formaldehyde (FA) exposure during pregnancy induced apoptosis of cardiomyocytes, and used an HL-1 cell line to confirmed the findings in vivo.Pregnant mice received different doses of FA (0.5 mg/kg, 1.0 mg/kg, 1.5 mg/kg, 0.1 μg Vit E, or 1.5 mg/kg + 0.1 μg Vit E). TUNEL staining was used to reveal the apoptosis in cardiomyocytes, and SOD, MDA, GSH, Livin, and Caspase-3 in cardiomyocytes were detected by ELISA, RT-PCR, and Western blot. For in vitro study, HL-1 cells were treated with vehicle, 5 μmol/L FA, 25 μmol/L FA, 50 μmol/L FA, 10 mg/L Vit. E, and 50 μmol/L FA+ 10 mg/L Vit E, respectively. CCK-8 assay and flow cytometry were used to evaluate cell vitality and apoptosis. A high dose of FA exposure led to cytotoxicity in both pregnant mice and offspring, as TUNEL staining revealed a significant apoptosis of cardiomyocytes, and the alternation in SOD, GSH, MDA, Livin, and Caspase-3 was found in cardiomyocytes. 0.1 μg Vit. E could reverse high doses of FA exposure induced apoptosis of cardiomyocytes in both pregnant mice and offspring. The in vitro study revealed that FA exposure induced a decrease of cell viability and increased cell apoptosis, as well as oxidative stress in HL-1 cells with alternation in SOD, GSH, MDA, Livin, and Caspase-3.This study revealed a high dose of FA induced oxidative stress and apoptosis of cardiomyocytes in both pregnant mice and offspring, and Vit E supplement during pregnancy reversed the systemic and myocardial toxicity of FA.

  20. The changes of heavy metal and metallothionein distribution in testis induced by cadmium exposure.

    PubMed

    Kusakabe, Takahiko; Nakajima, Katsuyuki; Suzuki, Keiji; Nakazato, Kyoumi; Takada, Hisashi; Satoh, Takahiro; Oikawa, Masakazu; Kobayashi, Kenji; Koyama, Hiroshi; Arakawa, Kazuo; Nagamine, Takeaki

    2008-02-01

    Cadmium (Cd) is known to cause various disorders in the testis, and metallothionein (MT) is known as a protein, which has a detoxification function for heavy metals. However, the changes of Fe, Cu, and Zn distribution in the testis induced by Cd exposure have not been well examined. Moreover, only a few studies have been reported on the localization of MT after Cd exposure. In this study, we have investigated the changes of Fe, Cu, and Zn distribution in Cd-exposed testis by a newly developed in air micro-Particle Induced X-ray Emission (PIXE) method. Also, we examined the distribution of MT expression in testis. In the testis of Cd-treated rats with significant increases of lipid peroxidation, the sertoli cell tight junction was damaged by Cd exposure, resulting from disintegration of the blood testis barrier (BTB). Evaluation by in air micro-PIXE method revealed that Cd and Fe distribution were increased in the interstitial tissues and seminiferous tubules. The histological findings indicated that the testicular tissue damage was advanced, which may have been caused by Fe flowing into seminiferous tubules followed by disintegration of the BTB. As a result, Fe was considered to enhance the tissue damage caused by Cd exposure. MT was detected in spermatogonia, spermatocytes, and Sertoli's cells in the testis of Cd-treated rats, but was not detected in interstitial tissues. These results suggested that MT was induced by Cd in spermatogonia, spermatocytes, and Sertoli's cells, and was involved in the resistance to tissue damage induced by Cd.

  1. Increased metallothionein content in rat liver induced by x irradiation and exposure to high oxygen tension

    SciTech Connect

    Shiraishi, N.; Aono, K.; Utsumi, K.

    1983-08-01

    X irradiation and exposure to high oxygen tension are known to induce lipid peroxidation. The effects of these stresses on hepatic content of metallothionein, which may be involved in the regulation of zinc and copper metabolism, have been studied. The amount of metallothionein in rat liver was increased 11-fold by a high dose of X irradiation (1000 R). Increased metallothionein content (about 15 times) was also observed in liver of rats exposed to high oxygen tension for 3 days.

  2. Similar Metabolic Changes Induced by HIPVs Exposure as Herbivore in Ammopiptanthus mongolicus

    PubMed Central

    Sun, Jingru; Zhang, Xiao; Cao, Chuanjian; Mei, Xindi; Wang, Ningning; Yan, Suli; Zong, Shixiang; Luo, Youqing; Yang, Haijun; Shen, Yingbai

    2014-01-01

    Herbivore-induced plant volatiles (HIPVs) are important compounds to prim neighboring undamaged plants; however, the mechanism for this priming process remains unclear. To reveal metabolic changes in plants exposed to HIPVs, metabolism of leaves and roots of Ammopiptanthus mongolicus seedlings exposed to HIPVs released from conspecific plants infested with larvae of Orgyia ericae were analyzed together with control and infested seedlings using nuclear magnetic resonance (NMR)-based metabolic technology and multi variate data analysis. Results presented showed that HIPVs exposure led to similar but specific metabolic changes compared with those induced by infestation in both leaves and roots. Furthermore, both HIPVs exposure and herbivore attack resulted in metabolic changes involving a series of primary and secondary metabolites in both leaves and roots. Taken together, these results suggested that priming of yet-damaged plants may be achieved by reconfiguring metabolic pathways in leaves and roots to make similar concentrations for all metabolites as those in seedlings infested. Therefore, we propose that improved readiness of defense induction of primed plants toward subsequent herbivore attack may be based on the similar metabolic profiling induced by HIPVs exposure as those caused by herbivore. PMID:24748156

  3. Brief exposure to copper induces apoptosis and alters mediators of olfactory signal transduction in coho salmon

    PubMed Central

    Wang, Lu; Espinoza, Herbert M.; Gallagher, Evan P.

    2013-01-01

    Pacific salmon are particularly susceptible to copper (Cu)-induced olfactory injuries that can ultimately inhibit neurobehaviors critical to survival. However, the molecular mechanisms underlying Cu-mediated olfactory impairment remain poorly understood. In the present study, we conducted a short-term Cu exposure at levels relevant to urban runoff, and investigated the roles of impaired olfactory signal transduction and induced apoptosis as underlying mechanisms of olfactory injury. Increased cell death in the olfactory epithelium was evident in coho receiving 4 h exposures to 25 and 50 ppb Cu. Expression of olfactory marker protein (omp), a marker of mature olfactory sensory neurons, also decreased at 50 ppb Cu. Immunohistochemical analysis of coho olfactory epithelium demonstrated a loss of type 3 adenylate cyclase (ACIII) in the apical olfactory epithelium cilia at all levels of Cu exposure, suggesting an inhibitory effect of Cu in olfactory signaling. Accompanying the loss of ACIII in Cu-exposed coho were reduced intracellular cyclic guanosine monophosphate (cGMP) levels in the olfactory rosettes. Collectively, these results support a linkage among the initial steps of olfactory signaling in Cu-induced salmon olfactory injury, and suggesting that monitoring olfactory cGMP levels may aid in the assessment of salmon olfactory injury. PMID:24050714

  4. Genome-wide analysis of DNA methylation changes induced by gestational arsenic exposure in liver tumors.

    PubMed

    Suzuki, Takehiro; Yamashita, Satoshi; Ushijima, Toshikazu; Takumi, Shota; Sano, Tomoharu; Michikawa, Takehiro; Nohara, Keiko

    2013-12-01

    Inorganic arsenic is known to be a human carcinogen. Previous studies have reported that DNA methylation changes are involved in arsenic-induced carcinogenesis, therefore, DNA methylation changes that are specific to arsenic-induced tumors would be useful to distinguish tumors induced by arsenic from tumors caused by other factors and to dissect arsenic carcinogenesis. Previous studies have shown that gestational arsenic exposure of C3H mice, which tend to spontaneously develop liver tumors, increases the incidence of tumors in male offspring. In this study we used the same experimental protocol as in those previous studies and searched for DNA regions where methylation status was specifically altered in the liver tumors of arsenic-exposed offspring by using methylated DNA immunoprecipitation-CpG island microarrays. The methylation levels of the DNA regions selected were measured by quantitative methylation-specific PCR and bisulfite sequencing. The results of this study clarified a number of regions where DNA methylation status was altered in the liver tumors in the C3H mice compared to normal liver tissues. Among such regions, we showed that a gene body region of the oncogene Fosb underwent alteration in DNA methylation by gestational arsenic exposure. We also showed that Fosb expression significantly increased corresponding to the DNA methylation level of the gene body in the arsenic-exposed group. These findings suggest that the DNA methylation status can be used to identify tumors increased by gestational arsenic exposure. © 2013 Japanese Cancer Association.

  5. Exposure of mouse to high gravitation forces induces long-term potentiation in the hippocampus.

    PubMed

    Ishii, Masamitsu; Tomizawa, Kazuhito; Matsushita, Masayuki; Matsui, Hideki

    2004-06-01

    The central nervous system is highly plastic and has been shown to undergo both transient and chronic adaptive changes in response to environmental influences. The purpose of this study was to investigate the effect of hypergravic field on long-term potentiation (LTP) in the mouse hippocampus. Exposure of mice to 4G fields for 48 h had no effect on input-output coupling during extracellular stimulation of Schaffer collaterals and paired pulse facilitation, suggesting that the hypergravic exposure had no detrimental effect on basal neurotransmission in the hippocampus. However, the exposure to 4G fields for 48 h significantly induced LTP compared with the control mouse hippocampus. In contrast, no significant changes of late-phase LTP (L-LTP) were found in the hippocampi of mice exposed to the hypergravic field. Exposure of mice to 4G fields for 48 h enhanced AMPA receptor phosphorylation but not cyclic AMP-responsive element binding protein (CREB) phosphorylation. These results suggest that exposure to hyperdynamic fields influences the synaptic plasticity in the hippocampus.

  6. Endosulfan-induced hepatotoxicity is route of exposure independent in rats.

    PubMed

    Uboh, Friday Effiong; Asuquo, Ekpo Nya; Eteng, Mbeh Ubana

    2011-07-01

    Endosulfan is an important hepatotoxic agent that generates free oxygen radicals in liver. With the widespread use of endosulfan in agriculture, human beings are most likely to be exposed to it by eating food contaminated with endosulfan, exposure to its low levels by skin contact with contaminated soil, smoking cigarettes made from tobacco that has endosulfan residues on it, or by nose and whole body inhalation exposure in the farms during its application. Since endosulfan is a frequently used pesticide, and the incidence of toxic injury to the liver tissue in relation to its widespread use reported in the literature, we considered it necessary to investigate whether endosulfan-induced liver injury could be route of exposure dependent. Eighteen mature male albino Wistar rats, weighing between 180 and 220 g, were used in this study. The hepatotoxic effects of oral administration of endosulfan (5 mg/kg body weight) daily for 30 days, and 30 days whole body inhalation exposure to ungraded concentration of endosulfan were investigated in rats using serum liver enzymes and histopathological assay. At the end of the experimental period, serum alanine aminotransferase, aspartate amino transferase, alkaline phosphatase, and creatine kinase activities obtained for the group of rats exposed orally to endosulfan were not significantly different (p ≥ 0.05) from the activities obtained for rats exposed by whole body inhalation. However, the activity of these enzymes obtained for the rats exposed to endosulfan by both oral and inhalation routes were significantly increased (p ≤ 0.05) compared, respectively, to the control. Also, on microscopic examination, the liver tissues of experimental groups exhibited severe damage histopathologically. The results of the enzyme and histological analyses showed that both oral and whole body inhalation exposure to endosulfan may cause liver tissue damage in rats. The exposure to endosulfan in rats caused liver tissue damage independent

  7. DNA damage-inducible genes as biomarkers for exposures to environmental agents.

    PubMed

    Johnson, N F; Carpenter, T R; Jaramillo, R J; Liberati, T A

    1997-06-01

    A biodosimetric approach to determine alpha-particle dose to the respiratory tract epithelium from known exposures to radon has been developed in the rat. Cytotoxicity assays have been used to obtain dose-conversion factors for cumulative exposures typical of those encountered by underground uranium miners. However, this approach is not sensitive enough to derive dose-conversion factors for indoor radon exposures. The expression of DNA damage-inducible genes is being investigated as a biomarker of exposure to radon progeny. Exposure of cultures of A549 cells to alpha particles resulted in an increase in the protein levels of the DNA damage-inducible genes, p53, Cip1, and Gadd45. These protein changes were associated with a transient arrest of cells passing through the cell cycle. This arrest was typified by an increase in the number of cells in the G1 and G2 phases and a decrease in the number of cells in the S phase. The effect of inhaled alpha particles (radon progeny) in rats was examined in the epithelial cells of the lateral well of the anterior nasal cavity. Exposures to radon progeny resulted in a significant increase in the number of cells in the G1 phase and a decrease in the number of cells in the S phase. These cell-cycle changes were concomitant with an increase in the number of cells containing DNA strand breaks. These results suggest a commonality between cell-cycle events in vitro and in vivo following exposure to ionizing radiation. In addition to ionizing radiation, A549 cells were exposed to 4-nitroquinoline-1-oxide, methyl methanesulphonate, crocidolite asbestos, and glass microfiber. These studies showed that physical and chemical agents induce different expression patterns of p53, Cip1, and Gadd153 proteins and they could be used to discriminate between toxic and nontoxic materials such as asbestos and glass microfiber. The measurement of gene expression in A549 cells may provide a means to identify a broad spectrum of physical and chemical

  8. Assessment of the mode of action for hexavalent chromium-induced lung cancer following inhalation exposures.

    PubMed

    Proctor, Deborah M; Suh, Mina; Campleman, Sharan L; Thompson, Chad M

    2014-11-05

    Inhalation of hexavalent chromium [Cr(VI)] is associated with increased lung cancer risk among workers in several industries, most notably chromate production workers exposed to high concentrations of Cr(VI) (≥100 μg/m(3)), for which clear exposure-response relationships and respiratory irritation and tissue damage have been reported. Data from this industry are used to assess lung cancer risk associated with environmental and current occupational exposures, occurring at concentrations that are significantly lower. There is considerable uncertainty in the low dose extrapolation of historical occupational epidemiology data to assess risk at current exposures because no published or well recognized mode of action (MOA) for Cr(VI)-induced lung tumors exists. We conducted a MOA analysis for Cr(VI)-induced lung cancer evaluating toxicokinetic and toxicological data in humans and rodents and mechanistic data to assess plausibility, dose-response, and temporal concordance for potential MOAs. Toxicokinetic data support that extracellular reduction of Cr(VI), which limits intracellular absorption of Cr(VI) and Cr(VI)-induced toxicity, can be overwhelmed at high exposure levels. In vivo genotoxicity and mutagenicity data are mostly negative and do not support a mutagenic MOA. Further, both chronic bioassays and the epidemiologic literature support that lung cancer occurs at exposures that cause tissue damage. Based on this MOA analysis, the overall weight of evidence supports a MOA involving deposition and accumulation of particulate chromium in the bifurcations of the lung resulting in exceedance of clearance mechanisms and cellular absorption of Cr(VI). Once inside the cell, reduction of Cr(VI) results in oxidative stress and the formation of Cr ligands. Subsequent protein and DNA damage lead to tissue irritation, inflammation, and cytotoxicity. These effects, concomitant with increased cell proliferation, result in changes to DNA sequences and/or methylation status

  9. DNA damage-inducible genes as biomarkers for exposures to environmental agents.

    PubMed Central

    Johnson, N F; Carpenter, T R; Jaramillo, R J; Liberati, T A

    1997-01-01

    A biodosimetric approach to determine alpha-particle dose to the respiratory tract epithelium from known exposures to radon has been developed in the rat. Cytotoxicity assays have been used to obtain dose-conversion factors for cumulative exposures typical of those encountered by underground uranium miners. However, this approach is not sensitive enough to derive dose-conversion factors for indoor radon exposures. The expression of DNA damage-inducible genes is being investigated as a biomarker of exposure to radon progeny. Exposure of cultures of A549 cells to alpha particles resulted in an increase in the protein levels of the DNA damage-inducible genes, p53, Cip1, and Gadd45. These protein changes were associated with a transient arrest of cells passing through the cell cycle. This arrest was typified by an increase in the number of cells in the G1 and G2 phases and a decrease in the number of cells in the S phase. The effect of inhaled alpha particles (radon progeny) in rats was examined in the epithelial cells of the lateral well of the anterior nasal cavity. Exposures to radon progeny resulted in a significant increase in the number of cells in the G1 phase and a decrease in the number of cells in the S phase. These cell-cycle changes were concomitant with an increase in the number of cells containing DNA strand breaks. These results suggest a commonality between cell-cycle events in vitro and in vivo following exposure to ionizing radiation. In addition to ionizing radiation, A549 cells were exposed to 4-nitroquinoline-1-oxide, methyl methanesulphonate, crocidolite asbestos, and glass microfiber. These studies showed that physical and chemical agents induce different expression patterns of p53, Cip1, and Gadd153 proteins and they could be used to discriminate between toxic and nontoxic materials such as asbestos and glass microfiber. The measurement of gene expression in A549 cells may provide a means to identify a broad spectrum of physical and chemical

  10. Role of BAFF in pulmonary autoantibody responses induced by chronic cigarette smoke exposure in mice.

    PubMed

    Morissette, Mathieu C; Gao, Yang; Shen, Pamela; Thayaparan, Danya; Bérubé, Jean-Christophe; Paré, Peter D; Brandsma, Corry-Anke; Hao, Ke; Bossé, Yohan; Ettinger, Rachel; Herbst, Ronald; Humbles, Alison A; Kolbeck, Roland; Zhong, Nanshan; Chen, Rongchang; Stämpfli, Martin R

    2016-12-01

    Emerging evidence suggests that autoimmune processes are implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). In this study, we assessed the expression of B-cell activating factor (BAFF) in smokers, and investigated the functional importance of BAFF in the induction and maintenance of cigarette smoke-induced pulmonary antinuclear antibodies (ANA) and tertiary lymphoid tissues (TLTs) using a preclinical mouse model. We observed that BAFF levels were elevated in smokers and mice exposed to cigarette smoke. In mice, BAFF expression was rapidly induced in the lungs following 4 days of cigarette smoke exposure and remained elevated following 8 and 24 weeks of exposure. Alveolar macrophages were the major source of BAFF Blockade of BAFF using a BAFF receptor-Fc (BAFFR-Fc) construct prevented pulmonary ANA and TLT formation when delivered concurrent with cigarette smoke exposure. Under these conditions, no impact on lung inflammation was observed. However, administration of BAFFR-Fc following smoking cessation markedly reduced the number of TLTs and ANA levels and, of note, reduced pulmonary neutrophilia. Altogether, this study shows for the first time a central role of BAFF in the induction and maintenance of cigarette smoke-induced pulmonary ANA and suggests that BAFF blockade following smoking cessation could have beneficial effects on persistent inflammatory processes.In this study, we assessed the expression of B-cell activating factor (BAFF) in smokers, and investigated the functional importance of BAFF in the induction and maintenance of cigarette smoke-induced pulmonary antinuclear antibodies (ANA) and tertiary lymphoid tissues (TLTs) using a preclinical mouse model. Data presented show that BAFF plays a central role in the induction and maintenance of cigarette smoke-induced pulmonary ANA and suggest a therapeutic potential for BAFF blockade in limiting autoimmune processes associated with smoking. © 2016 The Authors. Physiological

  11. Early immunological response to German cockroach frass exposure induces a Th2/Th17 environment.

    PubMed

    Page, Kristen; Zhou, Ping; Ledford, John R; Day, Scottie B; Lutfi, Riad; Dienger, Krista; Lewkowich, Ian P

    2011-01-01

    Cockroach exposure is a major risk factor for the development of asthma; however, the early immune events induced by cockroach leading to the Th2 response are not fully understood. Exposure of naïve mice to German cockroach (GC) feces (frass) was sufficient to induce dendritic cell (DC) recruiting and activating chemokines C-C motif ligand 20, granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor and macrophage inflammatory protein-1α into the airways. This corresponded with an increase in myeloid DCs (mDCs) in the airways as well as increased expression of CD80 and CD86 on the mDCs. Plasmacytoid DCs in the lung were unchanged. Levels of IL-5, IL-17A and IL-6 cytokines in whole lung cultures were significantly increased 18 h following GC frass exposure demonstrating the early development of a mixed Th2/Th17 response. In addition, GC frass stimulated the production of IL-23, IL-6 and IL-12p70 from bone marrow-derived mDCs. Adoptive transfer of GC frass-pulsed mDCs induced airway reactivity, airway inflammation as well as eosinophilia and induced a strong Th2/Th17 response in the lung. MyD88-deficient bone marrow-derived mDCs did not respond to GC frass treatment, suggesting a functional Toll-like receptor pathway was important to induce the Th2/Th17 response. Together, our data show that GC frass activated the innate immune response to augment DC recruitment and activation of mDCs which promoted robust T cell-skewing cytokines and ultimately drive the development of airway inflammation.

  12. Digital music exposure reliably induces temporary threshold shift in normal-hearing human subjects.

    PubMed

    Le Prell, Colleen G; Dell, Shawna; Hensley, Brittany; Hall, James W; Campbell, Kathleen C M; Antonelli, Patrick J; Green, Glenn E; Miller, James M; Guire, Kenneth

    2012-01-01

    One of the challenges for evaluating new otoprotective agents for potential benefit in human populations is the availability of an established clinical paradigm with real-world relevance. These studies were explicitly designed to develop a real-world digital music exposure that reliably induces temporary threshold shift (TTS) in normal-hearing human subjects. Thirty-three subjects participated in studies that measured effects of digital music player use on hearing. Subjects selected either rock or pop music, which was then presented at 93 to 95 (n = 10), 98 to 100 (n = 11), or 100 to 102 (n = 12) dBA in-ear exposure level for a period of 4 hr. Audiograms and distortion product otoacoustic emissions (DPOAEs) were measured before and after music exposure. Postmusic tests were initiated 15 min, 1 hr 15 min, 2 hr 15 min, and 3 hr 15 min after the exposure ended. Additional tests were conducted the following day and 1 week later. Changes in thresholds after the lowest-level exposure were difficult to distinguish from test-retest variability; however, TTS was reliably detected after higher levels of sound exposure. Changes in audiometric thresholds had a "notch" configuration, with the largest changes observed at 4 kHz (mean = 6.3 ± 3.9 dB; range = 0-14 dB). Recovery was largely complete within the first 4 hr postexposure, and all subjects showed complete recovery of both thresholds and DPOAE measures when tested 1 week postexposure. These data provide insight into the variability of TTS induced by music-player use in a healthy, normal-hearing, young adult population, with music playlist, level, and duration carefully controlled. These data confirm the likelihood of temporary changes in auditory function after digital music-player use. Such data are essential for the development of a human clinical trial protocol that provides a highly powered design for evaluating novel therapeutics in human clinical trials. Care must be taken to fully inform potential subjects in

  13. Exposure to nickel oxide nanoparticles induces pulmonary inflammation through NLRP3 inflammasome activation in rats

    PubMed Central

    Cao, Zhengwang; Fang, Yiliang; Lu, Yonghui; Qian, Fenghua; Ma, Qinglong; He, Mingdi; Pi, Huifeng; Yu, Zhengping; Zhou, Zhou

    2016-01-01

    With recent advances in the manufacture and application of nickel oxide nanoparticles (NiONPs), concerns about their adverse effects on the respiratory system are increasing. However, the underlying cellular and molecular mechanisms of NiONP-induced pulmonary toxicity remain unclear. In this study, we focused on the impacts of NiONPs on pulmonary inflammation and investigated whether the NLRP3 inflammasome is involved in NiONP-induced pulmonary inflammation and injury. NiONP suspensions were administered by single intratracheal instillation to rats, and inflammatory responses were evaluated at 3 days, 7 days, or 28 days after treatment. NiONP exposure resulted in sustained pulmonary inflammation accompanied by inflammatory cell infiltration, alveolar proteinosis, and cytokine secretion. Expression of Nlrp3 was markedly upregulated by the NiONPs, which was accompanied by overexpression of the active form of caspase-1 (p20) and interleukin (IL)-1β secretion in vivo. NiONP-induced IL-1β secretion was partially prevented by co-treatment with a caspase-1 inhibitor in macrophages. Moreover, siRNA-mediated Nlrp3 knockdown completely attenuated NiONP-induced cytokine release and caspase-1 activity in macrophages in vitro. In addition, NiONP-induced NLRP3 inflammasome activation requires particle uptake and reactive oxygen species production. Collectively, our findings suggest that the NLRP3 inflammasome participates in NiONP-induced pulmonary inflammation and offer new strategies to combat the pulmonary toxicity induced by NiONPs. PMID:27524893

  14. Gestational exposure to yellow fever vaccine at different developmental stages induces behavioral alterations in the progeny.

    PubMed

    Marianno, P; Salles, M J S; Sonego, A B; Costa, G A; Galvão, T C; Lima, G Z; Moreira, E G

    2013-01-01

    The most effective method to prevent yellow fever and control the disease is a vaccine made with attenuated live virus. Due to the neurological tropism of the virus, preventive vaccination is not recommended for infants under 6 months and for pregnant women. However there is a paucity of data regarding the safety for pregnant women and there are no experimental studies investigating adverse effects to the offspring after maternal exposure to the vaccine. This study aimed to investigate, in mice, the effects of maternal exposure to the yellow fever vaccine at three different gestational ages on the physical and behavioral development of the offspring. Pregnant Swiss mice received a single subcutaneous injection of water for injection (control groups) or 2 log Plaque Forming Units (vaccine-treated groups) of the yellow fever vaccine on gestational days (GD) 5, 10 or 15. Neither maternal signs of toxicity nor alterations in physical development and reflex ontogeny of the offspring were observed in any of the groups. Data from behavioral evaluation indicated that yellow fever vaccine exposure induced motor hypoactivity in 22-day-old females independent of the day of exposure; and in 60-day-old male and female pups exposed at GD 10. Moreover, 22-day-old females also presented with a deficit in habituation memory. Altogether, these results indicate that in utero exposure to the yellow fever vaccine may induce behavioral alterations in the pups that may persist to adulthood in the absence of observed maternal toxicity or disruption of physical development milestones or reflex ontogeny. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Exposure to nicotine during periadolescence or early adulthood alters aversive and physiological effects induced by ethanol.

    PubMed

    Rinker, Jennifer A; Hutchison, Mary Anne; Chen, Scott A; Thorsell, Annika; Heilig, Markus; Riley, Anthony L

    2011-07-01

    The majority of smokers begin their habit during adolescence, which often precedes experimentation with alcohol. Interestingly, very little preclinical work has been done examining how exposure to nicotine during periadolescence impacts the affective properties of alcohol in adulthood. Understanding how periadolescent nicotine exposure influences the aversive effects of alcohol might help to explain why it becomes more acceptable to this preexposed population. Thus, Experiment 1 exposed male Sprague Dawley rats to either saline or nicotine (0.4mg/kg, IP) from postnatal days 34 to 43 (periadolescence) and then examined changes in the aversive effects of alcohol (0, 0.56, 1.0 and 1.8g/kg, IP) in adulthood using the conditioned taste aversion (CTA) design. Changes in blood alcohol concentration (BAC) as well as alcohol-induced hypothermia and locomotor suppression were also assessed. To determine if changes seen were specific to nicotine exposure during periadolescence, the procedures were replicated in adults (Experiment 2). Preexposure to nicotine during periadolescence attenuated the acquisition of the alcohol-induced CTAs (at 1.0g/kg) and the hypothermic effects of alcohol (1.0g/kg). Adult nicotine preexposure produced similar attenuation in alcohol's aversive (at 1.8g/kg) and hypothermic (1.8g/kg) effects. Neither adolescent nor adult nicotine preexposure altered BACs or alcohol-induced locomotor suppression. These results suggest that nicotine may alter the aversive and physiological effects of alcohol, regardless of the age at which exposure occurs, possibly increasing its overall reinforcing value and making it more likely to be consumed.

  16. Glutathione-S-transferase P protects against endothelial dysfunction induced by exposure to tobacco smoke.

    PubMed

    Conklin, Daniel J; Haberzettl, Petra; Prough, Russell A; Bhatnagar, Aruni

    2009-05-01

    Exposure to tobacco smoke impairs endothelium-dependent arterial dilation. Reactive constituents of cigarette smoke are metabolized and detoxified by glutathione-S-transferases (GSTs). Although polymorphisms in GST genes are associated with the risk of cancer in smokers, the role of these enzymes in regulating the cardiovascular effects of smoking has not been studied. The P isoform of GST (GSTP), which catalyzes the conjugation of electrophilic molecules in cigarette smoke such as acrolein, was expressed in high abundance in the mouse lung and aorta. Exposure to tobacco smoke for 3 days (5 h/day) decreased total plasma protein. These changes were exaggerated in GSTP(-/-) mice. Aortic rings isolated from tobacco smoke-exposed GSTP(-/-) mice showed greater attenuation of ACh-evoked relaxation than those from GSTP(+/+) mice. The lung, plasma, and aorta of mice exposed to tobacco smoke or acrolein (for 5 h) accumulated more acrolein-adducted proteins than those tissues of mice exposed to air, indicating that exposure to tobacco smoke results in the systemic delivery of acrolein. Relative to GSTP(+/+) mice, modification of some proteins by acrolein was increased in the aorta of GSTP(-/-) mice. Aortic rings prepared from GSTP(-/-) mice that inhaled acrolein (1 ppm, 5 h/day for 3 days) or those exposed to acrolein in an organ bath showed diminished ACh-induced arterial relaxation more strongly than GSTP(+/+) mice. Acrolein-induced endothelial dysfunction was prevented by pretreatment of the aorta with N-acetylcysteine. These results indicate that GSTP protects against the endothelial dysfunction induced by tobacco smoke exposure and that this protection may be related to the detoxification of acrolein or other related cigarette smoke constituents.

  17. [Effect of copper sulphate on the lung damage induced by chronic intermittent exposure to ozone].

    PubMed

    Oyarzún G, Manuel J; Sánchez R, Susan A; Dussaubat D, Nelson; Miller A, María E; González B, Sergio

    2017-01-01

    Ozone exposure could increase lung damage induced by airborne particulate matter. Particulate matter lung toxicity has been attributed to its metallic content. To evaluate the acute effect of intratracheal administration of copper sulfate (CuSO4) on rat lungs previously damaged by a chronic intermittent ozone exposure. Two-months-old male Sprague-Dawley rats were exposed to 0.5 ppm ozone four h per day, five days a week, during two months. CuSO4 was intratracheally instilled 20 h after ozone exposure. Controls breathed filtered air or were instilled with 0.9% NaCl or with CuSO4 or were only exposed to ozone. We evaluated lung histopathology. F2 isoprostanes were determined in plasma. Cell count, total proteins, γ glutamyl-transpeptidase (GGT) and alkaline phosphatases (AP) were determined in bronchoalveolar lavage fluid (BALF). Ozone increased total cell count, macrophages, proteins and AP in BALF (p < 0.05), and induced pulmonary neutrophil inflammation. CuSO4 plus air increased plasma F2 isoprostane levels and total cell count, neutrophils and proteins in BALF (p < 0.05). Histopathology showed foamy macrophages. Ozone plus CuSO4 exposed animals showed a neutrophil inflammatory lung response and an increase in total cell count, proteins, GGT and AP in BALF (p < 0.05). Foamy and pigmented alveolar macrophages were detected in all lungs of these animals (p < 0.001). Intratracheal instillation of a single dose of CuSO4 in rats previously subjected to a chronic and intermittent exposure to ozone induces a neutrophil pulmonary inflammatory response and cytoplasmic damage in macrophages.

  18. Exposure to Nicotine During Periadolescence or Early Adulthood Alters Aversive and Physiological Effects Induced by Ethanol

    PubMed Central

    Rinker, Jennifer A.; Hutchison, Mary Anne; Chen, Scott A.; Thorsell, Annika; Heilig, Markus; Riley, Anthony L.

    2011-01-01

    The majority of smokers begin their habit during adolescence, which often precedes experimentation with alcohol. Interestingly, very little preclinical work has been done examining how exposure to nicotine during periadolescence impacts the affective properties of alcohol in adulthood. Understanding how periadolescent nicotine exposure influences the aversive effects of alcohol might help to explain why it becomes more acceptable to this preexposed population. Thus, Experiment 1 exposed male Sprague Dawley rats to either saline or nicotine (0.4 mg/kg, IP) from postnatal day 34 to 43 (periadolescence) and then examined changes in the aversive effects of alcohol (0, 0.56, 1.0 and 1.8 g/kg, IP) in adulthood using the conditioned taste aversion (CTA) design. Changes in blood alcohol concentration (BAC) as well as alcohol-induced hypothermia and locomotor suppression were also assessed. To determine if changes seen were specific to nicotine exposure during periadolescence, the procedures were replicated in adults (Experiment 2). Preexposure to nicotine during periadolescence attenuated the acquisition of the alcohol-induced CTAs (at 1.0 g/kg) and the hypothermic effects of alcohol (1.0 g/kg). Adult nicotine preexposure produced similar attenuation in alcohol's aversive (at 1.8 g/kg) and hypothermic (1.8 g/kg) effects. Neither adolescent nor adult nicotine preexposure altered BACs or alcohol-induced locomotor suppression. These results suggest that nicotine can alter the aversive and physiological effects of alcohol, regardless of the age at which exposure occurs, possibly increasing its overall reinforcing value and making it more likely to be consumed. PMID:21420998

  19. Hyperactivity induced by prenatal BrdU exposure across several experimental conditions.

    PubMed

    Kuwagata, Makiko; Ogawa, Tetsuo; Muneoka, Katsumasa; Shioda, Seiji

    2011-12-01

    Behavioral results are sometimes not reproducible even in the positive controls of developmental neurotoxicity (DNT) tests. Effects of several factors on the results should be considered. In the present paper, we examined the effects of strain-, gender-, and test-condition differences on BrdU-induced hyperactivity. The results showed that BrdU-induced hyperactivity was reproducible in two rat strains (SD and F344 rats), rodent species (rat and mouse), and both sexes. When the level of background sound in a test room was increased, the hyperactivity was persistent, resulting in no effect of background sound on BrdU-induced hyperactivity. Thus, we have demonstrated that the BrdU-animal model is a useful positive control via prenatal exposure to validate the entire DNT test process.

  20. Allergic Responses Induced by the Immunomodulatory Effects of Nanomaterials upon Skin Exposure

    PubMed Central

    Yoshioka, Yasuo; Kuroda, Etsushi; Hirai, Toshiro; Tsutsumi, Yasuo; Ishii, Ken J.

    2017-01-01

    Over the past decade, a vast array of nanomaterials has been created through the development of nanotechnology. With the increasing application of these nanomaterials in various fields, such as foods, cosmetics, and medicines, there has been concern about their safety, that is, nanotoxicity. Therefore, there is an urgent need to collect information about the biological effects of nanomaterials so that we can exploit their potential benefits and design safer nanomaterials, while avoiding nanotoxicity as a result of inhalation or skin exposure. In particular, the immunomodulating effect of nanomaterials is one of most interesting aspects of nanotoxicity. However, the immunomodulating effects of nanomaterials through skin exposure have not been adequately discussed compared with the effects of inhalation exposure, because skin penetration by nanomaterials is thought to be extremely low under normal conditions. On the other hand, the immunomodulatory effects of nanomaterials via skin may cause severe problems for people with impaired skin barrier function, because some nanomaterials could penetrate the deep layers of their allergic or damaged skin. In addition, some studies, including ours, have shown that nanomaterials could exhibit significant immunomodulating effects even if they do not penetrate the skin. In this review, we summarize our current knowledge of the allergic responses induced by nanomaterials upon skin exposure. First, we discuss nanomaterial penetration of the intact or impaired skin barrier. Next, we describe the immunomodulating effects of nanomaterials, focusing on the sensitization potential of nanomaterials and the effects of co-exposure of nanomaterials with substances such as chemical sensitizers or allergens, on the onset of allergy, following skin exposure. Finally, we discuss the potential mechanisms underlying the immunomodulating effects of nanomaterials by describing the involvement of the protein corona in the interaction of

  1. Long-term changes in amphetamine-induced reinforcement and aversion in rats following exposure to 56Fe particle

    NASA Astrophysics Data System (ADS)

    Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.

    Exposing rats to heavy particles produces alterations in the functioning of dopaminergic neurons and in the behaviors that depend upon the integrity of the dopaminergic system. Two of these dopamine-dependent behaviors include amphetamine-induced reinforcement, measure using the conditioned place preference procedure, and amphetamine-induced reinforcement, measured using the conditioned place preference procedure, and amphetamine-induced aversion, measured using the conditioned taste aversion. Previous research has shown that exposing rats to 1.0 Gy of 1GeV/n 56Fe particles produced a disruption of an amphetamine-induced taste aversion 3 days following exposure, but produced an apparent enhancement of the aversion 112 days following exposure. The present experiments were designed to provide a further evaluation of these results by examining taste aversion learning 154 days following exposure to 1.0Gy 56Fe particles and to establish the convergent validity of the taste aversion results by looking at the effects of exposure on the establishment of an amphetamine-induced conditioned place preference 3, 7, and 16 weeks following irradiation. The taste aversion results failed to confirm the apparent enhancement of the amphetamine-induced CTA observed in the prior experiment. However, exposure to 56Fe particles prevented the acquisition of amphetamine-induced place preference at all three-time intervals. The results are interpreted as indicating that exposure to heavy particles can produce long-term changes in behavioral functioning.

  2. Long-term changes in amphetamine-induced reinforcement and aversion in rats following exposure to 56Fe particle

    NASA Technical Reports Server (NTRS)

    Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.

    2003-01-01

    Exposing rats to heavy particles produces alterations in the functioning of dopaminergic neurons and in the behaviors that depend upon the integrity of the dopaminergic system. Two of these dopamine-dependent behaviors include amphetamine-induced reinforcement, measure using the conditioned place preference procedure, and amphetamine-induced reinforcement, measured using the conditioned place preference procedure, and amphetamine-induced aversion, measured using the conditioned taste aversion. Previous research has shown that exposing rats to 1.0 Gy of 1GeV/n 56Fe particles produced a disruption of an amphetamine-induced taste aversion 3 days following exposure, but produced an apparent enhancement of the aversion 112 days following exposure. The present experiments were designed to provide a further evaluation of these results by examining taste aversion learning 154 days following exposure to 1.0 Gy 56Fe particles and to establish the convergent validity of the taste aversion results by looking at the effects of exposure on the establishment of an amphetamine-induced conditioned place preference 3, 7, and 16 weeks following irradiation. The taste aversion results failed to confirm the apparent enhancement of the amphetamine-induced CTA observed in the prior experiment. However, exposure to 56Fe particles prevented the acquisition of amphetamine-induced place preference at all three-time intervals. The results are interpreted as indicating that exposure to heavy particles can produce long-term changes in behavioral functioning. c2002 COSPAR. Published by Elsevier Science Ltd. All rights reserved.

  3. Long-term changes in amphetamine-induced reinforcement and aversion in rats following exposure to 56Fe particle

    NASA Technical Reports Server (NTRS)

    Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.

    2003-01-01

    Exposing rats to heavy particles produces alterations in the functioning of dopaminergic neurons and in the behaviors that depend upon the integrity of the dopaminergic system. Two of these dopamine-dependent behaviors include amphetamine-induced reinforcement, measure using the conditioned place preference procedure, and amphetamine-induced reinforcement, measured using the conditioned place preference procedure, and amphetamine-induced aversion, measured using the conditioned taste aversion. Previous research has shown that exposing rats to 1.0 Gy of 1GeV/n 56Fe particles produced a disruption of an amphetamine-induced taste aversion 3 days following exposure, but produced an apparent enhancement of the aversion 112 days following exposure. The present experiments were designed to provide a further evaluation of these results by examining taste aversion learning 154 days following exposure to 1.0 Gy 56Fe particles and to establish the convergent validity of the taste aversion results by looking at the effects of exposure on the establishment of an amphetamine-induced conditioned place preference 3, 7, and 16 weeks following irradiation. The taste aversion results failed to confirm the apparent enhancement of the amphetamine-induced CTA observed in the prior experiment. However, exposure to 56Fe particles prevented the acquisition of amphetamine-induced place preference at all three-time intervals. The results are interpreted as indicating that exposure to heavy particles can produce long-term changes in behavioral functioning. c2002 COSPAR. Published by Elsevier Science Ltd. All rights reserved.

  4. Human color vision deficits induced by accidental laser exposure and potential for long-term recovery

    NASA Astrophysics Data System (ADS)

    Zwick, Harry; Lund, Brian J.; Brown, Jeremiah, Jr.; Stuck, Bruce E.; Loveday, J.

    2003-06-01

    Purpose: To evaluate long term deficits in human color discrimination induced by accidental laser macular damage and assess potential for recovery of color vision deficits. Methods: Nine laser accident cases (Q-switched Neodymium) presenting initially with confined or vitreous macular hemorrhage were evaluated with the Farnsworth-Munsell 100 Hue test within 2 days to 3 months post exposure. Both total as well as partial errors in the blue/yellow (B/Y) and red/green (R/G) regions were assessed. Independent assessment of axis orientation and complexity were obtained via a Fourier series expansion of error scores. Comparisons of both total and partial B/Y and R/G errors were made with age matched normal subjects, idiopathic and juvenile onset macular holes. Confocal Scanning Laser Ophthalmoscopy and Optical Coherence Tomography characterized the presence of retinal traction, intraretinal scar, macular thickness and macular hole formation. Results: Comparison of exposed and non-exposed age matched individuals were significant (P<.001) for both total and partial errors. In four cases where macular injury ranged from mild scar to macular hole, color discrimination errors achieved normal levels in 1 to 12 months post exposure. A mild tritan axis, dominant B/Y ("blue/yellow") errors, and retinal traction were observed in a macular hole case. At 12 months post exposure, traction about the hole disappeared, and total and partial errors were normal. Where damage involved a greater degree of scarring, retinal traction and multiple injury sites, long term recovery of total and partial error recovery was retarded with complex axis makeup. Single exposures in the paramacula produced tritan axes, while multiple exposures within and external to the macula increased total and partial R/G ("red/green") error scores. Total errors increased when paramacular hole enlargement induced macular traction. Such hole formation produced significant increases in total errors, complex axis

  5. Genotoxicity Induced by Foetal and Infant Exposure to Magnetic Fields and Modulation of Ionising Radiation Effects

    PubMed Central

    Udroiu, Ion; Antoccia, Antonio; Tanzarella, Caterina; Giuliani, Livio; Pacchierotti, Francesca; Cordelli, Eugenia; Eleuteri, Patrizia; Villani, Paola; Sgura, Antonella

    2015-01-01

    Background Few studies have investigated the toxicity and genotoxicity of extremely low frequency magnetic fields (ELF-MF) during prenatal and neonatal development. These phases of life are characterized by cell proliferation and differentiation, which might make them sensitive to environmental stressors. Although in vitro evidences suggest that ELF-MF may modify the effects of ionizing radiation, no research has been conducted so far in vivo on the genotoxic effects of ELF-MF combined with X-rays. Aim and methods Aim of this study was to investigate in somatic and germ cells the effects of chronic ELF-MF exposure from mid gestation until weaning, and any possible modulation produced by ELF-MF exposure on ionizing radiation-induced damage. Mice were exposed to 50 Hz, 65 μT magnetic field, 24 hours/day, for a total of 30 days, starting from 12 days post-conception. Another group was irradiated with 1 Gy X-rays immediately before ELF-MF exposure, other groups were only X-irradiated or sham-exposed. Micronucleus test on blood erythrocytes was performed at multiple times from 1 to 140 days after birth. Additionally, 42 days after birth, genotoxic and cytotoxic effects on male germ cells were assessed by comet assay and flow cytometric analysis. Results ELF-MF exposure had no teratogenic effect and did not affect survival, growth and development. The micronucleus test indicated that ELF-MF induced a slight genotoxic damage only after the maximum exposure time and that this effect faded away in the months following the end of exposure. ELF-MF had no effects on ionizing radiation (IR)-induced genotoxicity in erythrocytes. Differently, ELF–MF appeared to modulate the response of male germ cells to X-rays with an impact on proliferation/differentiation processes. These results point to the importance of tissue specificity and development on the impact of ELF-MF on the early stages of life and indicate the need of further research on the molecular mechanisms underlying

  6. Neonatal Isoflurane Exposure Induces Neurocognitive Impairment and Abnormal Hippocampal Histone Acetylation in Mice

    PubMed Central

    Zhong, Tao; Guo, Qulian; Zou, Wangyuan; Zhu, Xiaoyan; Song, Zongbin; Sun, Bei; He, Xin; Yang, Yong

    2015-01-01

    Background Neonatal exposure to isoflurane may induce long-term memory impairment in mice. Histone acetylation is an important form of chromatin modification that regulates the transcription of genes required for memory formation. This study investigated whether neonatal isoflurane exposure-induced neurocognitive impairment is related to dysregulated histone acetylation in the hippocampus and whether it can be attenuated by the histone deacetylase (HDAC) inhibitor trichostatin A (TSA). Methods C57BL/6 mice were exposed to 0.75% isoflurane three times (each for 4 h) at postnatal days 7, 8, and 9. Contextual fear conditioning (CFC) was tested at 3 months after anesthesia administration. TSA was intraperitoneally injected 2 h before CFC training. Hippocampal histone acetylation levels were analyzed following CFC training. Levels of the neuronal activation and synaptic plasticity marker c-Fos were investigated at the same time point. Results Mice that were neonatally exposed to isoflurane showed significant memory impairment on CFC testing. These mice also exhibited dysregulated hippocampal H4K12 acetylation and decreased c-Fos expression following CFC training. TSA attenuated isoflurane-induced memory impairment and simultaneously increased histone acetylation and c-Fos levels in the hippocampal cornu ammonis (CA)1 area 1 h after CFC training. Conclusions Memory impairment induced by repeated neonatal exposure to isoflurane is associated with dysregulated histone H4K12 acetylation in the hippocampus, which probably affects downstream c-Fos gene expression following CFC training. The HDAC inhibitor TSA successfully rescued impaired contextual fear memory, presumably by promoting histone acetylation and histone acetylation-mediated gene expression. PMID:25928815

  7. Prenatal nicotine exposure changes natural and drug-induced reinforcement in adolescent male rats.

    PubMed

    Franke, Ryan M; Park, Minjung; Belluzzi, James D; Leslie, Frances M

    2008-06-01

    Clinical studies have demonstrated an increased incidence of substance misuse and obesity in adolescents whose mothers smoked during pregnancy. Although dopamine systems that mediate natural and drug-induced reinforcement have been shown in animal studies to be altered by gestational nicotine treatment, it is not clear whether there are concomitant changes in reinforcement sensitivity. To test whether prenatal nicotine exposure influences sensitivity to natural and drug rewards, timed pregnant rats were implanted with osmotic minipumps delivering saline or nicotine (3 mg/kg/day) from gestational day 4 to 18. Male offspring were tested as adolescents, on postnatal day 32, for operant responding maintained by sucrose pellets or i.v. cocaine (200 or 500 mug/kg per injection). Cocaine-induced stereotypy and c-fos mRNA expression in cortex and striatum were also examined. Complex changes in reward circuitry were observed in the offspring of nicotine-exposed dams. Nicotine-exposed adolescents did not self-administer the low dose of cocaine, but, at the higher dose, exhibited significantly greater cocaine intake and c-fos mRNA expression in nucleus accumbens than did controls. In contrast, control animals showed significantly greater drug-induced stereotypy at both cocaine doses. Operant responding maintained by sucrose was also influenced by gestational nicotine exposure. At a fixed ratio (FR) 1 schedule, although the number of pellets eaten by the two experimental groups was equivalent, more pellets were left uneaten by nicotine-exposed offspring. At FR2 and FR5 schedules, the responding maintained by sucrose pellets was lower in nicotine-exposed offspring. These findings suggest that nicotine exposure during gestation may induce changes in both natural and drug reward pathways.

  8. Chronic exposure to water-pipe smoke induces cardiovascular dysfunction in mice.

    PubMed

    Nemmar, Abderrahim; Al-Salam, Suhail; Yuvaraju, Priya; Beegam, Sumaya; Yasin, Javed; Ali, Badreldin H

    2017-02-01

    Water-pipe tobacco smoking is becoming prevalent in all over the world including Western countries. There are limited data on the cardiovascular effects of water-pipe smoke (WPS), in particular following chronic exposure. Here, we assessed the chronic cardiovascular effects of nose-only WPS exposure in C57BL/6 mice. The duration of the session was 30 minutes/day, 5 days/week for 6 consecutive months. Control mice were exposed to air. WPS significantly increased systolic blood pressure. The relative heart weight and plasma concentrations of troponin-I and B-type natriuretic peptide were increased in mice exposed to WPS. Arterial blood gas analysis showed that WPS caused a significant decrease in [Formula: see text] and an increase in [Formula: see text] WPS significantly shortened the thrombotic occlusion time in pial arterioles and venules and increased the number of circulating platelet. Cardiac lipid peroxidation, measured as thiobarbituric acid-reactive substances, was significantly increased, while superoxide dismutase activity, total nitric oxide activity, and glutathione concentration were reduced by WPS exposure. Likewise, immunohistochemical analysis of the heart revealed an increase in the expression of inducible nitric oxide synthase and cytochrome c by cardiomyocytes of WPS-exposed mice. Moreover, hearts of WPS-exposed mice showed the presence of focal interstitial fibrosis. WPS exposure significantly increased heart DNA damage assessed by Comet assay. We conclude that chronic nose-only exposure to WPS impairs cardiovascular homeostasis. Our findings provide evidence that long-term exposure to WPS is harmful to the cardiovascular system and supports interventions to control the spread of WPS, particularly amid youths.NEW & NOTEWORTHY No data are available on the chronic cardiovascular effects of water-pipe smoke (WPS). Our findings provide experimental evidence that chronic exposure to WPS increased blood pressure, relative heart weight, troponin I, and

  9. Locomotor damage and brain oxidative stress induced by lead exposure are attenuated by gallic acid treatment.

    PubMed

    Reckziegel, Patrícia; Dias, Verônica Tironi; Benvegnú, Dalila; Boufleur, Nardeli; Silva Barcelos, Raquel Cristine; Segat, Hecson Jesser; Pase, Camila Simonetti; Dos Santos, Clarissa Marques Moreira; Flores, Erico Marlon Moraes; Bürger, Marilise Escobar

    2011-05-30

    We investigated the antioxidant potential of gallic acid (GA), a natural compound found in vegetal sources, on the motor and oxidative damages induced by lead. Rats exposed to lead (50 mg/kg, i.p., once a day, 5 days) were treated with GA (13.5mg/kg, p.o.) or EDTA (110 mg/kg, i.p.) daily, for 3 days. Lead exposure decreased the locomotor and exploratory activities, reduced blood ALA-D activity, and increased brain catalase (CAT) activity without altering other antioxidant defenses. Brain oxidative stress (OS) estimated by lipid peroxidation (TBARS) and protein carbonyl were increased by lead. GA reversed the motor behavior parameters, the ALA-D activity, as well as the markers of OS changed by lead exposure. CAT activity remained high, possibly as a compensatory mechanism to eliminate hydroperoxides during lead poisoning. EDTA, a conventional chelating agent, was not beneficial on the lead-induced motor behavior and oxidative damages. Both GA (less) and EDTA (more) reduced the lead accumulation in brain tissue. Negative correlations were observed between the behavioral parameters and lipid peroxidation and the lead levels in brain tissue. In conclusion, GA may be an adjuvant in lead exposure, mainly by its antioxidant properties against the motor and oxidative damages resulting from such poisoning. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  10. Wood dust exposure induces cell transformation through EGFR-mediated OGG1 inhibition.

    PubMed

    Staffolani, Sara; Manzella, Nicola; Strafella, Elisabetta; Nocchi, Linda; Bracci, Massimo; Ciarapica, Veronica; Amati, Monica; Rubini, Corrado; Re, Massimo; Pugnaloni, Armanda; Pasquini, Ernesto; Tarchini, Paolo; Valentino, Matteo; Tomasetti, Marco; Santarelli, Lory

    2015-07-01

    A high risk of neoplastic transformation of nasal and paranasal sinuses mucosa is related to the occupational exposure to wood dust. However, the role of occupational exposures in the aetiology of the airway cancers remains largely unknown. Here, an in vitro model was performed to investigate the carcinogenic effect of wood dusts. Human bronchial epithelial cells were incubated with hard and soft wood dusts and the DNA damage and response to DNA damage evaluated. Wood dust exposure induced accumulation of oxidised DNA bases, which was associated with a delay in DNA repair activity. By exposing cells to wood dust at a prolonged time, wood dust-initiated cells were obtained. Initiated-cells were able to form colonies in soft agar, and to induce blood vessel formation. These cells showed extensive autophagy, reduced DNA repair, which was associated with reduced OGG1 expression and oxidised DNA base accumulation. These events were found related to the activation of EGFR/AKT/mTOR pathway, through phosphorylation and subsequent inactivation of tuberin. The persistence in the tissue of wood dusts, their repetitious binding with EGFR may continually trigger the activation switch, leading to chronic down-regulation of genes involved in DNA repair, leading to cell transformation and proliferation.

  11. Short-term cadmium exposure induces stress responses in frog (Pelophylax bergeri) skin organ culture.

    PubMed

    Simoncelli, Francesca; Belia, Silvia; Di Rosa, Ines; Paracucchi, Romina; Rossi, Roberta; La Porta, Gianandrea; Lucentini, Livia; Fagotti, Anna

    2015-12-01

    There have been a few studies on the negative effects of pollutants on amphibian skin, the first structural barrier that interacts with the environment and its potential contaminants. In this study an ex vivo skin organ culture from the amphibian Pelophylax bergeri was used to evaluate cell stress responses induced by short-term exposure to cadmium (Cd), a toxic heavy metal known to be an environmental hazard to both humans and wildlife. Histopathological studies were carried out on skin explants using light microscopy and changes in the expression of stress proteins, such as Metallothionein (MT) and Heat shock proteins (HSPs), were investigated by Real-time RT-PCR. Results revealed that amphibian skin reacts to Cd-induced stress by activating biological responses such as morphological alterations and dose- and time-dependent induction of Mt and Hsp70 mRNA expression, suggesting their potential role as biomarkers of exposure to Cd. This work provides a basis for a better understanding of the tissue-specific responses of amphibian skin as a target organ to Cd exposure and its in vitro use for testing potentially harmful substances present in the environment. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Metabolic and histopathological alterations in the marine bivalve Mytilus galloprovincialis induced by chronic exposure to acrylamide.

    PubMed

    Larguinho, Miguel; Cordeiro, Ana; Diniz, Mário S; Costa, Pedro M; Baptista, Pedro V

    2014-11-01

    Although the neurotoxic and genotoxic potential of acrylamide has been established in freshwater fish, the full breadth of the toxicological consequences induced by this xenobiotic has not yet been disclosed, particularly in aquatic invertebrates. To assess the effects of acrylamide on a bivalve model, the Mediterranean mussel (Mytilus galloprovincialis), two different setups were accomplished: 1) acute exposure to several concentrations of waterborne acrylamide to determine lethality thresholds of the substance and 2) chronic exposure to more reduced acrylamide concentrations to survey phases I and II metabolic endpoints and to perform a whole-body screening for histopathological alterations. Acute toxicity was low (LC50≈400mg/L). However, mussels were responsive to prolonged exposure to chronic concentrations of waterborne acrylamide (1-10mg/L), yielding a significant increase in lipid peroxidation plus EROD and GST activities. Still, total anti-oxidant capacity was not exceeded. In addition, no neurotoxic effects could be determined through acetylcholine esterase (AChE) activity. The findings suggest aryl-hydrocarbon receptor (Ahr)-dependent responses in mussels exposed to acrylamide, although reduced comparatively to vertebrates. No significant histological damage was found in digestive gland or gills but female gonads endured severe necrosis and oocyte atresia. Altogether, the results indicate that acrylamide may induce gonadotoxicity in mussels, although the subject should benefit from further research. Altogether, the findings suggest that the risk of acrylamide to aquatic animals, especially molluscs, may be underestimated. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Effect of Maternal Electroacupuncture on Perinatal Nicotine Exposure-Induced Lung Phenotype in Offspring.

    PubMed

    Ji, Bo; Zhao, Guo-Zhen; Sakurai, Reiko; Cao, Yu; Zhang, Zi-Jian; Wang, Dan; Yan, Ming-Na; Rehan, Virender K

    2016-08-01

    Pregnant women exposed to tobacco smoke predispose the offspring to many adverse consequences including an altered lung development and function. There is no effective therapeutic intervention to block the effects of smoke exposure on the developing lung. Clinical and animal studies demonstrate that acupuncture can modulate a variety of pathophysiological processes, including those involving the respiratory system; however, whether acupuncture affects the lung damage caused by perinatal smoke exposure is not known. To determine the effect of acupuncture on perinatal nicotine exposure on the developing lung, pregnant rat dams were administered (1) saline, (2) nicotine, or (3) nicotine + electroacupuncture (EA). Nicotine was administered (1 mg/kg subcutaneously) once a day and EA was applied to both "Zusanli" (ST 36) points. Both interventions were administered from gestational day 6 to postnatal day 21 (PND21), following which pups were sacrificed. Lungs, blood, and brain were collected to examine markers of lung injury, repair, and hypothalamic pituitary adrenal (HPA) axis. Concomitant EA application blocked nicotine-induced changes in lung morphology, lung peroxisome proliferator-activated receptor γ and wingless-int signaling, two key lung developmental signaling pathways, hypothalamic pituitary adrenal axis (hypothalamic corticotropic releasing hormone and lung glucocorticoid receptor levels), and plasma β-endorphin levels. Electroacupuncture blocks the nicotine-induced changes in lung developmental signaling pathways and the resultant myogenic lung phenotype, known to be present in the affected offspring. We conclude that EA is a promising novel intervention against the smoke exposed lung damage to the developing lung.

  14. Cat exposure induces both intra- and extracellular Hsp72: the role of adrenal hormones.

    PubMed

    Fleshner, Monika; Campisi, Jay; Amiri, Leila; Diamond, David M

    2004-10-01

    Heat-shock proteins (Hsp) play an important role in stress physiology. Exposure to a variety of stressors will induce intracellular Hsp72, and this induction is believed to be beneficial for cell survival. In contrast, Hsp72 released during stress (extracellular Hsp72; eHsp72) activates pro-inflammatory responses. Clearly, physical stressors such as heat, cold, H(2)O(2), intense exercise and tail shock will induce both intra- and extracellular Hsp72. The current study tested whether a psychological stressor, cat exposure, would also trigger this response. In addition, the potential role of adrenal hormones in the Hsp72 response was examined. Adult, male Sprague Dawley rats were either adrenalectomized (ADX) or sham operated. Ten days post-recovery, rats were exposed to either a cat with no physical contact or control procedures (n = 5-6/group) for 2 h. Levels of intracellular Hsp72 were measured in the brain (frontal cortex, hippocampus, hypothalamus, dorsal vagal complex) and pituitary (ELISA). Levels of eHsp72 (ELISA) and corticosterone (RIA) were measured from serum obtained at the end of the 2-h stress period. Rats that were exposed to a cat had elevated intracellular Hsp72 in hypothalamus and dorsal vagal complex, and elevated eHsp72 and corticosterone in serum. Both the intra- and extracellular Hsp72 responses were blocked or attenuated by ADX. This study demonstrates that cat exposure can stimulate the Hsp72 response and that adrenal hormones contribute to this response.

  15. Alterations induced by chronic lead exposure on the cells of circadian pacemaker of developing rats

    PubMed Central

    Rojas-Castañeda, Julio César; Vigueras-Villaseñor, Rosa María; Rojas, Patricia; Chávez-Saldaña, Margarita; Pérez, Oscar Gutiérrez; Montes, Sergio; Ríos, Camilo

    2011-01-01

    Lead (Pb) exposure alters the temporal organization of several physiological and behavioural processes in which the suprachiasmatic nucleus (SCN) of the hypothalamus plays a fundamental role. In this study, we evaluated the effects of chronic early Pb exposure (CePbe) on the morphology, cellular density and relative optical density (OD) in the cells of the SCN of male rats. Female Wistar rats were exposed during gestation and lactation to a Pb solution containing 320 ppm of Pb acetate through drinking water. After weaning, the pups were maintained with the same drinking water until sacrificed at 90 days of age. Pb levels in the blood, hypothalamus, hippocampus and prefrontal cortex were significantly increased in the experimental group. Chronic early Pb exposure induced a significant increase in the minor and major axes and somatic area of vasoactive intestinal polypeptide (VIP)- and vasopressin (VP)-immunoreactive neurons. The density of VIP-, VP- and glial fibrillary acidic protein (GFAP)-immunoreactive cells showed a significant decrease in the experimental group. OD analysis showed a significant increase in VIP neurons of the experimental group. The results showed that CePbe induced alterations in the cells of the SCN, as evidenced by modifications in soma morphology, cellular density and OD in circadian pacemaker cells. These findings provide a morphological and cellular basis for deficits in circadian rhythms documented in Pb-exposed animals. PMID:21324006

  16. In utero arsenic exposure induces early onset of atherosclerosis in ApoE−/− mice

    PubMed Central

    Srivastava, Sanjay; D’Souza, Stanley E.; Sen, Utpal; States, J. Christopher

    2007-01-01

    Consumption of arsenic contaminated drinking water has been linked to higher rates of coronary disease, stroke, and peripheral arterial disease. Recent evidence suggests that early life exposures may play a significant role in the onset of chronic adult diseases. To investigate the potential for in utero exposure to accelerate the onset of cardiovascular disease we exposed pregnant ApoE-knockout (ApoE−/−) mice to arsenic in their drinking water and examined the aortic trees of their male offspring for evidence of early disease 10 and 16 weeks after birth. Mice were maintained on normal chow after weaning. ApoE−/− mice are a commonly used model for atherogenesis and spontaneously develop atherosclerotic disease. Mice exposed to arsenic in utero showed a >2-fold increase in lesion formation in the aortic roots as well as the aortic arch compared to control mice at both 10 and 16 weeks of age. The mice exposed to arsenic also had a 20 – 40% decrease in total triglycerides, but no change in total cholesterol, phospholipids and total abundance of VLDL or HDL particles. Subfractionation of VLDL particles showed a decrease in large VLDL particles. In addition, the arsenic exposed mice showed a vasorelaxation defect in response to acetylcholine suggesting disturbance of endothelial cell signalling. These results indicate that in utero arsenic exposure induces an early onset of atherosclerosis in ApoE−/− mice without a hyperlipidemic diet and support the hypothesis that in utero arsenic exposure may be atherogenic in humans. PMID:17317095

  17. Gap states in pentacene thin film induced by inert gas exposure.

    PubMed

    Bussolotti, Fabio; Kera, Satoshi; Kudo, Kazuhiro; Kahn, Antoine; Ueno, Nobuo

    2013-06-28

    We studied gas-exposure effects on pentacene (Pn) films on SiO2 and Au(111) substrates by ultrahigh sensitivity photoelectron spectroscopy, which can detect the density of states of ∼10(16) states eV-1 cm-3 comparable to electrical measurements. The results show the striking effects for Pn/SiO2: exposure to inert gas (N2 and Ar) produces a sharp rise in gap states from ∼10(16) to ∼10(18) states eV-1 cm-3 and pushes the Fermi level closer to the valence band (0.15-0.17 eV), as does exposure to O2 (0.20 eV), while no such gas-exposure effect is observed for Pn/Au(111). The results demonstrate that these gap states originate from small imperfections in the Pn packing structure, which are induced by gas penetration into the film through the crystal grain boundaries.

  18. Developmental ethanol exposure-induced sleep fragmentation predicts adult cognitive impairment.

    PubMed

    Wilson, D A; Masiello, K; Lewin, M P; Hui, M; Smiley, J F; Saito, M

    2016-05-13

    Developmental ethanol (EtOH) exposure can lead to long-lasting cognitive impairment, hyperactivity, and emotional dysregulation among other problems. In healthy adults, sleep plays an important role in each of these behavioral manifestations. Here we explored circadian rhythms (activity, temperature) and slow-wave sleep (SWS) in adult mice that had received a single day of EtOH exposure on postnatal day 7 and saline littermate controls. We tested for correlations between slow-wave activity and both contextual fear conditioning and hyperactivity. Developmental EtOH resulted in adult hyperactivity within the home cage compared to controls but did not significantly modify circadian cycles in activity or temperature. It also resulted in reduced and fragmented SWS, including reduced slow-wave bout duration and increased slow-wave/fast-wave transitions over 24-h periods. In the same animals, developmental EtOH exposure also resulted in impaired contextual fear conditioning memory. The impairment in memory was significantly correlated with SWS fragmentation. Furthermore, EtOH-treated animals did not display a post-training modification in SWS which occurred in controls. In contrast to the memory impairment, sleep fragmentation was not correlated with the developmental EtOH-induced hyperactivity. Together these results suggest that disruption of SWS and its plasticity are a secondary contributor to a subset of developmental EtOH exposure's long-lasting consequences.

  19. Rat hippocampal alterations could underlie behavioral abnormalities induced by exposure to moderate noise levels.

    PubMed

    Uran, S L; Aon-Bertolino, M L; Caceres, L G; Capani, F; Guelman, L R

    2012-08-30

    Noise exposure is known to affect auditory structures in living organisms. However, it should not be ignored that many of the effects of noise are extra-auditory. Previous findings of our laboratory demonstrated that noise was able to induce behavioral alterations that are mainly related to the cerebellum (CE) and the hippocampus (HC). Therefore, the aim of this work was to reveal new data about the vulnerability of developing rat HC to moderate noise levels through the assessment of potential histological changes and hippocampal-related behavioral alterations. Male Wistar rats were exposed to noise (95-97 dB SPL, 2h daily) either for 1 day (acute noise exposure, ANE) or between postnatal days 15 and 30 (sub-acute noise exposure, SANE). Hippocampal histological evaluation as well as short (ST) and long term (LT) habituation and recognition memory assessments were performed. Results showed a mild disruption in the different hippocampal regions after ANE and SANE schemes, along with significant behavioral abnormalities. These data suggest that exposure of developing rats to noise levels of moderate intensity is able to trigger changes in the HC, an extra-auditory structure of the Central Nervous System (CNS), that could underlie the observed behavioral effects.

  20. Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome

    PubMed Central

    2012-01-01

    Background Induction and promotion of liver cancer by exposure to non-genotoxic carcinogens coincides with epigenetic perturbations, including specific changes in DNA methylation. Here we investigate the genome-wide dynamics of 5-hydroxymethylcytosine (5hmC) as a likely intermediate of 5-methylcytosine (5mC) demethylation in a DNA methylation reprogramming pathway. We use a rodent model of non-genotoxic carcinogen exposure using the drug phenobarbital. Results Exposure to phenobarbital results in dynamic and reciprocal changes to the 5mC/5hmC patterns over the promoter regions of a cohort of genes that are transcriptionally upregulated. This reprogramming of 5mC/5hmC coincides with characteristic changes in the histone marks H3K4me2, H3K27me3 and H3K36me3. Quantitative analysis of phenobarbital-induced genes that are involved in xenobiotic metabolism reveals that both DNA modifications are lost at the transcription start site, while there is a reciprocal relationship between increasing levels of 5hmC and loss of 5mC at regions immediately adjacent to core promoters. Conclusions Collectively, these experiments support the hypothesis that 5hmC is a potential intermediate in a demethylation pathway and reveal precise perturbations of the mouse liver DNA methylome and hydroxymethylome upon exposure to a rodent hepatocarcinogen. PMID:23034186

  1. Long-term nicotine exposure induces dysfunction of mouse endothelial progenitor cells

    PubMed Central

    Li, Wei; Du, Da-Yong; Liu, Yang; Jiang, Feng; Zhang, Pan; Li, Yun-Tian

    2017-01-01

    Endothelial progenitor cells (EPCs) have an important role in maintaining endothelial homeostasis. Previous studies reported that smoking has detrimental effects on EPCs; however, recent studies revealed that short-term nicotine exposure may benefit EPCs. As most smokers are exposed to nicotine over an extended time period, the present study aimed to investigate the long-term effects of nicotine on EPCs. Mice were administered nicotine orally for 1, 3 or 6 months. The mice exposed to nicotine for 1 month demonstrated increased EPC counts and telomerase activity and reduced cell senescence compared with control mice, consistent with previous reports. However, long-term nicotine exposure resulted in opposing effects on EPCs, causing decreased counts, functional impairment and reduced telomerase activity. Furthermore, the effects of nicotine exposure were correlated with changes in sirtuins type 1 (SIRT1) protein expression. The current study indicated that long-term nicotine exposure induces dysfunction and senescence of EPCs, which may be associated with impairment of telomerase activity through SIRT1 downregulation. The present results emphasize the necessity of smoking cessation to prevent dysfunction of EPCs. PMID:28123473

  2. Formaldehyde and co-exposure with benzene induce compensation of bone marrow and hematopoietic stem/progenitor cells in BALB/c mice during post-exposure period.

    PubMed

    Wei, Chenxi; Chen, Mouying; You, Huihui; Qiu, Feng; Wen, Huaxiao; Yuan, Junlin; Xiang, Shuanglin; Yang, Xu

    2017-06-01

    Formaldehyde (FA) is a human leukemogen. Since there is a latency period between initial FA exposure and the development of leukemia, the subsequent impact of FA on hematopoietic stem or progenitor cells (HSCs/HPCs) in post-exposure stage is crucial for a deep understanding of FA-induced hematotoxicity. BALB/c mice were exposed to 3mg/m(3) FA for 2weeks, mimicking occupational exposure, and were monitored for another 7days post-exposure. Meanwhile, we included benzene (BZ) as a positive control, separately and together with FA because co-exposure occurs frequently. After 7-day recovery, colonies of progenitors for CFU-GM and BFU-E, and nucleated bone marrow cells in FA-exposed mice were comparable to controls, although they were significantly reduced during exposure. Levels of reactive oxygen species (ROS) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in CFU-GM and BFU-E from FA-exposed mice were higher than controls, although the increase in 8-OHdG was not significant. Granulocyte-macrophage colony stimulating factor (GM-CSF) level in the FA group was lower than controls, but the expression level for the receptor was not upregulated. It suggests that HSCs/HPCs in FA-exposed mice respond to a small amount of GM-CSF and proliferate rapidly, which may cause a possible risk of expansion of abnormal stem/progenitor cell clones. FA co-exposure with BZ was more potent for promoting CFU-GM formation and inducing ROS in BFU-E and 8-OHdG in CFU-GM during the post-exposure period. The compensation of myeloid progenitors with elevated ROS and 8-OHdG may lead to a risk of transforming normal HSCs/HPCs to leukemic stem/progenitor cells. Thus, co-exposure may pose a greater leukemia risk. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Pulsed electromagnetic wave exposure induces ultrastructural damage and upregulated expression of heat shock protein 70 in the rat adenohypophysis.

    PubMed

    Cheng, Kang; Ren, Dong-Qing; Yi, Jun; Zhou, Xiao-Guang; Yang, Wen-Qing; Chen, Yong-Bin; Li, Yong-Qiang; Huang, Xiao-Feng; Zeng, Gui-Ying

    2015-08-01

    The aim of the present study was to investigate the ultrastructural damage and the expression of heat shock protein 70 (HSP70) in the rat adenohypophysis following pulsed electromagnetic wave (PEMW) exposure. The rats were randomly divided into four groups: Sham PEMW exposure, 1 x 10(4) pulses of PEMW exposure, 1 x 10(5) pulses of PEMW exposure and 3 x 10(5) pulses of PEMW exposure. Whole body radiation of 1 x 10(4) pulses, 1 x 10(5) pulses and 3 x 10(5) pulses of PEMW were delivered with a field strength of 100 kV/m. The rats in each group (n=6 in each) were sacrificed 12, 24, 48 and 96 h after PEMW exposure. Transmission electron microscopy was then used to detect the ultrastructural changes and immunocytochemistry was used to examine the expression of HSP70. Cellular damage, including mitochondrial vacuolation occurred as early as 12 h after PEMW exposure.More severe cellular damages, including cell degeneration and necrosis, occurred 24 and 48 h after PEMW exposure. The PEMW-induced cellular damage increased as the number of PEMW pulses increased. In addition, the expression of HSP70 significantly increased following PEMW exposure and peaked after 12 h. These findings suggested that PEMW induced ultrastructural damages in the rat adenohypophysis and that HSP70 may have contributed to the PEMW-induced adenohypophyseal damage.

  4. Ultrastructural changes in the lung following exposure to perfluoroisobutylene (PFIB) and potentiation of PFIB-induced lung injury by post-exposure exercise

    SciTech Connect

    Lehnert, B.E.; Stavert, D.M.

    1990-01-01

    The authors investigated the kinetics of development of the injurious effects of perfluoroisobutylene (PFIB) in the lower respiratory tract of the rat as a function of inhaled mass concentration. We additionally examined if exercise performed after exposure to PFIB can potentiate the severity of expression of PFIB-induced lung injury, while also assessing how PFIB exposure may result in reductions in work performance capacity. The severity of PFIB-induced lung injury was found to be directly proportional to inhaled PFIB mass concentration whereas the post-exposure kinetics of development of the injurious response was inversely proportional to the mass concentration of PFIB, with post-exposure latency periods prior to the onset of detectable injury increasing with decreasing inhaled mass concentration. Exercise was found to potentiate PFIB-induced lung injury only after pulmonary edema was demonstrably present using lung gravimetric and light histopathologic criteria, even though ultrastructural observations indicated significant cellular changes occur during the latency period. Our collective findings suggest that pre-existing permeability changes in the lung are a necessary prerequisite for post-exposure exercise to exert a potentiating effect. Reductions in work performance capacity occurred only after the latency period, and such reductions proportionately scaled with the severity of pulmonary edema. 9 refs., 5 figs.

  5. Long-term allergen exposure induces adipose tissue inflammation and circulatory system injury.

    PubMed

    Jung, Chien-Cheng; Su, Huey-Jen

    2016-05-01

    The purpose of this study was to study whether allergen exposure can induce inflammation and lower the anti-inflammation levels in serum and in adipose tissues, and further develop cardiovascular injury. Our data showed that heart rate was significantly higher in the OVA-challenged mice compared to control mice. Moreover, there were higher expressions of pro-inflammation genes in the OVA-challenged mice in adipose tissues, and the expressions of anti-inflammation genes were lower. The levels of inflammation mediators were associated in serum and adipose tissues. The level of circulatory injury lactate dehydrogenase was significantly associated with the levels of E-selectin, resistin and adiponectin in the serum. The hematoxylin and eosin and immunohistochemistry stains indicated the OVA-challenged mice had higher levels of inflammation. In summary, the current study demonstrated allergen exposure can cause cardiovascular injury, and inflammatory mediators in adipose tissues play an important role in the pathogenesis of cardiovascular injury.

  6. Prolonged exposure to insulin induces mitochondrion-derived oxidative stress through increasing mitochondrial cholesterol content in hepatocytes.

    PubMed

    Mei, Shuang; Gu, Haihua; Yang, Xuefeng; Guo, Huailan; Liu, Zhenqi; Cao, Wenhong

    2012-05-01

    We addressed the link between excessive exposure to insulin and mitochondrion-derived oxidative stress in this study and found that prolonged exposure to insulin increased mitochondrial cholesterol in cultured hepatocytes and in mice and stimulated production of reactive oxygen species (ROS) and decreased the reduced glutathione to glutathione disulfide ratio in cultured hepatocytes. Exposure of isolated hepatic mitochondria to cholesterol alone promoted ROS emission. The oxidative stress induced by the prolonged exposure to insulin was prevented by inhibition of cholesterol synthesis with simvastatin. We further found that prolonged exposure to insulin decreased mitochondrial membrane potential and the increased ROS production came from mitochondrial respiration complex I. Finally, we observed that prolonged exposure to insulin decreased mitochondrial membrane fluidity in a cholesterol synthesis-dependent manner. Together our results demonstrate that excess exposure to insulin causes mitochondrion-derived oxidative stress through cholesterol synthesis in hepatocytes.

  7. Vascular leakage induced by exposure to arsenic via increased production of NO, hydroxyl radical and peroxynitrite.

    PubMed

    Chen, Shih-Chieh; Chen, Wei-Chi

    2008-04-01

    Previous studies have shown that in situ exposure to arsenic induced increased vascular leakage. However, the underlying mechanism remains unclear. Reactive nitrogen and oxygen species such as nitric oxide (NO) and hydroxyl radical (OH(-)) are known to affect vascular permeability. Therefore, the goal of our present studies is to investigate the functional impact of the generation of NO or OH(-) on arsenic-induced vascular leakage. Vascular permeability changes were evaluated by means of Evans blue (EB) assay. Rats were anesthetized and intravenously injected with EB. Permeability changes were induced in back skin by intradermal injections of sodium arsenite mixed with NOS inhibitor: N(omega)-Nitro-L-arginine methyl ester (L-NAME) or aminoguanidine (AG) and OH(-) scavenger: 1,3 Dimethyl-2 thiourea (DMTU). Experiments were also performed to determine whether DMTU mixed with L-NAME would further inhibit arsenic-induced vascular leakage as compared with attenuation effects by either DMTU or L-NAME. One hour after administration, EB accumulated in the skin was extracted and quantified. Both L-NAME (0.02, 0.1 and 0.5 micromol/site) and DMTU (0.05, 0.2 and 1.2 micromol/site) inhibited the increase in vascular leakage induced by arsenite. However, only high dose (1 micromol/site) of AG significantly attenuated arsenite-induced vascular leakage. In contrast, neither D-NAME (0.02, 0.1 and 0.5 micromol/site) nor AG (0.04 and 0.2 micromol/site) attenuated increased vascular leakage by arsenic. DMTU mixed with L-NAME caused no further inhibition of arsenic-induced vascular leakage by either DMTU or L-NAME. The techniques of India ink and immunostaining were used to demonstrate both vascular labeling and nitrotyrosine staining in tissue treated with arsenic. L-NAME apparently reduced the density of leaky vessels and the levels of peroxynitrite staining induced by arsenite. These results suggest that NO, OH(-) and peroxynitrite play a role in increased vascular permeability

  8. Epicutaneous antigen exposure induces a Th17 response that drives airway inflammation after inhalation challenge

    PubMed Central

    He, Rui; Oyoshi, Michiko K.; Jin, Haoli; Geha, Raif S.

    2007-01-01

    IL-17 has been implicated in a number of inflammatory diseases, but the conditions of antigen exposure that drive the generation of Th17 responses have not been well defined. Epicutaneous (EC) immunization of mice with ovalbumin (OVA), which causes allergic skin inflammation with many characteristics of the skin lesions of atopic dermatitis, was found to also drive IL-17 expression in the skin. EC, but not i.p., immunization of mice with OVA drove the generation of IL-17-producing T cells in draining lymph nodes and spleen and increased serum IL-17 levels. OVA inhalation by EC-sensitized mice induced IL-17 and CXCL2 expression and neutrophil influx in the lung along with bronchial hyperreactivity, which were reversed by IL-17 blockade. Dendritic cells trafficking from skin to lymph nodes expressed more IL-23 and induced more IL-17 secretion by naïve T cells than splenic dendritic cells. This was inhibited by neutralizing IL-23 in vitro and by intradermal injection of anti-TGFβ neutralizing antibody in vivo. Our findings suggest that initial cutaneous exposure to antigens in patients with atopic dermatitis may selectively induce the production of IL-17, which, in turn, drives inflammation of their airways. PMID:17893340

  9. Characterization of skin inflammation induced by repeated exposure of toluene, xylene, and formaldehyde in mice.

    PubMed

    Saito, Asaka; Tanaka, Hiroyuki; Usuda, Haruki; Shibata, Tomonori; Higashi, Sayaka; Yamashita, Hirotaka; Inagaki, Naoki; Nagai, Hiroichi

    2011-06-01

    Volatile organic compounds (VOCs) are considered the main cause of sick building syndrome and they are likely to irritate the skin, eyes, and mucous membrane; however, the toxic threshold and the mechanisms of cutaneous reaction induced by long-time VOC exposure have not been clarified. In the present study, we investigated the effect of repeated painting of VOCs onto mouse skin. Various concentrations of toluene, xylene, and formaldehyde (FA) were applied once a week for 5 weeks. While FA solution (2-10%) induced remarkable ear swelling and caused evident infiltration of inflammatory cells, high concentrations of toluene and xylene (50 or 100%) evoked mild ear swelling and marginal inflammatory cell invasion. In addition, FA exposure markedly increased the expression of interleukin-4 (IL-4), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and transient receptor potential vanilloid-1 (TRPV-1) mRNAs in the ears and IL-4 and NT-3 mRNAs in the cervical lymph nodes. Furthermore, capsazepine, a TRPV-1 antagonist, significantly suppressed ear swelling caused by repeated painting of 5% FA. These findings demonstrate that FA has more potent irritancy against skin than toluene or xylene and suggest that the Th2 response, neurotrophins and TRPV-1 play important roles in FA-induced skin inflammation.

  10. Apoptosis induced by prolonged exposure to odorants in cultured cells from rat olfactory epithelium.

    PubMed

    Brauchi, Sebastian; Cea, Christian; Farias, Jorge G; Bacigalupo, Juan; Reyes, Juan G

    2006-08-04

    Multicellular organisms undergo programmed cell death (PCD) as a mechanism for tissue remodeling during development and tissue renewal throughout adult life. Overdose of some neuronal receptor agonists like glutamate can trigger a PCD process termed excitotoxicity in neurons of the central nervous system. Calcium has an important role in PCD processes, especially in excitotoxicity. Since the normal turnover of olfactory receptor neurons (ORNs) relies, at least in part, on an apoptotic mechanism and odor transduction in ORNs involves an increase in intracellular Ca2+ concentration ([Ca2+]i), we investigated the possibility that long-term exposures to odorants could trigger an excitotoxic process in olfactory epithelial cells (EC). We used single-cell [Ca2+]i determinations and fluorescence microscopy techniques to study the effects of sustained odorant exposures in olfactory EC in primary culture. Induction of PCD was evaluated successively by three independent criteria: (1) measurements of DNA fragmentation, (2) translocation of phosphatidylserine to the external leaflet of the plasma membrane, and (3) caspase-3 activation. Our results support the notion of an odorant-induced PCD in olfactory EC. This odorant-induced PCD was prevented by LY83583, an odorant response inhibitor, suggesting that ORNs are the main epithelial cell population undergoing odorant-induced PCD.

  11. Effect of ozone exposure on antigen-induced airway hyperresponsiveness in guinea pigs

    SciTech Connect

    Vargas, M.H.; Segura, P.; Campos, M.G.; Hong, E.; Montano, L.M.

    1994-12-31

    Airway hyperresponsiveness can be induced by several stimuli including antigen and ozone, both of which may be present in the air of polluted cities. Though the effect of ozone on the bronchoconstrictor response to antigen has been well described, the combined effect of these stimuli on airway hyperresponsiveness has not yet been studied. Sensitized guinea pigs with or without ozone exposure for 1 h at 3 ppm, 18 h prior to study, were challenged with a dose-response curve to histamine (0.01-1.8 {mu}g/kg, iv), and then by a second histamine dose-response curve 1 h later. Airway responses were measured as the increase in pulmonary insufflation pressure. In sensitized guinea pigs, the histamine ED50 significantly decreased after antigen challenge, demonstrating the development of airway hyperresponsiveness. Sensitized guinea pigs exposed to ozone showed airway hyperresponsiveness to histamine when compared with nonexposed animals, and such hyperresponsiveness was further enhanced after antigen challenge. We conclude that in this guinea pig model of acute allergic bronchoconstriction both antigen challenge and ozone induce airway hyperresponsiveness, while ozone exposure does not modify the development of antigen-induced hyperresponsiveness. 25 refs., 1 fig., 1 tab.

  12. Propolis prevents hepatorenal injury induced by chronic exposure to carbon tetrachloride.

    PubMed

    Bhadauria, Monika

    2012-01-01

    Carbon tetrachloride (CCl(4)) is a well-known hepatotoxicant, and its exposure induces hepatorenal injury via oxidative stress and biochemical alterations. This study had been conducted to confirm the protective role of propolis extract on CCl(4)-induced hepatorenal oxidative stress and resultant injury. Propolis extracts collected from Gwalior district and 24 female Sprague Dawley rats were used for experiment. Animals were exposed to CCl(4) (0.15 mL/kg, i.p.) for 12 weeks (5 days/week) followed by treatment with propolis extract (200 mg/kg, p.o.) for consecutive 2 weeks. CCl(4) exposure significantly depleted blood sugar and hemoglobin level and raised the level of transaminases, alkaline phosphatase, lactate dehydrogenase, protein, urea, albumin, bilirubin, creatinine, triglycerides, and cholesterol in serum. Lipid peroxidation was enhanced, whereas GSH was decreased significantly in liver and kidney in CCl(4)-intoxicated group. Ethanolic extract of propolis successfully prevented these alterations in experimental animals. Activities of catalase, adenosine triphosphatase, glucose-6-phosphatase, acid, and alkaline phosphatase were also maintained towards normal with propolis therapy. Light microscopical studies showed considerable protection in liver and kidney with propolis treatment, thus, substantiated biochemical observations. This study confirmed hepatoprotective potential of propolis extract against chronic injury induced by CCl(4) by regulating antioxidative defense activities.

  13. Chronic Exposure to Tributyltin Induces Brain Functional Damage in Juvenile Common Carp (Cyprinus carpio)

    PubMed Central

    Li, Zhi-Hua; Li, Ping; Shi, Ze-Chao

    2015-01-01

    The aim of the present study was to investigate the effect of Tributyltin (TBT) on brain function and neurotoxicity of freshwater teleost. The effects of long-term exposure to TBT on antioxidant related indices (MDA, malondialdehyde; SOD, superoxide dismutase; CAT, catalase; GR, glutathione reductase; GPx, glutathione peroxidase), Na+-K+-ATPase and neurological parameters (AChE, acetylcholinesterase; MAO, monoamine oxidase; NO, nitric oxide) in the brain of common carp were evaluated. Fish were exposed to sublethal concentrations of TBT (75 ng/L, 0.75 μg/L and 7.5 μg/L) for 15, 30, and 60 days. Based on the results, a low level and short-term TBT-induced stress could not induce the notable responses of the fish brain, but long-term exposure (more than 15 days) to TBT could lead to obvious physiological-biochemical responses (based on the measured parameters). The results also strongly indicated that neurotoxicity of TBT to fish. Thus, the measured physiological responses in fish brain could provide useful information to better understand the mechanisms of TBT-induced bio-toxicity. PMID:25879203

  14. Cold exposure impairs dark-pulse capacity to induce REM sleep in the albino rat.

    PubMed

    Baracchi, Francesca; Zamboni, Giovanni; Cerri, Matteo; Del Sindaco, Elide; Dentico, Daniela; Jones, Christine Ann; Luppi, Marco; Perez, Emanuele; Amici, Roberto

    2008-06-01

    In the albino rat, a REM sleep (REMS) onset can be induced with a high probability and a short latency when the light is suddenly turned off (dark pulse, DP) during non-REM sleep (NREMS). The aim of this study was to investigate to what extent DP delivery could overcome the integrative thermoregulatory mechanisms that depress REMS occurrence during exposure to low ambient temperature (Ta). To this aim, the efficiency of a non-rhythmical repetitive DP (3 min each) delivery during the first 6-h light period of a 12 h:12 h light-dark cycle in inducing REMS was studied in the rat, through the analysis of electroencephalogram, electrocardiogram, hypothalamic temperature and motor activity at different Tas. The results showed that DP delivery triggers a transition from NREMS to REMS comparable to that which occurs spontaneously. However, the efficiency of DP delivery in inducing REMS was reduced during cold exposure to an extent comparable with that observed in spontaneous REMS occurrence. Such impairment was associated with low Delta activity and high sympathetic tone when DPs were delivered. Repetitive DP administration increased REMS amount during the delivery period and a subsequent negative REMS rebound was observed. In conclusion, DP delivery did not overcome the integrative thermoregulatory mechanisms that depress REMS in the cold. These results underline the crucial physiological meaning of the mutual exclusion of thermoregulatory activation and REMS occurrence, and support the hypothesis that the suspension of the central control of body temperature is a prerequisite for REMS occurrence.

  15. Exposure to tobacco-derived materials induces overproduction of secreted proteinases in mast cells

    SciTech Connect

    Small-Howard, Andrea; Turner, Helen . E-mail: hturner@queens.org

    2005-04-15

    Mast cells reside at interfaces with the environment, including the mucosa of the respiratory and gastrointestinal tracts. This localization exposes mast cells to inhaled, or ingested, environmental challenges. In the airways of smokers, resident immune cells will be in contact with the condensed components of cigarette smoke. Mast cells are of particular interest due to their ability to promote airway remodeling and mucus hypersecretion. Clinical data show increased levels of mast cell-secreted tryptase and increased numbers of degranulated mast cells in the lavage and bronchial tissue of smokers. Since mast cell-secreted proteinases (MCPTs), including tryptases, contribute to pathological airway remodeling, we investigated the relationship between mast cell proteinases and smoke exposure. We exposed a mast cell line to cigarette smoke condensate (CSC). We show that CSC exposure increases MCPT levels in mast cells using an assay for tryptase-type MCPT activity. We hypothesized that this increase in MCPT activity reflects a CSC-induced increase in the cytosolic pool of proteinase molecules, via stimulation of MCPT transcription. Transcript array data suggested that mRNA changes in response to CSC were limited in number and peaked after 3 h of CSC exposure. However, we noted marked transcriptional regulation of several MCPT genes. CSC-induced changes in the mRNA levels for MCPTs were confirmed using quantitative RT-PCR. Taken together, our data suggest that chronic exposure to cigarette smoke up-regulates MCPT levels in mast cells at both the protein and the mRNA level. We suggest that the pathological airway remodeling that has been described in clinical studies of smoke inhalation may be attributable to MCPT overproduction in vivo.

  16. Bisphenol a induces steatosis in HepaRG cells using a model of perinatal exposure.

    PubMed

    Bucher, Simon; Jalili, Pégah; Le Guillou, Dounia; Begriche, Karima; Rondel, Karine; Martinais, Sophie; Zalko, Daniel; Corlu, Anne; Robin, Marie-Anne; Fromenty, Bernard

    2017-03-01

    Human exposure to bisphenol A (BPA) could favor obesity and related metabolic disorders such as hepatic steatosis. Investigations in rodents have shown that these deleterious effects are observed not only when BPA is administered during the adult life but also with different protocols of perinatal exposure. Whether perinatal BPA exposure could pose a risk in human is currently unknown, and thus appropriate in vitro models could be important to tackle this major issue. Accordingly, we determined whether long-term BPA treatment could induce steatosis in human HepaRG cells by using a protocol mimicking perinatal exposure. To this end, the kinetics of expression of seven proteins differentially expressed during liver development was determined during a 4-week period of cell culture required for proliferation and differentiation. By analogy with data reported in rodents and humans, our results indicated that the period of cell culture around day 15 and day 18 after seeding could be considered as the "natal" period. Consequently, HepaRG cells were treated for 3 weeks with BPA (from 0.2 to 2000 nM), with a treatment starting during the proliferating period. BPA was able to induce steatosis with a nonmonotonic dose response profile, with significant effects on neutral lipids and triglycerides observed for the 2 nM concentration. However, the expression of many enzymes involved in lipid and carbohydrate homeostasis was unchanged in exposed HepaRG cells. The expression of other potential BPA targets and enzymes involved in BPA biotransformation was also determined, giving answers as well as new questions regarding the mechanisms of action of BPA. Hence, HepaRG cells provide a valuable model that can prove useful for the toxicological assessment of endocrine disruptors on hepatic metabolisms, in particular in the developing liver. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1024-1036, 2017. © 2016 Wiley Periodicals, Inc.

  17. Clarithromycin ameliorates pulmonary inflammation induced by short term cigarette smoke exposure in mice.

    PubMed

    Nakamura, Masuo; Wada, Hiroo; Honda, Kojiro; Nakamoto, Keitaro; Inui, Toshiya; Sada, Mitsuru; Watanabe, Masato; Takata, Saori; Yokoyama, Takuma; Saraya, Takeshi; Kurai, Daisuke; Ishii, Haruyuki; Goto, Hajime; Kamma, Hiroshi; Takizawa, Hajime

    2015-12-01

    Cigarette smoking is considered to be one of major causes of acute worsening of asthma as well as chronic obstructive pulmonary disease (COPD). Macrolide antibiotics have been reported to reduce the risk of exacerbations of COPD, and possibly neutrophilic asthma. However, the effect of clarithromycin (CAM) on pulmonary inflammation caused by short term exposure to cigarette smoke still remains to be investigated. C57BL/6J female mice were daily exposed to tobacco smoke using a tobacco smoke exposure system, or clean air for 8 days, while simultaneously treated with either oral CAM or vehicles. Twenty four hours after the last exposure, mice were anaesthetized and sacrificed, and bronchoalveolar lavage (BAL) fluids were collected. Cellular responses in BAL fluids were evaluated. Levels of cytokine mRNA in the lung tissues were measured by quantitative RT-PCR. Paraffin-embedded lung tissues were evaluated to quantitate degree of neutrophil infiltration. The numbers of total cells, macrophages and neutrophils in the BAL fluid of smoke-exposed mice were significantly increased as compared to clean air group. These changes were significantly ameliorated in CAM-treated mice. The lung morphological analysis confirmed decrease of neutrophils by CAM treatment. Studies by quantitative PCR demonstrated CAM treatment significantly reduced lung expression levels of IL-17A, keratinocyte-derived chemokine (KC), granulocyte-macrophage colony stimulating factor (GM-CSF) and MMP-9 induced by cigarette smoke. We demonstrate that CAM administration resolves enhanced pulmonary inflammation induced by short term cigarette smoke exposure in mice. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Exposure of Allium cepa root cells to zidovudine or nevirapine induces cytogenotoxic changes.

    PubMed

    Onwuamah, Chika K; Ekama, Sabdat O; Audu, Rosemary A; Ezechi, Oliver C; Poirier, Miriam C; Odeigah, Peter G C

    2014-01-01

    Antiretroviral drugs have proved useful in the clinical management of HIV-infected persons, though there are concerns about the effects of exposure to these DNA-reactive drugs. We investigated the potential of the plant model Allium cepa root tip assay to demonstrate the cytogenotoxicity of zidovudine and nevirapine and as a replace-reduce-refine programme amenable to resource-poor research settings. Cells mitotic index were determined in squashed root cells from Allium cepa bulbs exposed to zidovudine or nevirapine for 48 hr. The concentration of zidovudine and nevirapine inhibiting 50% root growth after 96 hr exposure was 65.0 µM and 92.5 µM respectively. Root length of all antiretroviral-exposed roots after 96 hr exposure was significantly shorter than the unexposed roots while additional root growth during a subsequent 48 hr recovery period in the absence of drug was not significantly different. By ANOVA, there was a significant association between percentage of cells in mitosis and zidovudine dose (p=0.004), but not nevirapine dose (p=0.68). Chromosomal aberrations such as sticky chromosomes, chromatin bridges, multipolar mitoses and binucleated cells were observed in root cells exposed to zidovudine and nevirapine for 48 hr. The most notable chromosomal aberration was drug-related increases in sticky chromosomes. Overall, the study showed inhibition in root length growth, changes in the mitotic index, and the induction of chromosomal aberrations in Allium bulbs treated for 96 hr or 48 hr with zidovudine and nevirapine. The study reveals generalized cytogenotoxic damage induced by exposure to zidovudine and nevirapine, and further show that the two compounds differ in their effects on mitosis and the types of chromosomal aberrations induced.

  19. Antioxidant loading reduces oxidative stress induced by high-energy impulse noise (blast) exposure.

    PubMed

    Elsayed, N M; Armstrong, K L; William, M T; Cooper, M F

    2000-11-30

    Detonation of explosives, firing of large caliber weapons and occupational explosions, professional or accidental, produce high-energy impulse noise (blast) waves characterized by a rapid rise in atmospheric pressure (overpressure) followed by gradual decay to ambient level. Exposure to blast waves causes injury, predominantly to the hollow organs such as ears and lungs. We have previously reported that blast exposure can induce free radical-mediated oxidative stress in the lung characterized by antioxidant depletion, lipid peroxidation, and hemoglobin (Hb) oxidation. In this study, we examined whether pre-loading, adequately fed rats, with pharmacological doses of antioxidants would reduce the response to blast. Sprague-Dawley rats weighing 300-350 g were loaded with either 800 IU vitamin E (VE), 1000 mg vitamin C (VC) or 25 mg lipoic acid (LA) for 3 consecutive days by gavage before exposure to blast. Both VE, and LA were dissolved in 2 ml corn oil, but VC in 2 ml water. After the 3-day antioxidant loading, the rats were divided into six groups (five rats per group), deeply anesthetized with sodium pentobarbital (60 mg/kg body weight), then exposed to a low-level blast (62+/-2 kPa peak pressure and 5 ms duration). A matched number of groups were sham exposed and served as controls. One hour after exposure, all rats were euthanized then blood, and lung tissue was analyzed. We found that antioxidant loading resulted in restored Hb oxygenation, and reduced lipid peroxidation. Lung tissue VE content was elevated after loading but VC did not change possibly due to their different bioavailability and saturation kinetics. These observations, suggest that brief antioxidant loading with pharmacological doses can reduce blast-induced oxidative stress, and may have occupational and clinical implications.

  20. ADAM17 Inhibitors Attenuate Corneal Epithelial Detachment Induced by Mustard Exposure.

    PubMed

    DeSantis-Rodrigues, Andrea; Chang, Yoke-Chen; Hahn, Rita A; Po, Iris P; Zhou, Peihong; Lacey, C Jeffrey; Pillai, Abhilash; C Young, Sherri; Flowers, Robert A; Gallo, Michael A; Laskin, Jeffrey D; Gerecke, Donald R; Svoboda, Kathy K H; Heindel, Ned D; Gordon, Marion K

    2016-04-01

    Sulfur mustard, nitrogen mustard (NM), and 2-chloroethyl ethyl sulfide all cause corneal injury with epithelial-stromal separation, differing only by degree. Injury can resolve in a few weeks or develop into chronic corneal problems. These vesicants induce microbullae at the epithelial-stromal junction, which is partially caused by cleavage of transmembranous hemidesmosomal collagen XVII, a component anchoring the epithelium to the stroma. ADAM17 is an enzyme involved in wound healing and is able to cleave collagen XVII. The activity of ADAM17 was inhibited in vesicant-exposed corneas by four different hydroxamates, to evaluate their therapeutic potential when applied 2 hours after exposure, thereby allowing ADAM17 to perform its early steps in wound healing. Rabbit corneal organ cultures exposed to NM for 2 hours were washed, then incubated at 37°C for 22 hours, with or without one of the four hydroxamates (dose range, 0.3-100 nmol in 20 μL, applied four times). Corneas were analyzed by light and immunofluorescence microscopy, and ADAM17 activity assays. Nitrogen mustard-induced corneal injury showed significant activation of ADAM17 levels accompanying epithelial-stromal detachment. Corneas treated with hydroxamates starting 2 hours post exposure showed a dose-dependent ADAM17 activity inhibition up to concentrations of 3 nmol. Of the four hydroxamates, NDH4417 (N-octyl-N-hydroxy-2-[4-hydroxy-3-methoxyphenyl] acetamide) was most effective for inhibiting ADAM17 and retaining epithelial-stromal attachment. Mustard exposure leads to corneal epithelial sloughing caused, in part, by the activation of ADAM17 at the epithelial-stromal junction. Select hydroxamate compounds applied 2 hours after NM exposure mitigated epithelial-stromal separation.

  1. ADAM17 Inhibitors Attenuate Corneal Epithelial Detachment Induced by Mustard Exposure

    PubMed Central

    DeSantis-Rodrigues, Andrea; Chang, Yoke-Chen; A. Hahn, Rita; P. Po, Iris; Zhou, Peihong; Lacey, C. Jeffrey; Pillai, Abhilash; C. Young, Sherri; A. Flowers II, Robert; A. Gallo, Michael; D. Laskin, Jeffrey; R. Gerecke, Donald; K. H. Svoboda, Kathy; D. Heindel, Ned; Gordon, Marion K.

    2016-01-01

    Purpose Sulfur mustard, nitrogen mustard (NM), and 2-chloroethyl ethyl sulfide all cause corneal injury with epithelial–stromal separation, differing only by degree. Injury can resolve in a few weeks or develop into chronic corneal problems. These vesicants induce microbullae at the epithelial–stromal junction, which is partially caused by cleavage of transmembranous hemidesmosomal collagen XVII, a component anchoring the epithelium to the stroma. ADAM17 is an enzyme involved in wound healing and is able to cleave collagen XVII. The activity of ADAM17 was inhibited in vesicant-exposed corneas by four different hydroxamates, to evaluate their therapeutic potential when applied 2 hours after exposure, thereby allowing ADAM17 to perform its early steps in wound healing. Methods Rabbit corneal organ cultures exposed to NM for 2 hours were washed, then incubated at 37°C for 22 hours, with or without one of the four hydroxamates (dose range, 0.3–100 nmol in 20 μL, applied four times). Corneas were analyzed by light and immunofluorescence microscopy, and ADAM17 activity assays. Results Nitrogen mustard–induced corneal injury showed significant activation of ADAM17 levels accompanying epithelial–stromal detachment. Corneas treated with hydroxamates starting 2 hours post exposure showed a dose-dependent ADAM17 activity inhibition up to concentrations of 3 nmol. Of the four hydroxamates, NDH4417 (N-octyl-N-hydroxy-2-[4-hydroxy-3-methoxyphenyl] acetamide) was most effective for inhibiting ADAM17 and retaining epithelial–stromal attachment. Conclusions Mustard exposure leads to corneal epithelial sloughing caused, in part, by the activation of ADAM17 at the epithelial–stromal junction. Select hydroxamate compounds applied 2 hours after NM exposure mitigated epithelial–stromal separation. PMID:27058125

  2. Exposure of Allium cepa Root Cells to Zidovudine or Nevirapine Induces Cytogenotoxic Changes

    PubMed Central

    Onwuamah, Chika K.; Ekama, Sabdat O.; Audu, Rosemary A.; Ezechi, Oliver C.; Poirier, Miriam C.; Odeigah, Peter G C.

    2014-01-01

    Antiretroviral drugs have proved useful in the clinical management of HIV-infected persons, though there are concerns about the effects of exposure to these DNA-reactive drugs. We investigated the potential of the plant model Allium cepa root tip assay to demonstrate the cytogenotoxicity of zidovudine and nevirapine and as a replace-reduce-refine programme amenable to resource–poor research settings. Cells mitotic index were determined in squashed root cells from Allium cepa bulbs exposed to zidovudine or nevirapine for 48 hr. The concentration of zidovudine and nevirapine inhibiting 50% root growth after 96 hr exposure was 65.0 µM and 92.5 µM respectively. Root length of all antiretroviral-exposed roots after 96 hr exposure was significantly shorter than the unexposed roots while additional root growth during a subsequent 48 hr recovery period in the absence of drug was not significantly different. By ANOVA, there was a significant association between percentage of cells in mitosis and zidovudine dose (p = 0.004), but not nevirapine dose (p = 0.68). Chromosomal aberrations such as sticky chromosomes, chromatin bridges, multipolar mitoses and binucleated cells were observed in root cells exposed to zidovudine and nevirapine for 48 hr. The most notable chromosomal aberration was drug-related increases in sticky chromosomes. Overall, the study showed inhibition in root length growth, changes in the mitotic index, and the induction of chromosomal aberrations in Allium bulbs treated for 96 hr or 48 hr with zidovudine and nevirapine. The study reveals generalized cytogenotoxic damage induced by exposure to zidovudine and nevirapine, and further show that the two compounds differ in their effects on mitosis and the types of chromosomal aberrations induced. PMID:24599327

  3. Hypoxia-induced pulmonary arterial hypertension augments lung injury and airway reactivity caused by ozone exposure.

    PubMed

    Zychowski, Katherine E; Lucas, Selita N; Sanchez, Bethany; Herbert, Guy; Campen, Matthew J

    2016-08-15

    Ozone (O3)-related cardiorespiratory effects are a growing public health concern. Ground level O3 can exacerbate pre-existing respiratory conditions; however, research regarding therapeutic interventions to reduce O3-induced lung injury is limited. In patients with chronic obstructive pulmonary disease, hypoxia-associated pulmonary hypertension (HPH) is a frequent comorbidity that is difficult to treat clinically, yet associated with increased mortality and frequency of exacerbations. In this study, we hypothesized that established HPH would confer vulnerability to acute O3 pulmonary toxicity. Additionally, we tested whether improvement of pulmonary endothelial barrier integrity via rho-kinase inhibition could mitigate pulmonary inflammation and injury. To determine if O3 exacerbated HPH, male C57BL/6 mice were subject to either 3 weeks continuous normoxia (20.9% O2) or hypoxia (10.0% O2), followed by a 4-h exposure to either 1ppm O3 or filtered air (FA). As an additional experimental intervention fasudil (20mg/kg) was administered intraperitoneally prior to and after O3 exposures. As expected, hypoxia significantly increased right ventricular pressure and hypertrophy. O3 exposure in normoxic mice caused lung inflammation but not injury, as indicated by increased cellularity and edema in the lung. However, in hypoxic mice, O3 exposure led to increased inflammation and edema, along with a profound increase in airway hyperresponsiveness to methacholine. Fasudil administration resulted in reduced O3-induced lung injury via the enhancement of pulmonary endothelial barrier integrity. These results indicate that increased pulmonary vascular pressure may enhance lung injury, inflammation and edema when exposed to pollutants, and that enhancement of pulmonary endothelial barrier integrity may alleviate such vulnerability.

  4. Effects of cold environment exposure and cold acclimatization on exercise-induced salivary cortisol response.

    PubMed

    Izawa, Shuhei; Kim, Kijin; Akimoto, Takayuki; Ahn, Nayoung; Lee, Hoseong; Suzuki, Katsuhiko

    2009-01-01

    Considering the adverse effects of exercise-induced cortisol secretion on health in athletes, it is important to determine the environmental and individual factors that contribute to the variations in exercise-induced cortisol secretion. In this study, the effects of cold environment exposure and cold acclimatization on exercise-induced salivary cortisol responses were investigated. Short track skaters (n = 11), who usually practice under cold conditions, and inline skaters (n = 11), who usually practice under room temperature conditions, participated in a randomized crossover study. All participants cycled for 60 minutes at 65% Vo2 max under cold (ambient temperature: 5 +/- 1 degrees C, relative humidity 41% +/- 9%) and room temperature (ambient temperature: 21 +/- 1 degrees C, relative humidity 35% +/- 5%) conditions. The participants had a 120-minute bed rest recovery phase at room temperature after both exercise bouts. Cortisol levels were measured in saliva samples collected pre-exercise and postexercise at 1 minute, 30 minutes, 60 minutes, and 120 minutes. Both short track and inline skaters exhibited clear cortisol responses to exercise under cold and room temperature conditions. The magnitude of the cortisol response, however, was different between skaters and conditions. The inline skaters exhibited significantly higher cortisol values under cold conditions than under room temperature conditions (7.6 nmol/L and 4.2 nmol/L, respectively). However, the short track skaters exhibited significantly higher cortisol values under cold conditions compared to room temperature conditions (8.7 nmol/L and 5.4 nmol/L, respectively). The effects of cold environment exposure on exercise-induced cortisol response were different between skaters who usually practice under cold or room temperature conditions. These results can be interpreted as acclimatization to either cold or room temperature conditions attenuating the cortisol response, suggesting that acclimatization may

  5. Low Level Laser Therapy Reduces the Development of Lung Inflammation Induced by Formaldehyde Exposure

    PubMed Central

    Miranda da Silva, Cristiane; Peres Leal, Mayara; Brochetti, Robson Alexandre; Braga, Tárcio; Vitoretti, Luana Beatriz; Saraiva Câmara, Niels Olsen; Damazo, Amílcar Sabino; Ligeiro-de-Oliveira, Ana Paula; Chavantes, Maria Cristina; Lino-dos-Santos-Franco, Adriana

    2015-01-01

    Lung diseases constitute an important public health problem and its growing level of concern has led to efforts for the development of new therapies, particularly for the control of lung inflammation. Low Level Laser Therapy (LLLT) has been highlighted as a non-invasive therapy with few side effects, but its mechanisms need to be better understood and explored. Considering that pollution causes several harmful effects on human health, including lung inflammation, in this study, we have used formaldehyde (FA), an environmental and occupational pollutant, for the induction of neutrophilic lung inflammation. Our objective was to investigate the local and systemic effects of LLLT after FA exposure. Male Wistar rats were exposed to FA (1%) or vehicle (distillated water) during 3 consecutive days and treated or not with LLLT (1 and 5 hours after each FA exposure). Non-manipulated rats were used as control. 24 h after the last FA exposure, we analyzed the local and systemic effects of LLLT. The treatment with LLLT reduced the development of neutrophilic lung inflammation induced by FA, as observed by the reduced number of leukocytes, mast cells degranulated, and a decreased myeloperoxidase activity in the lung. Moreover, LLLT also reduced the microvascular lung permeability in the parenchyma and the intrapulmonary bronchi. Alterations on the profile of inflammatory cytokines were evidenced by the reduced levels of IL-6 and TNF-α and the elevated levels of IL-10 in the lung. Together, our results showed that LLLT abolishes FA-induced neutrophilic lung inflammation by a reduction of the inflammatory cytokines and mast cell degranulation. This study may provide important information about the mechanisms of LLLT in lung inflammation induced by a pollutant. PMID:26569396

  6. DNA strand breaks in human nasal respiratory epithelium are induced upon exposure to urban pollution

    SciTech Connect

    Calderon-Garciduenas, L.; Osnaya-Brizuela, N.; Ramirez-Martinez, L.

    1996-02-01

    All organisms have the ability to respond and adapt to a myriad of environmental insults. The human respiratory epithelium, when exposed to oxidant gases in photochemical smog, is at risk of DNA damage and requires efficient cellular adaptative responses to resist the environmentally induced cell damage. Ozone and its reaction products induce in vitro and in vivo DNA single strand breaks (SSBs) in respiratory epithelial cells and alveolar macrophages. To determine if exposure to a polluted atmosphere with ozone as the main criteria pollutant of 19 children and 13 adult males who lived in a low-polluted Pacific port, 69 males and 16 children who were permanent residents of Southwest Metropolitan Mexico City (SWMMC), and 22 young males newly arrived to SWMMC and followed for 12 weeks. Respiratory symptoms, nasal cytology and histopathology, cell viabilities, and single-cell gel electrophoresis were investigated. Atmospheric pollutant data were obtained from a fixed-site monitoring station. SWMMC volunteers spent >7 hr/day outdoors and all had upper respiratory symptoms. A significant difference in the numbers of DNA-damaged nasal cells was observed between control and chronically exposed subjects, both in children (p<0.00001) and in adults (p>0.01). SSBs in newly arrived subjects quickly increased upon arrival to the city, from 39.8 {+-}8.34% in the first week to 67.29 {+-}2.35 by week 2. Thereafter, the number of cells with SSBs remained stable in spite of the continuous increase in cumulative ozone, suggesting a threshold for cumulative DNA nasal damage. Exposure to a polluted urban atmosphere induces SSBs in human nasal respiratory epithelium, and nasal SSBs could serve as a biomarker of ozone exposure. Further, because DNA strand breaks are a threat to cell viability and genome integrity and appear to be a critical lesion responsible for p53 induction, nasal SSBs should be evaluated in ozone-exposed individuals. 43 refs., 5 figs., 4 tabs.

  7. Maternal and fetal metabonomic alterations in prenatal nicotine exposure-induced rat intrauterine growth retardation.

    PubMed

    Feng, Jiang-hua; Yan, You-e; Liang, Gai; Liu, Yan-song; Li, Xiao-jun; Zhang, Ben-jian; Chen, Liao-bin; Yu, Hong; He, Xiao-hua; Wang, Hui

    2014-08-25

    Prenatal nicotine exposure causes adverse birth outcome. However, the corresponding metabonomic alterations and underlying mechanisms of nicotine-induced developmental toxicity remain unclear. The aims of this study were to characterize the metabolic alterations in biofluids in nicotine-induced intrauterine growth retardation (IUGR) rat model. In the present study, pregnant Wistar rats were intragastrically administered with different doses of nicotine (0.5, 1.0 and 2.0 mg/kg d) from gestational day (GD) 11-20. The metabolic profiles of the biofluids, including maternal plasma, fetal plasma and amniotic fluid, were analyzed using (1)H nuclear magnetic resonance (NMR)-based metabonomic techniques. Prenatal nicotine exposure caused noticeably lower body weights, higher IUGR rates of fetal rats, and elevated maternal and fetal corticosterone (CORT) levels compared to the controls. The correlation analysis among maternal, fetal serum CORT levels and fetal bodyweight suggested that the levels of maternal and fetal serum CORT presented a positive correlation (r=0.356, n=32, P<0.05), while there was a negative correlation between fetal (r=-0.639, n=32, P<0.01) and maternal (r=-0.530, n=32, P<0.01) serum CORT level and fetal bodyweight. The fetal metabonome alterations included the stimulation of lipogenesis and the decreased levels of glucose and amino acids. The maternal metabonome alterations involved the enhanced blood glucose levels, fatty acid oxygenolysis, proteolysis and amino acid accumulation. These results suggested that prenatal nicotine exposure is associated with an altered maternal and fetal metabonome, which may be related to maternal increased glucocorticoid level induced by nicotine. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  8. Arsine toxicity is induced by inhalation but not by percutaneous exposure in hairless mice.

    PubMed

    Kato, Koichi; Yamanaka, Kenzo; Shimoda, Yasuyo; Yamano, Yuko; Nagano, Kasuke; Hata, Akihisa; Endo, Yoko; Tachikawa, Mariko; Endo, Ginji

    2014-04-01

    Arsine (AsH₃) is used in many industries, but there is insufficient knowledge about the potential for percutaneous absorption. In order to examine possible percutaneous absorption of arsine, we conducted inhalation studies. Arsine was generated by reducing arsenic trioxide with NaBH₄. Male 5-week-old Hos:HR-1 hairless mice were subjected to a single percutaneous exposure or whole-body inhalation exposure of ca. 300 ppm arsine for 5 min. The examination was performed 0-6 hr after the exposure. Total arsenic in whole blood and hematocrit (Ht) values were measured. Generation of an arsenic-hemoglobin (As-Hb) adduct in the blood was detected using high-performance liquid chromatography with an inductively coupled plasma mass spectrometer (HPLC-ICP-MS). Ht values in the inhalation group significantly decreased after 3 hr, but those in the percutaneous exposure group did not. Total arsenic in the inhalation group was 9.0-14.2 mg/l, which was significantly higher than that in the percutaneous group. The As-Hb adduct was detected only in mice in the inhalation group. Histopathological changes were noted only in the inhalation group, with marked deposition of eosinophilic globules in the proximal convoluted tubules of the kidneys, the Kupffer cells of the liver, and the red pulp in the spleen, but not in the lungs. Immunohistochemically, these eosinophilic globules were stained positively by hemoglobin (Hb) antibody. In the present study, arsine-induced hemolysis and deposition of Hb occurred in the kidney via the inhalation route but not via percutaneous exposure. The presence of As-Hb adduct may be a useful indicator for confirming arsine poisoning.

  9. Oral Exposure to Bisphenol A Increases Dimethylbenzanthracene-Induced Mammary Cancer in Rats

    PubMed Central

    Jenkins, Sarah; Raghuraman, Nandini; Eltoum, Isam; Carpenter, Mark; Russo, Jose; Lamartiniere, Coral A.

    2009-01-01

    Background Bisphenol A (BPA) is widely used in the manufacture of polycarbonate plastics, including infant formula bottles. Objectives Based on the reported endocrine disruptor activity of this polyphenol, we hypothesized that exposure to BPA early in life would elicit developmental changes in the mammary tissue and cause a predisposition for mammary cancer. Methods We exposed neonatal/prepubertal rats to BPA via lactation from nursing dams treated orally with 0, 25, and 250 μg BPA/kg body weight/day. For tumorigenesis studies, female offspring were exposed to 30 mg dimethylbenzanthracene (DMBA)/kg body weight at 50 days of age. Results The combination of DMBA treatment with lactational exposure to BPA demonstrated a dose-dependent increase in mammary tumor multiplicity and reduced tumor latency compared with controls. In the absence of DMBA treatment, lactational BPA exposure resulted in increased cell proliferation and decreased apoptosis at 50 but not 21 days postpartum (shortly after last BPA treatment). Using Western blot analysis, we determined that steroid receptor coactivators (SRCs) 1–3, Akt, phosphorylated Akt, progesterone receptor A (PR-A), and erbB3 proteins were significantly up-regulated at 50 days of age. Conclusions The data presented here provide the first evidence that maternal exposure to BPA during lactation increases mammary carcinogenesis in a DMBA-induced model of rodent mammary cancer. Changes in PR-A, SRC 1–3, erbB3, and Akt activity are consistent with increased cell proliferation and decreased apoptosis playing a role in mammary cancer susceptibility. These alterations provide an explanation of enhanced mammary carcinogenesis after lactational BPA exposure. PMID:19590682

  10. Repeated cocaine exposure facilitates the expression of incentive motivation and induces habitual control in rats.

    PubMed

    LeBlanc, Kimberly H; Maidment, Nigel T; Ostlund, Sean B

    2013-01-01

    There is growing evidence that mere exposure to drugs can induce long-term alterations in the neural systems that mediate reward processing, motivation, and behavioral control, potentially causing the pathological pursuit of drugs that characterizes the addicted state. The incentive sensitization theory proposes that drug exposure potentiates the influence of reward-paired cues on behavior. It has also been suggested that drug exposure biases action selection towards the automatic execution of habits and away from more deliberate goal-directed control. The current study investigated whether rats given repeated exposure to peripherally administered cocaine would show alterations in incentive motivation (assayed using the Pavlovian-to-instrumental transfer (PIT) paradigm) or habit formation (assayed using sensitivity to reward devaluation). After instrumental and Pavlovian training for food pellet rewards, rats were given 6 daily injections of cocaine (15 mg/kg, IP) or saline, followed by a 10-d period of rest. Consistent with the incentive sensitization theory, cocaine-treated rats showed stronger cue-evoked lever pressing than saline-treated rats during the PIT test. The same rats were then trained on a new instrumental action with a new food pellet reward before undergoing a reward devaluation testing. Although saline-treated rats exhibited sensitivity to reward devaluation, indicative of goal-directed performance, cocaine-treated rats were insensitive to this treatment, suggesting a reliance on habitual processes. These findings, when taken together, indicate that repeated exposure to cocaine can cause broad alterations in behavioral control, spanning both motivational and action selection processes, and could therefore help explain aberrations of decision-making that underlie drug addiction.

  11. Exposure Stress Induces Reversible Corneal Graft Opacity in Recipients With Herpes Simplex Virus-1 Infections

    PubMed Central

    Rowe, Alexander M.; Yun, Hongmin; Hendricks, Robert L.

    2017-01-01

    Purpose Most of the inflammation in murine herpes simplex virus type 1 (HSV-1)-induced stromal keratitis (HSK) is due to exposure stress resulting from loss of corneal nerves and blink reflex. Corneal grafts often fail when placed on corneal beds with a history of HSK. We asked if corneal exposure contributes to the severe pathology of corneal grafts on HSV-1–infected corneal beds. Methods Herpes simplex virus type 1–infected corneas were tested for blink reflex. Opacity and vascularization were monitored in allogeneic and syngeneic corneal grafts that were transplanted to corneal beds with no blink reflex or to those that retained blink reflex in at least one quadrant following infection. Results Retention of any level of blink reflex significantly reduced inflammation in HSV-1–infected corneas. Corneal allografts placed on HSV-1–infected beds lacking corneal blink reflex developed opacity faster and more frequently than those placed on infected beds that partially or completely retained blink reflex. Corneal grafts placed on infected corneal beds with no blink reflex rapidly became opaque to a level that would be considered rejection. However, protecting these grafts from exposure by tarsorrhaphy prevented or reversed the opacity in both syngeneic and allogenic grafts. Conclusions Exposure due to HSV-1–engendered hypoesthesia causes rapid, severe, persistent, but reversible opacification of both allogeneic and syngeneic corneal grafts. This opacity should not be interpreted as immunologic rejection. Exposure stress may contribute to the high rate of corneal graft pathology in patients with recurrent HSK. PMID:28055100

  12. Gestational Toluene Exposure Effects on Spontaneous and Amphetamine-Induced Locomotor Behavior in Rats

    PubMed Central

    Mohammadi, Michael H.; Batis, Jeffery C.; Hannigan, John H.

    2007-01-01

    The abuse of volatile organic solvents (inhalants) continues to be a major health concern throughout the world. Toluene, which is found in many products such as glues and household cleaners, is among the most commonly abused organic solvents. The neurobehavioral teratogenic sequelae of solvent abuse (i.e., repeated, brief inhalation exposures to very high concentrations of solvents) have not been examined thoroughly. In a preclinical model of inhalant abuse, timed-pregnant Sprague-Dawley rats were exposed to 0, 8,000, or 12,000 parts per million (ppm) for 15 min twice daily from gestation day 8 (GD8) through GD20. In the first experiment, separate groups of offspring were observed individually in an open-field on postnatal day 22 (PN22), PN42 or PN63. In the second experiment, other offspring given identical prenatal toluene exposures were observed in an “open-field” following an acute i.p. injection of amphetamine (0, 0.56, 1.78 mg/kg) on PN28. Automated measurements of distance traveled and ambulatory time were recorded. Prenatal toluene exposure resulted in small alterations in spontaneous activity compared to non-exposed rats. Prenatal exposure to 12,000 ppm toluene resulted in significant hyposensitivity to the locomotor stimulatory effects of the amphetamine challenge in male but not female rats on PN28. The results demonstrate that prenatal exposure to abuse patterns of high concentrations of toluene through inhalation can alter spontaneous and amphetamine-induced locomotor behavior in rats. The expression of these effects also appears to depend upon the postnatal age of testing. These results imply that abuse of organic solvents during pregnancy in humans may also produce long-lasting effects on biobehavioral development. PMID:17112700

  13. Repeated Cocaine Exposure Facilitates the Expression of Incentive Motivation and Induces Habitual Control in Rats

    PubMed Central

    LeBlanc, Kimberly H.; Maidment, Nigel T.; Ostlund, Sean B.

    2013-01-01

    There is growing evidence that mere exposure to drugs can induce long-term alterations in the neural systems that mediate reward processing, motivation, and behavioral control, potentially causing the pathological pursuit of drugs that characterizes the addicted state. The incentive sensitization theory proposes that drug exposure potentiates the influence of reward-paired cues on behavior. It has also been suggested that drug exposure biases action selection towards the automatic execution of habits and away from more deliberate goal-directed control. The current study investigated whether rats given repeated exposure to peripherally administered cocaine would show alterations in incentive motivation (assayed using the Pavlovian-to-instrumental transfer (PIT) paradigm) or habit formation (assayed using sensitivity to reward devaluation). After instrumental and Pavlovian training for food pellet rewards, rats were given 6 daily injections of cocaine (15 mg/kg, IP) or saline, followed by a 10-d period of rest. Consistent with the incentive sensitization theory, cocaine-treated rats showed stronger cue-evoked lever pressing than saline-treated rats during the PIT test. The same rats were then trained on a new instrumental action with a new food pellet reward before undergoing a reward devaluation testing. Although saline-treated rats exhibited sensitivity to reward devaluation, indicative of goal-directed performance, cocaine-treated rats were insensitive to this treatment, suggesting a reliance on habitual processes. These findings, when taken together, indicate that repeated exposure to cocaine can cause broad alterations in behavioral control, spanning both motivational and action selection processes, and could therefore help explain aberrations of decision-making that underlie drug addiction. PMID:23646106

  14. Drug development and hormesis: changing conceptual understanding of the dose response creates new challenges and opportunities for more effective drugs.

    PubMed

    Calabrese, Edward J; Staudenmayer, John W; Stanek, Edward J

    2006-01-01

    This review proposes that the emerging acceptance of the hormetic dose-response model in toxicology and pharmacology has the potential to significantly change important aspects of drug development. Two situations where the hormesis concept may affect drug development are considered: one in which low-dose stimulation may represent an adverse/unwanted effect (eg, stimulation of tumor cell proliferation by antitumor drugs), the other in which low-dose stimulation defines the therapeutic zone (ie, a beneficial or intended effect; eg, cognition enhancement in Alzheimer's disease treatment). Examples are used to demonstrate that the hormetic dose-response model has implications for the definition of an ideal candidate for a therapeutic agent, as well as implications for study designs needed to assess the quantitative features of the dose-response relationship.

  15. PERM Hypothesis: The Fundamental Machinery Able to Elucidate the Role of Xenobiotics and Hormesis in Cell Survival and Homeostasis

    PubMed Central

    Chirumbolo, Salvatore; Bjørklund, Geir

    2017-01-01

    In this article the Proteasome, Endoplasmic Reticulum and Mitochondria (PERM) hypothesis is discussed. The complex machinery made by three homeostatic mechanisms involving the proteasome (P), endoplasmic reticulum (ER) and mitochondria (M) is addressed in order to elucidate the beneficial role of many xenobiotics, either trace metals or phytochemicals, which are spread in the human environment and in dietary habits, exerting their actions on the mechanisms underlying cell survival (apoptosis, cell cycle regulation, DNA repair and turnover, autophagy) and stress response. The “PERM hypothesis” suggests that xenobiotics can modulate this central signaling and the regulatory engine made fundamentally by the ER, mitochondria and proteasome, together with other ancillary components such as peroxisomes, by acting on the energetic balance, redox system and macromolecule turnover. In this context, reactive species and stressors are fundamentally signalling molecules that could act as negative-modulating signals if PERM-mediated control is offline, impaired or dysregulated, as occurs in metabolic syndrome, degenerative disorders, chronic inflammation and cancer. Calcium is an important oscillatory input of this regulation and, in this hypothesis, it might play a role in maintaining the correct rhythm of this PERM modulation, probably chaotic in its nature, and guiding cells to a more drastic decision, such as apoptosis. The commonest effort sustained by cells is to maintain their survival balance and the proterome has the fundamental task of supporting this mechanism. Mild stress is probably the main stimulus in this sense. Hormesis is therefore re-interpreted in the light of this hypothetical model and that experimental evidence arising from flavonoid and hormesis reasearch. PMID:28098843

  16. PERM Hypothesis: The Fundamental Machinery Able to Elucidate the Role of Xenobiotics and Hormesis in Cell Survival and Homeostasis.

    PubMed

    Chirumbolo, Salvatore; Bjørklund, Geir

    2017-01-15

    In this article the Proteasome, Endoplasmic Reticulum and Mitochondria (PERM) hypothesis is discussed. The complex machinery made by three homeostatic mechanisms involving the proteasome (P), endoplasmic reticulum (ER) and mitochondria (M) is addressed in order to elucidate the beneficial role of many xenobiotics, either trace metals or phytochemicals, which are spread in the human environment and in dietary habits, exerting their actions on the mechanisms underlying cell survival (apoptosis, cell cycle regulation, DNA repair and turnover, autophagy) and stress response. The "PERM hypothesis" suggests that xenobiotics can modulate this central signaling and the regulatory engine made fundamentally by the ER, mitochondria and proteasome, together with other ancillary components such as peroxisomes, by acting on the energetic balance, redox system and macromolecule turnover. In this context, reactive species and stressors are fundamentally signalling molecules that could act as negative-modulating signals if PERM-mediated control is offline, impaired or dysregulated, as occurs in metabolic syndrome, degenerative disorders, chronic inflammation and cancer. Calcium is an important oscillatory input of this regulation and, in this hypothesis, it might play a role in maintaining the correct rhythm of this PERM modulation, probably chaotic in its nature, and guiding cells to a more drastic decision, such as apoptosis. The commonest effort sustained by cells is to maintain their survival balance and the proterome has the fundamental task of supporting this mechanism. Mild stress is probably the main stimulus in this sense. Hormesis is therefore re-interpreted in the light of this hypothetical model and that experimental evidence arising from flavonoid and hormesis reasearch.

  17. Herbicide toxicity, selectivity and hormesis of nicosulfuron on 10 Trichogrammatidae (Hymenoptera) species parasitizing Anagasta ( = Ephestia) kuehniella (Lepidoptera: Pyralidae) eggs.

    PubMed

    Leite, Germano L D; de Paulo, Paula D; Zanuncio, José C; Tavares, Wagner De S; Alvarenga, Anarelly C; Dourado, Luan R; Bispo, Edilson P R; Soares, Marcus A

    2017-01-02

    Selective agrochemicals including herbicides that do not affect non-target organisms such as natural enemies are important in the integrated pest management (IPM) programs. The aim of this study was to evaluate the herbicide toxicity, selectivity and hormesis of nicosulfuron, recommended for the corn Zea mays L. (Poaceae) crop, on 10 Trichogrammatidae (Hymenoptera) species. A female of each Trichogramma spp. or Trichogrammatoidea annulata De Santis, 1972 was individually placed in plastic test tubes (no choice) with a cardboard containing 45 flour moth Anagasta ( = Ephestia) kuehniella Zeller, 1879 (Lepidoptera: Pyralidae) eggs. Parasitism by these natural enemies was allowed for 48 h and the cardboards were sprayed with the herbicide nicosulfuron at 1.50 L.ha(-1), along with the control (only distilled water). Nicosulfuron reduced the emergence rate of Trichogramma bruni Nagaraja, 1983 females, but increased that of Trichogramma pretiosum Riley, 1879, Trichogramma acacioi Brun, Moraes and Smith, 1984 and T. annulata females. Conversely, this herbicide increased the emergence rate of Trichogramma brasiliensis Ashmead, 1904, T. bruni, Trichogramma galloi Zucchi, 1988 and Trichogramma soaresi Nagaraja, 1983 males and decreased those of T. acacioi, Trichogramma atopovilia Oatman and Platner, 1983 and T. pretiosum males. In addition, nicosulfuron reduced the sex ratio of T. galloi, Trichogramma bennetti Nagaraja and Nagarkatti, 1973 and T. pretiosum and increased that of T. acacioi, T. bruni, T. annulata, Trichogramma demoraesi Nagaraja, 1983, T. soaresi and T. brasiliensis. The herbicide nicosulfuron was "harmless" (class 1, <30% reduction) for females and the sex ratio of all Trichogrammatidae species based on the International Organization for Biological Control (IOBC) classification. The possible hormesis effect of nicosulfuron on Trichogrammatidae species and on the bacterium Wolbachia sp. (Rickettsiales: Rickettsiaceae) was also discussed.

  18. Chromatin Modifications during Repair of Environmental Exposure-Induced DNA Damage: A Potential Mechanism for Stable Epigenetic Alterations

    PubMed Central

    O’Hagan, Heather M.

    2014-01-01

    Exposures to environmental toxicants and toxins cause epigenetic changes that likely play a role in the development of diseases associated with exposure. The mechanism behind these exposure-induced epigenetic changes is currently unknown. One commonality between most environmental exposures is that they cause DNA damage either directly or through causing an increase in reactive oxygen species, which can damage DNA. Like transcription, DNA damage repair must occur in the context of chromatin requiring both histone modifications and ATP-dependent chromatin remodeling. These chromatin changes aid in DNA damage accessibility and signaling. Several proteins and complexes involved in epigenetic silencing during both development and cancer have been found to be localized to sites of DNA damage. The chromatin-based response to DNA damage is considered a transient event, with chromatin being restored to normal as DNA damage repair is completed. However, in individuals chronically exposed to environmental toxicants or with chronic inflammatory disease, repeated DNA damage-induced chromatin rearrangement may ultimately lead to permanent epigenetic alterations. Understanding the mechanism behind exposure-induced epigenetic changes will allow us to develop strategies to prevent or reverse these changes. This review focuses on epigenetic changes and DNA damage induced by environmental exposures, the chromatin changes that occur around sites of DNA damage, and how these transient chromatin changes may lead to heritable epigenetic alterations at sites of chronic exposure. PMID:24259318

  19. Exposure to Anisakis extracts can induce inflammation on in vitro cultured human colonic cells.

    PubMed

    Speciale, Antonio; Trombetta, Domenico; Saija, Antonella; Panebianco, Antonio; Giarratana, Filippo; Ziino, Graziella; Minciullo, Paola Lucia; Cimino, Francesco; Gangemi, Sebastiano

    2017-07-12

    Anisakis spp. is a parasitic nematode whose infective third-stage larvae may be found within the flesh of fish species commonly consumed by humans. Thorough cooking or freezing should render the fish safe for consumption; furthermore, marinating solutions containing biocidal agents might have a significant action against Anisakis larvae. Some studies suggest a relationship between some parasitic infections and development of inflammatory bowel disorders, and Anisakis infection might be a risk factor for stomach or colon cancer. The aim of our study was to investigate if crude extracts (CEs) obtained from Anisakis larvae marinated in a solution with added allyl isothiocyanate (ACE-AITC) and frozen, or from frozen only Anisakis larvae (ACE), can induce an inflammatory effect on in vitro differentiated colonic Caco-2 cells exposed or not to LPS. Caco-2 exposure to the two CEs induced a marked COX-2 expression and potentiated LPS-induced COX-2 overexpression, confirming that substances present in Anisakis larvae can induce an inflammatory response in the intestinal epithelium, possibly also exacerbating the effects of other inflammatory stimuli. ACE induced a marked decrease in caspase-3 activation, while AITC-ACE increased its activation. However, LPS-induced caspase-3 activation appeared lower in cells treated with ACE and with the lower concentration of AITC-ACE. Thus, it is evident that Anisakis CEs may affect various cell pathways crucial not only in the inflammatory process but also in cell growth and death. Thus, CEs obtained from nonviable Anisakis larvae retain or are otherwise provided with noxious properties able to induce a strong inflammation response in intestinal epithelial cells. Furthermore, their influence may persist also following pretreatment with the biocidal agent AITC, indicating that the harmful substances contained in crude extracts from Anisakis larvae are resistant to the thermal or biocidal agent treatments.

  20. Lanthanum Affects Bell Pepper Seedling Quality Depending on the Genotype and Time of Exposure by Differentially Modifying Plant Height, Stem Diameter and Concentrations of Chlorophylls, Sugars, Amino Acids, and Proteins.

    PubMed

    García-Jiménez, Atonaltzin; Gómez-Merino, Fernando C; Tejeda-Sartorius, Olga; Trejo-Téllez, Libia I

    2017-01-01

    Lanthanum (La) is considered a beneficial element, capable of inducing hormesis. Hormesis is a dose-response relationship phenomenon characterized by low-dose stimulation and high-dose inhibition. Herein we tested the effect of 0 and 10 μM La on growth and biomolecule concentrations of seedlings of four sweet bell pepper (Capsicum annuum L.) varieties, namely Sven, Sympathy, Yolo Wonder, and Zidenka. Seedling evaluations were performed 15 and 30 days after treatment applications (dat) under hydroponic greenhouse conditions. Seedling height was significantly increased by La, growing 20% taller in Yolo Wonder plants, in comparison to the control. Similarly, La significantly enhanced shoot diameter, with increases of 9 and 9.8% in measurements performed 15 and 30 dat, respectively, as compared to the control. Likewise, La-treated seedlings had a higher number of flower buds than the control. An increase in the number of leaves because of La application was observed in Yolo Wonder seedlings, both 15 and 30 dat, while leaf area was augmented in this variety only 30 dat. Nevertheless, La did not affect dry biomass accumulation. La effects on biomolecule concentration were differential over time. In all varieties, La stimulated the biosynthesis of chlorophyll a, b and total 15 dat, though 30 dat only the varieties Sympathy and Yolo Wonder showed enhanced concentrations of these molecules because of La. Total soluble sugars increased in La-treated seedlings 30 dat. Interestingly, while most varieties exposed to La showed a reduction in amino acid concentration 15 dat, the opposite trend was observed 30 dat. Importantly, in all varieties evaluated, La stimulated soluble protein concentration 30 dat. It is important to note that while chlorophyll concentrations increased in all varieties exposed to La, both 15 and 30 dat, those of soluble sugars and proteins consistently increased only 30 dat, but not 15 dat. Our results confirm that La may improve seedling quality by

  1. Fucoidan Extracted from Hijiki Protects Brain Microvessel Endothelial Cells Against Diesel Exhaust Particle Exposure-Induced Disruption.

    PubMed

    Choi, Young-Sook; Eom, Sang-Yong; Kim, In-Soo; Ali, Syed F; Kleinman, Michael T; Kim, Yong-Dae; Kim, Heon

    2016-05-01

    This study was performed to evaluate the protective effects of fucoidan against the decreased function of primary cultured bovine brain microvessel endothelial cells (BBMECs) after exposure to diesel exhaust particles (DEPs). BBMECs were extracted from bovine brains and cultured until confluent. To evaluate the function of BBMECs, we performed a permeability test using cell-by-cell equipment and by Western blot analysis for zonular occludens-1 (ZO-1), which is a tight junction protein of BMECs, and evaluated oxidative stress in BBMECs using the DCFH-DA assay and the CUPRAC-BCS assay. The increased oxidative stress in BBMECs following DEP exposure was suppressed by fucoidan. In addition, permeability of BBMECs induced by DEP exposure was decreased by fucoidan treatment. Our results showed that fucoidan protects against BBMEC disruption induced by DEP exposure. This study provides evidence that fucoidan might protect the central nervous system (CNS) against DEP exposure.

  2. Short exposure to the DNA intercalator DRAQ5 dislocates the transcription machinery and induces cell death.

    PubMed

    Richard, Elodie; Causse, Sébastien; Spriet, Corentin; Fourré, Nicolas; Trinel, Dave; Darzacq, Xavier; Vandenbunder, Bernard; Heliot, Laurent

    2011-01-01

    The fluorescent probe DRAQ5 which rapidly permeates cells and binds to DNA is potentially useful for functional studies of molecular dynamics and interactions in living nuclei. Within minutes after the incubation of human osteosarcoma U2OS cells with 5μm DRAQ5, the distributions of RNA polymerase II and some of its associated regulatory proteins HEXIM and cyclin T1 in the nucleus are severely impaired, and transcription is inhibited. Furthermore, 30min exposure to DRAQ5 induces death of U2OS cells 24h later. Incubation with Hoechst 33342 under similar conditions does not induce these effects. These results emphasize the importance of carefully examining the functional consequences of labeling DNA with intercalating fluorescent dyes before use. © 2010 The Authors. Photochemistry and Photobiology © 2010 The American Society of Photobiology.

  3. Repeated exposure to MDMA provides neuroprotection against subsequent MDMA-induced serotonin depletion in brain

    PubMed Central

    Bhide, Nirmal S.; Lipton, Jack; Cunningham, Jacobi; Yamamoto, Bryan K.; Gudelsky, Gary A.

    2009-01-01

    Repeated exposure to sub-lethal insults has been reported to result in neuroprotection against a subsequent deleterious insult. The purpose of this study was to evaluate whether repeated exposure (preconditioning) to a non-5-HT depleting dose of MDMA in adult rats provides neuroprotection against subsequent MDMA induced 5-HT depletion. Treatment of rats with MDMA (10 mg/kg, ip every 2 hrs for 4 injections) resulted in a 50-65% depletion of 5-HT in the striatum, hippocampus and cortex, and these depletions were significantly attenuated in rats that received a preconditioning regimen of MDMA (10 mg/kg, ip daily for 4 days). The 5-HT depleting regimen of MDMA also resulted in a 40-80% reduction in 5-HT transporter immunoreactivity (SERTir), and the reduction in SERTir also was completely attenuated in MDMA preconditioned animals. Preconditioning with MDMA (10 mg/kg, i.p.) daily for 4 days provided neuroprotection against methamphetamine-induced 5-HT depletion, but not DA depletion, in the striatum. Additional studies were conducted to exclude the possibility that alterations in MDMA pharmacokinetics or MDMA induced hyperthermia in rats previously exposed to MDMA contributes towards neuroprotection. During the administration of the 5-HT depleting regimen of MDMA, there was no difference in the extracellular concentration of the drug in the striatum of rats that had received 4 prior, daily injections of vehicle or MDMA. Moreover, there was no difference in the hyperthermic response to the 5-HT depleting regimen of MDMA in rats that had earlier received 4 daily injections of vehicle or MDMA. Furthermore, hyperthermia induced by MDMA during preconditioning appears not to contribute toward neuroprotection, inasmuch as preconditioning with MDMA at a low ambient temperature at which hyperthermia was absent did not alter the neuroprotection provided by the preconditioning regimen. Thus, prior exposure to MDMA affords protection against the long-term depletion of brain 5-HT

  4. Challenge exposure to isocyanates induces changes in nasal patency in patients reporting work-related respiratory symptoms.

    PubMed

    Castano, Roberto; Johnson, Victor J; Cartier, Andre

    2013-08-01

    To examine the utility of specific inhalation challenge (SIC) in assessing the nasal congestive response to isocyanate exposure. Nine patients complaining of work-related respiratory symptoms underwent SIC with exposure to isocyanate for 4 and 120 minutes on different days. Nasal volume was monitored by acoustic rhinometry and nasal congestion by the visual analogue scale (VAS) for up to 6 hours. The 4-minute isocyanate SIC induced a nonsignificant fall in nasal volume and no increase in the VAS score. The 120-minute isocyanate SIC induced a significant fall in nasal volume at 15, 30, and 60 minutes postchallenge that was associated with a significant increase in the VAS score at 15 and 30 minutes postchallenge. SIC appears useful to assess changes in nasal patency after exposure to isocyanate. Exposure to isocyanates can induce nasal congestion that can be objectively monitored during SIC.

  5. PRENATAL ETHANOL EXPOSURE LEADS TO GREATER ETHANOL-INDUCED APPETITIVE REINFORCEMENT

    PubMed Central

    Pautassi, Ricardo M.; Nizhnikov, Michael E.; Spear, Norman E.; Molina, Juan C.

    2012-01-01

    Prenatal ethanol significantly heightens later alcohol consumption, but the mechanisms that underlie this phenomenon are poorly understood. Little is known about the basis of this effect of prenatal ethanol on the sensitivity to ethanol’s reinforcing effects. One possibility is that prenatal ethanol exposure makes subjects more sensitive to the appetitive effects of ethanol or less sensitive to ethanol’s aversive consequences. The present study assessed ethanol-induced second-order conditioned place preference (CPP) and aversion and ethanol-induced conditioned taste aversion (CTA) in infant rats prenatally exposed to ethanol (2.0 g/kg) or vehicle (water) or left untreated. The involvement of the κ opioid receptor system in ethanol-induced CTA was also explored. When place conditioning occurred during the ascending limb of the blood-ethanol curve (Experiment 1), the pups exposed to ethanol in utero exhibited greater CPP than untreated controls, with a shift to the right of the dose-response curve. Conditioning during a later phase of intoxication (30–45 min post-administration; Experiment 2) resulted in place aversion in control pups exposed to vehicle during late gestation but not in pups that were exposed to ethanol in utero. Ethanol induced a reliable and similar CTA (Experiment 3) in the pups treated with vehicle or ethanol during gestation, and CTA was insensitive to κ antagonism. These results suggest that brief exposure to a moderate ethanol dose during late gestation promotes ethanol-mediated reinforcement and alters the expression of conditioned aversion by ethanol. This shift in the motivational reactivity to ethanol may be an underlying basis of the effect of prenatal ethanol on later ethanol acceptance. PMID:22698870

  6. Upregulation of Bax and Bcl-2 following prenatal cocaine exposure induces apoptosis in fetal rat brain.

    PubMed

    Xiao, DaLiao; Zhang, Lubo

    2008-01-01

    Cocaine abuse during pregnancy has been associated with numerous adverse perinatal outcomes. The present study was to determine whether prenatal cocaine exposure induced apoptosis and the possible role of Bcl-2 family genes in the programming cell death in fetal rat brain. Pregnant rats were treated with cocaine subcutaneously (30 & 60 mg/kg/day) from day 15 to 21 of gestation. Then the fetal and maternal brains were isolated. Cocaine produced a dose-dependent decrease in fetal brain weight and brain/body weight ratio (P<0.05). Apoptotic nuclei in fetal brain were increased from 2.6 +/- 0.1 (control) to 8.1+/- 0.6 (low dose) and 10.4 +/- 0.2% (high dose) (P<0.05). In accordance, cocaine dose dependently increased activities of caspase-3, caspase-8, and caspase-9 (% of control) in the fetal brain by 177%, 155%, 174%, respectively, at 30 mg/kg/day, and by 191%, 176%, 274%, respectively, at 60 mg/kg/day. In contrast, cocaine showed no effect on caspase activities in the maternal brain. Cocaine produced a dose-dependent increase in both Bcl-2 and Bax protein expression in the fetal brain, and increased the ratio of Bax/Bcl-2 at dose of 30 mg/kg/day (P<0.05). Our study has demonstrated that prenatal cocaine exposure induces apoptosis in the fetal brain, and suggested that up-regulating Bax/Bcl-2 gene expression may be involved in cocaine-induced apoptosis. The increased apoptosis of neuronal cells in the fetal brain is likely to play a key role in cocaine-induced neuronal defects during fetal development.

  7. Prenatal ethanol exposure leads to greater ethanol-induced appetitive reinforcement.

    PubMed

    Pautassi, Ricardo M; Nizhnikov, Michael E; Spear, Norman E; Molina, Juan C

    2012-09-01

    Prenatal ethanol significantly heightens later alcohol consumption, but the mechanisms that underlie this phenomenon are poorly understood. Little is known about the basis of 'this effect of prenatal ethanol on the sensitivity to ethanol's reinforcing effects. One possibility is that prenatal ethanol exposure makes subjects more sensitive to the appetitive effects of ethanol or less sensitive to ethanol's aversive consequences. The present study assessed ethanol-induced second-order conditioned place preference (CPP) and aversion and ethanol-induced conditioned taste aversion (CTA) in infant rats prenatally exposed to ethanol (2.0 g/kg) or vehicle (water) or left untreated. The involvement of the κ opioid receptor system in ethanol-induced CTA was also explored. When place conditioning occurred during the ascending limb of the blood-ethanol curve (Experiment 1), the pups exposed to ethanol in utero exhibited greater CPP than untreated controls, with a shift to the right of the dose-response curve. Conditioning during a later phase of intoxication (30-45 min post-administration; Experiment 2) resulted in place aversion in control pups exposed to vehicle during late gestation but not in pups that were exposed to ethanol in utero. Ethanol induced a reliable and similar CTA (Experiment 3) in the pups treated with vehicle or ethanol during gestation, and CTA was insensitive to κ antagonism. These results suggest that brief exposure to a moderate ethanol dose during late gestation promotes ethanol-mediated reinforcement and alters the expression of conditioned aversion by ethanol. This shift in the motivational reactivity to ethanol may be an underlying basis of the effect of prenatal ethanol on later ethanol acceptance.

  8. Chronic ultraviolet exposure-induced p53 gene alterations in sencar mouse skin carcinogenesis model

    SciTech Connect

    Tong, Ying; Smith, M.A.; Tucker, S.B.

    1997-06-27

    Alterations of the tumor suppressor gene p53 have been found in ultraviolet radiation (UVR) related human skin cancers and in UVR-induced murine skin tumors. However, links between p53 gene alterations and the stages of carcinogenesis induced by UVR have not been clearly defined. We established a chronic UVR exposure-induced Sencar mouse skin carcinogenesis model to determine the frequency of p53 gene alterations in different stages of carcinogenesis, including UV-exposed skin, papillomas, squamous-cell carcinomas (SCCs), and malignant spindle-cell tumors (SCTs). A high incidence of SCCs and SCTs were found in this model. Positive p53 nuclear staining was found in 10137 (27%) of SCCs and 12124 (50%) of SCTs, but was not detected in normal skin or papillomas. DNA was isolated from 40 paraffin-embedded normal skin, UV-exposed skin, and tumor sections. The p53 gene (exons 5 and 6) was amplified from the sections by using nested polymerase chain reaction (PCR). Subsequent single-strand conformation polymorphism (SSCP) assay and sequencing analysis revealed one point mutation in exon 6 (coden 193, C {r_arrow} A transition) from a UV-exposed skin sample, and seven point mutations in exon 5 (codens 146, 158, 150, 165, and 161, three C {r_arrow} T, two C {r_arrow} A, one C {r_arrow} G, and one A {r_arrow} T transition, respectively) from four SCTs, two SCCs and one UV-exposed skin sample. These experimental results demonstrate that alterations in the p53 gene are frequent events in chronic UV exposure-induced SCCs and later stage SCTs in Sencar mouse skin. 40 refs., 5 figs., 1 tab.

  9. Cardiovascular training effects in fighter pilots induced by occupational high G exposure.

    PubMed

    Newman, David G; Callister, Robin

    2008-08-01

    A fundamental difference in the cardiovascular response to acceleration between a group of fighter pilots (FP) and a group of non-pilots (NP) has been demonstrated previously. This study investigated the longitudinal effects of repetitive occupational +Gz exposure on the cardiovascular response to acceleration. There were 6 FP and 6 NP subjects who underwent rapid +75 degrees head-up tilt (HUT) on two separate occasions. The FP group were tested after a non-flying period of 5 wk (Test 1), and tested again after a period of repetitive exposure to high +Gz missions (Test 2). The NP group did not fly at all between Test 1 and Test 2. Mean arterial pressure (MAP), heart rate (HR), stroke volume (SV), and total peripheral resistance (TPR) were all determined non-invasively. SV was determined using impedance cardiography and calculated via the Kubicek equation. For each variable, resting values and the response to tilt for both HUT tests within and between each group were compared. In the FP group, resting MAP was higher (86 mmHg) in Test 2 compared with Test 1 (78 mmHg). Between groups, FP resting MAP was only different from the NP resting MAP in Test 2. The FP HR response to HUT increased significantly between the two tests. These findings suggest a +Gz-induced cardiovascular training effect in the FP group. Repetitive exposure to +Gz results in an increased resting MAP and an elevated HR response to tilt, which may provide benefits to operational fighter pilots.

  10. DNA damage and oxidative stress induced by imidacloprid exposure in the earthworm Eisenia fetida.

    PubMed

    Wang, Juan; Wang, Jinhua; Wang, Guangchi; Zhu, Lusheng; Wang, Jun

    2016-02-01

    To investigate the soil ecological effect of imidacloprid, earthworm Eisenia fetida was exposed to various concentrations of imidacloprid (0.10, 0.50, and 1.00 mg kg(-1) soil) respectively after 7, 14, 21, and 28 d. The effect of imidacloprid on reactive oxygen species (ROS) generation, antioxidant enzymes activity [superoxide dismutase (SOD) and catalase (CAT), glutathione S-transferase enzyme (GST)], malondialdehyde (MDA) content and DNA damage of the E. fetida was investigated. Significant increase of the ROS level was observed. The SOD and GST activity were significantly induced at most exposure intervals. CAT activity was inhibited and reflected a dose-dependent relationship on days 7, 14 and 21. High MDA levels were observed and the olive tail moment (OTM) as well as the percentage of DNA in the comet tail (tail DNA%) in comet assay declined with increasing concentrations and exposure time after 7 d. Our results suggested that the sub-chronic exposure of imidacloprid caused DNA damage and lipid peroxidation (LPO) leading to antioxidant responses in earthworm E. fetida.

  11. Exposure to BDE-153 induces autophagy in HepG2 cells.

    PubMed

    Pereira, Lilian Cristina; Duarte, Filipe Valente; Varela, Ana Teresa Inácio Ferreira; Rolo, Anabela Pinto; Palmeira, Carlos Manuel Marques; Dorta, Daniel Junqueira

    2017-08-01

    Autophagy is a pro-survival process that occurs under stressful "life-threatening" conditions. This process clears the cells of damaged organelles, long-lived proteins, and/or misfolded proteins. Under stressful conditions, activation of the autophagic process leads to cell death and acts as a protective mechanism against xenobiotic, which is the most widely accepted mechanism in the literature. Exposure to flame retardants and other pollutants is associated with several diseases, during which cell death and mitochondrial damage takes place. Although a body of research has aimed to understand the toxicity mechanism of flame retardants better, risk evaluation and the consequences of exposure to these toxicants have been poorly described. In this work, we have found that the BDE-153 congener (representant of flame retardants) induces autophagy after 24 and 48h (0.1-25μM). The autophagic process is associated with accumulation of lysosomes, and process triggering is evident from the levels of autophagy-related proteins such as p62 and LC3. Mitophagy (an autophagic process that specifically involves damaged mitochondria) may be involved, as judged from the decreased amount of mitochondrial DNA. Taken together, our results point out that induction of autophagy upon cell should contribute to better understanding of the consequences of human exposure to this class of environmental contaminants. Copyright © 2017. Published by Elsevier Ltd.

  12. Exposure and compositional factors that influence polarization induced birefringence in silica glass

    NASA Astrophysics Data System (ADS)

    Allan, Douglas C.; Mlejnek, Michal; Neukirch, Ulrich; Smith, Charlene M.; Smith, Frances M.

    2007-03-01

    Silica glass exhibits a permanent anisotropic response, referred to as polarization induced birefringence (PIB), when exposed to short wavelength, polarized light. The magnitude of the PIB has been empirically correlated with the OH content of the glass. Our recent studies pertaining to PIB have focused on careful characterization of PIB, with particular emphasis on understanding all of the contributions to the measured birefringence signal and finally extracting only that signal associated with birefringence arising from exposure to a polarized light beam. We will demonstrate that a critical contributor to the total birefringence signal is birefringence that comes from exposure beam inhomogeneities. After subtracting beam profile effects we are able to show that PIB is proportional to the OH content of the glass. Polarized infrared (IR) measurements were performed on glasses that developed PIB as a consequence of exposure to polarized 157-nm light. These studies reveal that there is preferential bleaching of a specific hydroxyl (OH) species in the glass with OH aligned parallel to the incident polarization undergoing more bleaching than those perpendicular. Further, we observe a very strong correlation between the measured PIB of these samples and the anisotropic bleaching. From these studies we propose a mechanism that can explain the role of hydroxyl in PIB.

  13. Manganese exposure induces α-synuclein aggregation in the frontal cortex of non-human primates.

    PubMed

    Verina, Tatyana; Schneider, Jay S; Guilarte, Tomás R

    2013-03-13

    Aggregation of α-synuclein (α-syn) in the brain is a defining pathological feature of neurodegenerative disorders classified as synucleinopathies. They include Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Occupational and environmental exposure to manganese (Mn) is associated with a neurological syndrome consisting of psychiatric symptoms, cognitive impairment and parkinsonism. In this study, we examined α-syn immunoreactivity in the frontal cortex of Cynomolgus macaques as part of a multidisciplinary assessment of the neurological effects produced by exposure to moderate levels of Mn. We found increased α-syn-positive cells in the gray matter of Mn-exposed animals, typically observed in pyramidal and medium-sized neurons in deep cortical layers. Some of these neurons displayed loss of Nissl staining with α-syn-positive spherical aggregates. In the white matter we also observed α-syn-positive glial cells and in some cases α-syn-positive neurites. These findings suggest that Mn exposure promotes α-syn aggregation in neuronal and glial cells that may ultimately lead to degeneration in the frontal cortex gray and white matter. To our knowledge, this is the first report of Mn-induced neuronal and glial cell α-syn accumulation and aggregation in the frontal cortex of non-human primates.

  14. Exposure smart hearing protector for reducing noise-induced hearing loss

    NASA Astrophysics Data System (ADS)

    Nykaza, Ed; Frank, Tom

    2003-10-01

    The Exposure Smart Hearing Protector (ESHP) is a new device that can be used for measuring noise exposure levels (NELs) and the prevention of noise induced hearing loss (NIHL). The ESHP consists of two microphones, located in a right and left earplug, that are connected to a dosimeter. In practice, the user wears the ESHP. When the noise level exceeds a safe dose a warning light comes on. The user then inserts the earplugs. If the earplugs are correctly inserted and the noise level in the user's earcanal is below a safe level the warning lights go off. As a result, the ESHP measures the user's total daily noise exposure (unprotected and protected). To increase the efficiency of using the ESHP for preventing NIHL, the user downloads the information stored in the ESHP via a scanner into user friendly-software. The software can be used not only to record a user's daily NELs, but more importantly to determine if the user needs intervention because the NELs exceed a safe level. The purpose of this poster session is to demonstrate the ESHP and software, and to report the results of a pilot study. [Work supported by NIOSH/CDC Grant No. U60/CCU 315855.

  15. Whole body exposure at 2100 MHz induced by plane wave of random incidences in a population

    NASA Astrophysics Data System (ADS)

    Conil, Emmanuelle; Hadjem, Abdelhamid; El Habachi, Aimad; Wiart, J.

    2010-11-01

    In this article, the whole body exposure induced by plane wave coming from a random direction of arrival is analyzed at 2100 MHz. This work completes previous studies on the influence of different parameters on the whole body exposure (such as morphology, frequency or usage in near field). The Visible Human phantom has been used to build a surrogate model to predict the whole body exposure depending on the highlighted surface of the phantom and on the direction of arrival of the incident plane wave. For the Visible Human, the error on the whole body averaged Specific Absorption Rate (SAR) is on average 4%. The surrogate model is applied to other 3D anthropomorphic phantoms for a frontal incidence with an averaged error of 10%. The great interest of the surrogate model is the possibility to apply a Monte Carlo process to assess probability distribution function of a population. A recent French anthropometric database of more than 3500 adults is used to build the probability distribution function of the whole body SAR for a random direction of arrival.

  16. Metformin-Induced Fixed-Drug Eruption Confirmed by Multiple Exposures.

    PubMed

    Steber, Carolyn J; Perkins, Scott L; Harris, Kira B

    2016-04-08

    A fixed-drug eruption (FDE) is a reaction characterized by cutaneous lesions that appear due to exposure to a particular drug. Barbiturates, carbamazepine, sulfamethoxazole, and tetracyclines have all been associated with causation of FDEs. Although these drugs are more commonly associated with FDEs, any introduction of a medication has the potential to result in a FDE. Metformin, a commonly used medication to improve glycemic control, has been reported to cause dermatologic reactions in some case reports, but only a single previously documented case report discusses the potential of metformin-associated FDE. We describe a 56-year-old woman who developed a FDE with multiple exposures to metformin. Upon each exposure, small, round, erythematic lesions developed on the palms of the hands and soles of the feet; these lesions resolved each time after discontinuation of metformin. According to the Naranjo scale, there is a definite association between metformin and FDE in this case (score of 8). This report contributes to the limited documented literature on metformin-induced FDE. Clinicians should be made aware of possible FDEs associated with this commonly used medication.

  17. Metformin-Induced Fixed-Drug Eruption Confirmed by Multiple Exposures

    PubMed Central

    Steber, Carolyn J.; Perkins, Scott L.; Harris, Kira B.

    2016-01-01

    Patient: Female, 56 Final Diagnosis: Fixed-drug eruption Symptoms: — Medication: Metformin Clinical Procedure: Discontinued metformin Specialty: Family Medicine Objective: Unusual or unexpected effect of treatment Background: A fixed-drug eruption (FDE) is a reaction characterized by cutaneous lesions that appear due to exposure to a particular drug. Barbiturates, carbamazepine, sulfamethoxazole, and tetracyclines have all been associated with causation of FDEs. Although these drugs are more commonly associated with FDEs, any introduction of a medication has the potential to result in a FDE. Metformin, a commonly used medication to improve glycemic control, has been reported to cause dermatologic reactions in some case reports, but only a single previously documented case report discusses the potential of metformin-associated FDE. Case Report: We describe a 56-year-old woman who developed a FDE with multiple exposures to metformin. Upon each exposure, small, round, erythematic lesions developed on the palms of the hands and soles of the feet; these lesions resolved each time after discontinuation of metformin. According to the Naranjo scale, there is a definite association between metformin and FDE in this case (score of 8). Conclusions: This report contributes to the limited documented literature on metformin-induced FDE. Clinicians should be made aware of possible FDEs associated with this commonly used medication. PMID:27056044

  18. Dieldrin exposure induces oxidative damage in the mouse nigrostriatal dopamine system

    PubMed Central

    Hatcher, Jaime M.; Richardson, Jason R.; Guillot, Thomas S.; McCormack, Alison L.; Di Monte, Donato A.; Jones, Dean P.; Pennell, Kurt D.; Miller, Gary W.

    2007-01-01

    Numerous epidemiological studies have shown an association between pesticide exposure and an increased risk of developing Parkinson’s disease (PD). Here, we provide evidence that the insecticide dieldrin causes specific oxidative damage in the nigrostriatal dopamine (DA) system. We report that exposure of mice to low levels of dieldrin for 30 days resulted in alterations in dopamine-handling as evidenced by a decrease in dopamine metabolites, DOPAC (31.7% decrease) and HVA (29.2% decrease) and significantly increased cysteinyl-catechol levels in the striatum. Furthermore, dieldrin resulted in a 53% decrease in total glutathione, an increase in the redox potential of glutathione, and a 90% increase in protein carbonyls. α-Synuclein protein expression was also significantly increased in the striatum (25% increase). Finally, dieldrin caused a significant decrease in striatal expression of the dopamine transporter as measured by 3H-WIN 35,428 binding and 3H-dopamine uptake. These alterations occurred in the absence of dopamine neuron loss in the substantia nigra pars compacta. These effects represent the ability of low doses of dieldrin to increase the vulnerability of nigrostriatal dopamine neurons by inducing oxidative stress and suggest that pesticide exposure may act as a promoter of PD. PMID:17291500

  19. Dieldrin exposure induces oxidative damage in the mouse nigrostriatal dopamine system.

    PubMed

    Hatcher, Jaime M; Richardson, Jason R; Guillot, Thomas S; McCormack, Alison L; Di Monte, Donato A; Jones, Dean P; Pennell, Kurt D; Miller, Gary W

    2007-04-01

    Numerous epidemiological studies have shown an association between pesticide exposure and an increased risk of developing Parkinson's disease (PD). Here, we provide evidence that the insecticide dieldrin causes specific oxidative damage in the nigrostriatal dopamine (DA) system. We report that exposure of mice to low levels of dieldrin for 30 days resulted in alterations in dopamine-handling as evidenced by a decrease in dopamine metabolites, DOPAC (31.7% decrease) and HVA (29.2% decrease) and significantly increased cysteinyl-catechol levels in the striatum. Furthermore, dieldrin resulted in a 53% decrease in total glutathione, an increase in the redox potential of glutathione, and a 90% increase in protein carbonyls. Alpha-synuclein protein expression was also significantly increased in the striatum (25% increase). Finally, dieldrin caused a significant decrease in striatal expression of the dopamine transporter as measured by (3)H-WIN 35,428 binding and (3)H-dopamine uptake. These alterations occurred in the absence of dopamine neuron loss in the substantia nigra pars compacta. These effects represent the ability of low doses of dieldrin to increase the vulnerability of nigrostriatal dopamine neurons by inducing oxidative stress and suggest that pesticide exposure may act as a promoter of PD.

  20. Parental exposure to microcystin-LR induced thyroid endocrine disruption in zebrafish offspring, a transgenerational toxicity.

    PubMed

    Cheng, Houcheng; Yan, Wei; Wu, Qin; Liu, Chunsheng; Gong, Xiuying; Hung, Tien-Chieh; Li, Guangyu

    2017-11-01

    Microcystin-LR is the most poisonous and commonly encountered hepatotoxin produced by cyanobacteria in an aquatic ecosystem, and it may cause thyroid dysfunction in fish. The present study aimed to reveal the effects of transgenerational toxicity of MCLR on the thyroid endocrine system under sub-chronic exposure conditions. Adult zebrafish (F0) were exposed to environmentally relevant concentrations (1, 5 and 25 μg/L) of MCLR for 45 days. The produced F1 embryos were then tested without further MCLR treatment. In the F0 generation, exposure to 25 μg/L MCLR reduced thyroxine (T4) but not 3, 5, 3'-triiodothyronine (T3) levels in females, while the T4 and T3 levels were unchanged in males. After parental exposure to MCLR, we observed a decreased hatching and growth retardation correlated with reduced thyroid hormone levels in the F1 offspring. The gene transcription and protein expression along the hypothalamic-pituitary-thyroid axis were detected to further investigate the possible mechanisms of MCLR-induced thyroid disruption. Our results indicated MCLR could disturb the thyroid endocrine system under environmentally relevant concentrations and the disrupting effects could be remarkably transmitted to its F1 offspring. We regard these adverse effects as a parental transgenerational toxicity of MCLR. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Chronic cadmium exposure in vitro induces cancer cell characteristics in human lung cells

    SciTech Connect

    Person, Rachel J.; Tokar, Erik J.; Xu, Yuanyuan; Orihuela, Ruben; Ngalame, Ntube N. Olive; Waalkes, Michael P.

    2013-12-01

    Cadmium is a known human lung carcinogen. Here, we attempt to develop an in vitro model of cadmium-induced human lung carcinogenesis by chronically exposing the peripheral lung epithelia cell line, HPL-1D, to a low level of cadmium. Cells were chronically exposed to 5 μM cadmium, a noncytotoxic level, and monitored for acquired cancer characteristics. By 20 weeks of continuous cadmium exposure, these chronic cadmium treated lung (CCT-LC) cells showed marked increases in secreted MMP-2 activity (3.5-fold), invasion (3.4-fold), and colony formation in soft agar (2-fold). CCT-LC cells were hyperproliferative, grew well in serum-free media, and overexpressed cyclin D1. The CCT-LC cells also showed decreased expression of the tumor suppressor genes p16 and SLC38A3 at the protein levels. Also consistent with an acquired cancer cell phenotype, CCT-LC cells showed increased expression of the oncoproteins K-RAS and N-RAS as well as the epithelial-to-mesenchymal transition marker protein Vimentin. Metallothionein (MT) expression is increased by cadmium, and is typically overexpressed in human lung cancers. The major MT isoforms, MT-1A and MT-2A were elevated in CCT-LC cells. Oxidant adaptive response genes HO-1 and HIF-1A were also activated in CCT-LC cells. Expression of the metal transport genes ZNT-1, ZNT-5, and ZIP-8 increased in CCT-LC cells culminating in reduced cadmium accumulation, suggesting adaptation to the metal. Overall, these data suggest that exposure of human lung epithelial cells to cadmium causes acquisition of cancer cell characteristics. Furthermore, transformation occurs despite the cell's ability to adapt to chronic cadmium exposure. - Highlights: • Chronic cadmium exposure induces cancer cell characteristics in human lung cells. • This provides an in vitro model of cadmium-induced human lung cell transformation. • This occurred with general and lung specific changes typical for cancer cells. • These findings add insight to the relationship

  2. +Gz-induced loss of consciousness: a case for training exposure to unconsciousness.

    PubMed

    Whinnery, J E; Burton, R R

    1987-05-01

    +Gz-induced loss of consciousness (G-LOC) continues to be a threat to aircrew flying high-performance fighter aircraft. All avenues to prevent G-LOC, and to reduce the resulting incapacitation should G-LOC occur, must be explored. Research has begun to accurately quantify all aspects of the G-LOC phenomenon. The emerging pattern from this research indicates that, theoretically, G-LOC incapacitation could be significantly reduced. Comparison of G-LOC with LOC induced by acute arrest of cerebral circulation reveals that the G-LOC incapacitation could be reduced by as much as 17 s. Results also indicate that the relative incapacitation period (confusion and disorientation) following unconsciousness could be reduced by at least 9 s for an individual who has previously experienced G-LOC. This suggests that exposure to G-LOC during centrifuge training could provide this orientation to G-LOC and potentially reduce the incapacitation period should it occur inflight. This exposure may be likened to the current altitude-hypoxia training requirement for aircrew. Experience to date supports the contention that such training may be accomplished with an acceptable safety margin.

  3. Transcriptional changes induced by in vivo exposure to pentachlorophenol (PCP) in Chironomus riparius (Diptera) aquatic larvae.

    PubMed

    Morales, Mónica; Martínez-Paz, Pedro; Martín, Raquel; Planelló, Rosario; Urien, Josune; Martínez-Guitarte, José Luis; Morcillo, Gloria

    2014-12-01

    Pentachlorophenol (PCP) has been extensively used worldwide as a pesticide and biocide and is frequently detected in the aquatic environment. In the present work, the toxicity of PCP was investigated in Chironomus riparius aquatic larvae. The effects following short- and long-term exposures were evaluated at the molecular level by analyzing changes in the transcriptional profile of different endocrine genes, as well as in genes involved in the stress response and detoxification. Interestingly, although no differences were found after 12- and 24-h treatments, at 96-h exposures PCP was able to induce significant increases in transcripts from the ecdysone receptor gene (EcR), the early ecdysone-inducible E74 gene, the estrogen-related receptor gene (ERR), the Hsp70 gene and the CYP4G gene. In contrast, the Hsp27 gene appeared to be downregulated, while the ultraspiracle gene (usp) (insect ortholog of the retinoid X receptor) was not altered in any of the conditions assayed. Moreover, Glutathione-S-Transferase (GST) activity was not affected. The results obtained show the ability of PCP to modulate transcription of different biomarker genes from important cellular metabolic activities, which could be useful in genomic approaches to monitoring. In particular, the significant upregulation of hormonal genes represents the first evidence at the genomic level of the potential endocrine disruptive effects of PCP on aquatic invertebrates. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Resveratrol protects the loss of connexin 43 induced by ethanol exposure in neonatal mouse cardiomyocytes.

    PubMed

    Tu, Su; Cao, Fu-Tao; Fan, Xiao-Chun; Yang, Cheng-Jian

    2017-06-01

    Excessive alcohol consumption provides risk to cardiomyopathy with unknown mechanisms. Resveratrol, a plant polyphenol, is widely reported for its cardiovascular benefits, while its effect on alcohol-induced impairments in cardiomyocytes largely remains unknown. Effects of resveratrol on the cardiomyocytes under ethanol insult were studied in vitro. Ethanol exposure in mouse neonatal cardiomyocytes increased cell death and induced a specific loss of tight junction protein, connexin 43. In spite of adverse effects at higher concentrations, resveratrol at 10 μM improved cell viability of cardiomyocytes in the presence of a deleterious dose of ethanol. Importantly, the co-treatment of resveratrol with ethanol exhibited the restoration of connexin 43 protein. Further assays showed that these effects were likely associated with the antioxidative actions of resveratrol, and correlated with the alleviation of MAP kinase activation in cultured cardiomyocytes in response to ethanol. Our data suggests a novel mechanism of cardiomyocyte cell loss under ethanol exposure and provides new evidence of protective effects of resveratrol in the cardiomyocytes.

  5. Exposure to ethanol and nicotine induces stress responses in human placental BeWo cells.

    PubMed

    Repo, Jenni K; Pesonen, Maija; Mannelli, Chiara; Vähäkangas, Kirsi; Loikkanen, Jarkko

    2014-01-13

    Human placental trophoblastic cancer BeWo cells can be used as a model of placental trophoblasts. We found that combined exposure to relevant exposure concentrations of ethanol (2‰) and nicotine (15 μM) induces an increase in the amount of reactive oxygen species (ROS). Neither ethanol or nicotine alone, nor their combination affected cell viability. However, nicotine decreased cell proliferation, both alone and combined with ethanol. Nicotine increased the expression of the endoplasmic reticulum (ER)-stress related protein GRP78/BiP, but not another marker of ER-stress, IRE1α. We also studied the effects of nicotine and/or ethanol on phosphorylation and expression of three mitogen-activated protein kinases (MAPKs), i.e. JNK, p38 and ERK1/2. Nicotine decreased the phosphorylation of JNK and also had similar effect on total amount of this protein. Phosphorylation and expression of p38 were increased 1.7- and 1.6-fold, respectively, by nicotine alone, and 1.9- and 2.1-fold by the combined treatment. Some increase (1.8-fold) was also seen in the phosphorylation of ERK2 at 48 h, in cells exposed to both ethanol and nicotine. This study shows that ethanol and nicotine, which harm the development of fetus may induce both oxidative and ER stress responses in human placental trophoblastic cells, implicating these mechanisms in their fetotoxic effects.

  6. Sub-chronic exposure to paraoxon neither induces nor exacerbates diabetes mellitus in Wistar rat.

    PubMed

    Nurulain, Syed M; Petroianu, Georg; Shafiullah, Mohamed; Kalász, Huba; Oz, Murat; Saeed, Tariq; Adem, Abdu; Adeghate, Ernest

    2013-10-01

    There is an increasing belief that organophosphorus compounds (OPCs) impair glucose homeostasis and cause hyperglycemia and diabetes mellitus. The present study was undertaken to investigate the putative diabetogenic effect of sub-lethal and sub-chronic exposure to paraoxon (POX), an extremely hazardous OPC used in pesticides. The effect of paraoxon on streptozotocin-induced diabetic rats was also examined. Each rat was injected with 100 nmol of POX 5 days per week for 6 weeks. Blood glucose levels and red blood cell acetylcholinesterase activity were measured weekly. Biochemical analysis and morphological studies were performed at the end of the experiment. The results revealed that POX neither induces nor exacerbates diabetes mellitus in experimental rats. Liver and kidney/body weight ratios revealed statistically insignificant differences when compared with controls. Biochemical analysis of urine samples showed a small but not significant increase in protein level in all groups. Urine bilirubin was significantly higher in the diabetes + POX group when compared with the control group. The number of blood cells in urine was significantly higher in the POX-treated group compared with the control group. Hyperglycemia was noted in the diabetes and diabetes + POX groups, but neither in the saline control nor in POX-treated normal rats. Electron microscopy of POX-treated pancreas did not show any morphological changes in beta cells. These results suggest that POX does not cause diabetes mellitus at sub-lethal sub-chronic exposure. Copyright © 2012 John Wiley & Sons, Ltd.

  7. Behavioral training reverses global cortical network dysfunction induced by perinatal antidepressant exposure

    PubMed Central

    Zhou, Xiaoming; Lu, Jordan Y.-F.; Darling, Ryan D.; Simpson, Kimberly L.; Zhu, Xiaoqing; Wang, Fang; Yu, Liping; Sun, Xinde; Merzenich, Michael M.; Lin, Rick C. S.

    2015-01-01

    Abnormal cortical circuitry and function as well as distortions in the modulatory neurological processes controlling cortical plasticity have been argued to underlie the origin of autism. Here, we chemically distorted those processes using an antidepressant drug-exposure model to generate developmental neurological distortions like those characteristics expressed in autism, and then intensively trained altered young rodents to evaluate the potential for neuroplasticity-driven renormalization. We found that young rats that were injected s.c. with the antidepressant citalopram from postnatal d 1–10 displayed impaired neuronal repetition-rate following capacity in the primary auditory cortex (A1). With a focus on recovering grossly degraded auditory system processing in this model, we showed that targeted temporal processing deficits induced by early-life antidepressant exposure within the A1 were almost completely reversed through implementation of a simple behavioral training strategy (i.e., a modified go/no-go repetition-rate discrimination task). Degraded parvalbumin inhibitory GABAergic neurons and the fast inhibitory actions that they control were also renormalized by training. Importantly, antidepressant-induced degradation of serotonergic and dopaminergic neuromodulatory systems regulating cortical neuroplasticity was sharply reversed. These findings bear important implications for neuroplasticity-based therapeutics in autistic patients. PMID:25646455

  8. Chronic corticosterone exposure reduces hippocampal glycogen level and induces depression-like behavior in mice.

    PubMed

    Zhang, Hui-yu; Zhao, Yu-nan; Wang, Zhong-li; Huang, Yu-fang

    2015-01-01

    Long-term exposure to stress or high glucocorticoid levels leads to depression-like behavior in rodents; however, the cause remains unknown. Increasing evidence shows that astrocytes, the most abundant cells in the central nervous system (CNS), are important to the nervous system. Astrocytes nourish and protect the neurons, and serve as glycogen repositories for the brain. The metabolic process of glycogen, which is closely linked to neuronal activity, can supply sufficient energy substrates for neurons. The research team probed into the effects of chronic corticosterone (CORT) exposure on the glycogen level of astrocytes in the hippocampal tissues of male C57BL/6N mice in this study. The results showed that chronic CORT injection reduced hippocampal neurofilament light protein (NF-L) and synaptophysin (SYP) levels, induced depression-like behavior in male mice, reduced hippocampal glycogen level and glycogen synthase activity, and increased glycogen phosphorylase activity. The results suggested that the reduction of the hippocampal glycogen level may be the mechanism by which chronic CORT treatment damages hippocampal neurons and induces depression-like behavior in male mice.

  9. Chronic corticosterone exposure reduces hippocampal glycogen level and induces depression-like behavior in mice*

    PubMed Central

    Zhang, Hui-yu; Zhao, Yu-nan; Wang, Zhong-li; Huang, Yu-fang

    2015-01-01

    Long-term exposure to stress or high glucocorticoid levels leads to depression-like behavior in rodents; however, the cause remains unknown. Increasing evidence shows that astrocytes, the most abundant cells in the central nervous system (CNS), are important to the nervous system. Astrocytes nourish and protect the neurons, and serve as glycogen repositories for the brain. The metabolic process of glycogen, which is closely linked to neuronal activity, can supply sufficient energy substrates for neurons. The research team probed into the effects of chronic corticosterone (CORT) exposure on the glycogen level of astrocytes in the hippocampal tissues of male C57BL/6N mice in this study. The results showed that chronic CORT injection reduced hippocampal neurofilament light protein (NF-L) and synaptophysin (SYP) levels, induced depression-like behavior in male mice, reduced hippocampal glycogen level and glycogen synthase activity, and increased glycogen phosphorylase activity. The results suggested that the reduction of the hippocampal glycogen level may be the mechanism by which chronic CORT treatment damages hippocampal neurons and induces depression-like behavior in male mice. PMID:25559957

  10. Active Immunity Induced by Passive IgG Post-Exposure Protection against Ricin

    PubMed Central

    Hu, Charles Chen; Yin, Junfei; Chau, Damon; Cherwonogrodzky, John W.; Hu, Wei-Gang

    2014-01-01

    Therapeutic antibodies can confer an instant protection against biothreat agents when administered. In this study, intact IgG and F(ab’)2 from goat anti-ricin hyperimmune sera were compared for the protection against lethal ricin mediated intoxication. Similar ricin-binding affinities and neutralizing activities in vitro were observed between IgG and F(ab’)2 when compared at the same molar concentration. In a murine ricin intoxication model, both IgG and F(ab’)2 could rescue 100% of the mice by one dose (3 nmol) administration of antibodies 1 hour after 5 × LD50 ricin challenge. Nine days later, when the rescued mice received a second ricin challenge (5 × LD50), only the IgG-treated mice survived; the F(ab’)2-treated mice did not. The experimental design excluded the possibility of residual goat IgG responsible for the protection against the second ricin challenge. Results confirmed that the active immunity against ricin in mice was induced quickly following the passive delivery of a single dose of goat IgG post-exposure. Furthermore, it was demonstrated that the induced active immunity against ricin in mice lasted at least 5 months. Therefore, passive IgG therapy not only provides immediate protection to the victim after ricin exposure, but also elicits an active immunity against ricin that subsequently results in long term protection. PMID:24451844

  11. Aluminium exposure induces Alzheimer's disease-like histopathological alterations in mouse brain.

    PubMed

    Rodella, L F; Ricci, F; Borsani, E; Stacchiotti, A; Foglio, E; Favero, G; Rezzani, R; Mariani, C; Bianchi, R

    2008-04-01

    Aluminium (Al) is a neurotoxic metal and Al exposure may be a factor in the aetiology of various neurodegenerative diseases such as Alzheimer's disease (AD). The major pathohistological findings in the AD brain are the presence of neuritic plaques containing beta-amyloid (Abeta) which may interfere with neuronal communication. Moreover, it has been observed that GRP78, a stress-response protein induced by conditions that adversely affect endoplasmic reticulum (ER) function, is reduced in the brain of AD patients. In this study, we investigated the correlation between the expression of Abeta and GRP78 in the brain cortex of mice chronically treated with aluminium sulphate. Chronic exposure over 12 months to aluminium sulphate in drinking water resulted in deposition of Abeta similar to that seen in congophilic amyloid angiopathy (CAA) in humans and a reduction in neuronal expression of GRP78 similar to what has previously been observed in Alzheimer's disease. So, we hypothesise that chronic Al administration is responsible for oxidative cell damage that interferes with ER functions inducing Abeta accumulation and neurodegenerative damage.

  12. Oral Exposure to Atrazine Induces Oxidative Stress and Calcium Homeostasis Disruption in Spleen of Mice

    PubMed Central

    Wang, Zhichun; Zhang, Chonghua; Jia, Liming

    2016-01-01

    The widely used herbicide atrazine (ATR) can cause many adverse effects including immunotoxicity, but the underlying mechanisms are not fully understood. The current study investigated the role of oxidative stress and calcium homeostasis in ATR-induced immunotoxicity in mice. ATR at doses of 0, 100, 200, or 400 mg/kg body weight was administered to Balb/c mice daily for 21 days by oral gavage. The studies performed 24 hr after the final exposure showed that ATR could induce the generation of reactive oxygen species in the spleen of the mice, increase the level of advanced oxidation protein product (AOPP) in the host serum, and cause the depletion of reduced glutathione in the serum, each in a dose-related manner. In addition, DNA damage was observed in isolated splenocytes as evidenced by increase in DNA comet tail formation. ATR exposure also caused increases in intracellular Ca2+ within splenocytes. Moreover, ATR treatment led to increased expression of genes for some antioxidant enzymes, such as HO-1 and Gpx1, as well as increased expression of NF-κB and Ref-1 proteins in the spleen. In conclusion, it appears that oxidative stress and disruptions in calcium homeostasis might play an important role in the induction of immunotoxicity in mice by ATR. PMID:27957240

  13. Active immunity induced by passive IgG post-exposure protection against ricin.

    PubMed

    Hu, Charles Chen; Yin, Junfei; Chau, Damon; Cherwonogrodzky, John W; Hu, Wei-Gang

    2014-01-21

    Therapeutic antibodies can confer an instant protection against biothreat agents when administered. In this study, intact IgG and F(ab')2 from goat anti-ricin hyperimmune sera were compared for the protection against lethal ricin mediated intoxication. Similar ricin-binding affinities and neutralizing activities in vitro were observed between IgG and F(ab')2 when compared at the same molar concentration. In a murine ricin intoxication model, both IgG and F(ab')2 could rescue 100% of the mice by one dose (3 nmol) administration of antibodies 1 hour after 5 × LD50 ricin challenge. Nine days later, when the rescued mice received a second ricin challenge (5 × LD50), only the IgG-treated mice survived; the F(ab')2-treated mice did not. The experimental design excluded the possibility of residual goat IgG responsible for the protection against the second ricin challenge. Results confirmed that the active immunity against ricin in mice was induced quickly following the passive delivery of a single dose of goat IgG post-exposure. Furthermore, it was demonstrated that the induced active immunity against ricin in mice lasted at least 5 months. Therefore, passive IgG therapy not only provides immediate protection to the victim after ricin exposure, but also elicits an active immunity against ricin that subsequently results in long term protection.

  14. Environmental exposure and HPV infection may act synergistically to induce lung tumorigenesis in nonsmokers

    PubMed Central

    Cheng, Ya-Wen; Lin, Frank Cheau-Feng; Chen, Chih-Yi; Hsu, Nan-Yung

    2016-01-01

    Most studies of lung tumorigenesis have focused on smokers rather than nonsmokers. In this study, we used human papillomavirus (HPV)-positive and HPV-negative lung cancer cells to test the hypothesis that HPV infection synergistically increases DNA damage induced by exposure to the carcinogen benzo[a]pyrene (B[a]P), and contributes to lung tumorigenesis in nonsmokers. DNA adduct levels induced by B[a]P in HPV-positive cells were significantly higher than in HPV-negative cells. The DNA adduct formation was dependent on HPV E6 oncoprotein expression. Gene and protein expression of two DNA repair genes, XRCC3 and XRCC5, were lower in B[a]P-treated E6-positive cells than in E6-negative lung cancer cells. The reduced expression was also detected immunohistochemically and was caused by increased promoter hypermethylation. Moreover, mutations of p53 and epidermal growth factor receptor (EGFR) genes in lung cancer patients were associated with XRCC5 inactivation. In sum, our study indicates that HPV E6-induced promoter hypermethylation of the XRCC3 and XRCC5 DNA repair genes and the resultant decrease in their expression increases B[a]P-induced DNA adducts and contributes to lung tumorigenesis in nonsmokers. PMID:26918347

  15. Characterization of seizures induced by acute exposure to an organophosphate herbicide, glufosinate-ammonium.

    PubMed

    Calas, André-Guilhem; Perche, Olivier; Richard, Olivier; Perche, Astrid; Pâris, Arnaud; Lauga, Fabien; Herzine, Ameziane; Palomo, Jennifer; Ardourel, Marie-Yvonne; Menuet, Arnaud; Mortaud, Stéphane; Pichon, Jacques; Montécot-Dubourg, Céline

    2016-05-04

    Glufosinate-ammonium (GLA), the active component of a widely used herbicide, induces convulsions in rodents and humans. In mouse, intraperitoneal treatment with 75 mg/kg GLA generates repetitive tonic-clonic seizures associated with 100% mortality within 72 h after treatment. In this context, we characterized GLA-induced seizures, their histological consequences and the effectiveness of diazepam treatment. Epileptic discharges on electroencephalographic recordings appeared simultaneously in the hippocampus and the cerebral cortex. Diazepam treatment at 6 h immediately stopped the seizures and prevented animal death. However, intermittent seizures were recorded on electroencephalogram from 6 h after diazepam treatment until 24 h, but had disappeared after 15 days. In our model, neuronal activation (c-Fos immunohistochemistry) was observed 6 h after GLA exposure in the dentate gyrus, CA1, CA3, amygdala, piriform and entorhinal cortices, indicating the activation of the limbic system. In these structures, Fluoro-Jade C and Cresyl violet staining did not show neuronal suffering. However, astroglial activation was clearly observed at 24 h and 15 days after GLA treatment in the amygdala, piriform and entorhinal cortices by PCR quantitative, western blot and immunohistochemistry. Concomitantly, glutamine synthetase mRNA expression (PCR quantitative), protein expression (western blot) and enzymatic activity were upregulated. In conclusion, our study suggests that GLA-induced seizures: (a) involved limbic structures and (b) induced astrocytosis without neuronal degeneration as an evidence of a reactive astrocyte beneficial effect for neuronal protection.

  16. Brain signaling and behavioral responses induced by exposure to (56)Fe-particle radiation

    NASA Technical Reports Server (NTRS)

    Denisova, N. A.; Shukitt-Hale, B.; Rabin, B. M.; Joseph, J. A.

    2002-01-01

    Previous experiments have demonstrated that exposure to 56Fe-particle irradiation (1.5 Gy, 1 GeV) produced aging-like accelerations in neuronal and behavioral deficits. Astronauts on long-term space flights will be exposed to similar heavy-particle radiations that might have similar deleterious effects on neuronal signaling and cognitive behavior. Therefore, the present study evaluated whether radiation-induced spatial learning and memory behavioral deficits are associated with region-specific brain signaling deficits by measuring signaling molecules previously found to be essential for behavior [pre-synaptic vesicle proteins, synaptobrevin and synaptophysin, and protein kinases, calcium-dependent PRKCs (also known as PKCs) and PRKA (PRKA RIIbeta)]. The results demonstrated a significant radiation-induced increase in reference memory errors. The increases in reference memory errors were significantly negatively correlated with striatal synaptobrevin and frontal cortical synaptophysin expression. Both synaptophysin and synaptobrevin are synaptic vesicle proteins that are important in cognition. Striatal PRKA, a memory signaling molecule, was also significantly negatively correlated with reference memory errors. Overall, our findings suggest that radiation-induced pre-synaptic facilitation may contribute to some previously reported radiation-induced decrease in striatal dopamine release and for the disruption of the central dopaminergic system integrity and dopamine-mediated behavior.

  17. Brain signaling and behavioral responses induced by exposure to (56)Fe-particle radiation

    NASA Technical Reports Server (NTRS)

    Denisova, N. A.; Shukitt-Hale, B.; Rabin, B. M.; Joseph, J. A.

    2002-01-01

    Previous experiments have demonstrated that exposure to 56Fe-particle irradiation (1.5 Gy, 1 GeV) produced aging-like accelerations in neuronal and behavioral deficits. Astronauts on long-term space flights will be exposed to similar heavy-particle radiations that might have similar deleterious effects on neuronal signaling and cognitive behavior. Therefore, the present study evaluated whether radiation-induced spatial learning and memory behavioral deficits are associated with region-specific brain signaling deficits by measuring signaling molecules previously found to be essential for behavior [pre-synaptic vesicle proteins, synaptobrevin and synaptophysin, and protein kinases, calcium-dependent PRKCs (also known as PKCs) and PRKA (PRKA RIIbeta)]. The results demonstrated a significant radiation-induced increase in reference memory errors. The increases in reference memory errors were significantly negatively correlated with striatal synaptobrevin and frontal cortical synaptophysin expression. Both synaptophysin and synaptobrevin are synaptic vesicle proteins that are important in cognition. Striatal PRKA, a memory signaling molecule, was also significantly negatively correlated with reference memory errors. Overall, our findings suggest that radiation-induced pre-synaptic facilitation may contribute to some previously reported radiation-induced decrease in striatal dopamine release and for the disruption of the central dopaminergic system integrity and dopamine-mediated behavior.

  18. Diclofenac systemic exposure is not increased when topical diclofenac is applied to ultraviolet-induced erythema.

    PubMed

    Magnette, J-L; Kienzler, J-L; Sallin, D; Ménart, C; Nollevaux, F; Knops, A

    2004-10-01

    Diclofenac is a non-steroidal anti-inflammatory drug used for a variety of painful and inflammatory conditions. A new low-dose, topical-gel form of diclofenac sodium (diclofenac-Na) has been developed for pain relief and redness reduction after sunburn. The objective was to compare exposure to oral diclofenac-Na with the systemic exposure to diclofenac after application of the new topical diclofenac-Na 0.1% Emulgel gel (diclofenac-Na gel) to normal skin and to that with ultraviolet-induced erythema relative. This study was an open, single-centre, three-period, non-randomised trial in 18 healthy Caucasian subjects. During the first period, 12.5 g gel (12.5 mg diclofenac-Na) was applied twice on a single day to normal skin. During the second period, a 25-mg diclofenac-Na, enteric-coated tablet was given orally three times in a single day. During the third period, the diclofenac-Na gel was applied, as in the first period, but during the early phase of an erythema induced by three times the ultraviolet minimal erythema dose, i.e. a first-degree sunburn associated with pain. During each period, venous blood samples were collected over 24 h and urine was collected over 72 h after first administration for the determination of diclofenac in plasma and urine and of 4'-OH-diclofenac in urine. The systemic exposure after topical application of 25 mg diclofenac-Na on sunburned skin was less than 3% that of 75 mg oral diclofenac-Na and was not increased to that measured on normal skin. The diclofenac-Na 0.1% Emulgel gel can be applied safely to sunburned skin (superficial sunburn, i.e. first degree) as well as to normal skin.

  19. Biomass Smoke Exposure Enhances Rhinovirus-Induced Inflammation in Primary Lung Fibroblasts.

    PubMed

    Capistrano, Sarah J; Zakarya, Razia; Chen, Hui; Oliver, Brian G

    2016-08-25

    Biomass smoke is one of the major air pollutants and contributors of household air pollution worldwide. More than 3 billion people use biomass fuels for cooking and heating, while other sources of exposure are from the occurrence of bushfires and occupational conditions. Persistent biomass smoke exposure has been associated with acute lower respiratory infection (ALRI) as a major environmental risk factor. Children under the age of five years are the most susceptible in developing severe ALRI, which accounts for 940,000 deaths globally. Around 90% of cases are attributed to viral infections, such as influenza, adenovirus, and rhinovirus. Although several epidemiological studies have generated substantial evidence of the association of biomass smoke and respiratory infections, the underlying mechanism is still unknown. Using an in vitro model, primary human lung fibroblasts were stimulated with biomass smoke extract (BME), specifically investigating hardwood and softwood types, and human rhinovirus-16 for 24 h. Production of pro-inflammatory mediators, such as IL-6 and IL-8, were measured via ELISA. Firstly, we found that hardwood and softwood smoke extract (1%) up-regulate IL-6 and IL-8 release (p ≤ 0.05). In addition, human rhinovirus-16 further increased biomass smoke-induced IL-8 in fibroblasts, in comparison to the two stimulatory agents alone. We also investigated the effect of biomass smoke on viral susceptibility by measuring viral load, and found no significant changes between BME exposed and non-exposed infected fibroblasts. Activated signaling pathways for IL-6 and IL-8 production by BME stimulation were examined using signaling pathway inhibitors. p38 MAPK inhibitor SB239063 significantly attenuated IL-6 and IL-8 release the most (p ≤ 0.05). This study demonstrated that biomass smoke can modulate rhinovirus-induced inflammation during infection, which can alter the severity of the disease. The mechanism by which biomass smoke exposure increases

  20. Effect of Maternal Electroacupuncture on Perinatal Nicotine Exposure-Induced Lung Phenotype in Offspring

    PubMed Central

    Ji, Bo; Zhao, Guo-Zhen; Sakurai, Reiko; Cao, Yu; Zhang, Zi-Jian; Wang, Dan; Yan, Ming-Na; Rehan, Virender K.

    2016-01-01

    Introduction Pregnant women exposed to tobacco smoke predispose the offspring to many adverse consequences including an altered lung development and function. There is no effective therapeutic intervention to block the effects of smoke exposure on the developing lung. Clinical and animal studies demonstrate that acupuncture can modulate a variety of pathophysiological processes, including those involving the respiratory system; however, whether acupuncture affects the lung damage caused by perinatal smoke exposure is not known. Methods To determine the effect of acupuncture on perinatal nicotine exposure on the developing lung, pregnant rat dams were administered (1) Saline; (2) Nicotine; or (3) Nicotine + electroacupuncture (EA). Nicotine was administered (1 mg/kg subcutaneously) once a day and EA was applied to both “Zusanli” (ST 36) points. Both interventions were administered from gestational day 6 to postnatal day 21 (PND21), following which pups were sacrificed. Lungs, blood and brain were collected to examine the markers of lung injury, repair and hypothalamic pituitary adrenal (HPA) axis. Results Concomitant EA application blocked nicotine-induced changes in lung morphology, lung Peroxisome Proliferator-Activated Receptor γ and Wingless-int signaling, two key lung developmental signaling pathways, hypothalamic pituitary adrenal axis (hypothalamic corticotropic releasing hormone and lung glucocorticoid receptor levels), and plasma β-endorphin levels. Conclusions Electroacupuncture blocks the nicotine-induced changes in lung developmental signaling pathways and the resultant myogenic lung phenotype, known to be present in the affected offspring. We conclude that EA is a promising novel intervention against the smoke exposed lung damage to the developing lung. PMID:27179524

  1. Intraperitoneal exposure of whitefish to microcystin-LR induces rapid liver injury followed by regeneration and resilience to subsequent exposures.

    PubMed

    Woźny, Maciej; Lewczuk, Bogdan; Ziółkowska, Natalia; Gomułka, Piotr; Dobosz, Stefan; Łakomiak, Alicja; Florczyk, Maciej; Brzuzan, Paweł

    2016-12-15

    To date, there has been no systematic approach comprehensively describing the sequence of pathological changes in fish during prolonged exposure to microcystin-LR (MC-LR). Towards this aim, juvenile whitefish individuals received an intraperitoneal injection with pure MC-LR, and the injection was repeated every week to maintain continuous exposure for 28days. During the exposure period, growth and condition of the fish were assessed based on biometric measurements. Additionally, selected biochemical markers were analysed in the fishes' blood, and their livers were carefully examined for morphological, ultrastructural, and molecular changes. The higher dose of MC-LR (100μg·kg(-1)) caused severe liver injury at the beginning of the exposure period, whereas the lower dose (10μg·kg(-1)) caused less, probably reversible injury, and its effects began to be observed later in the exposure period. These marked changes were accompanied by substantial MC-LR uptake by the liver. However, starting on the 7th day of exposure, cell debris began to be removed by phagocytes, then by 14th day, proliferation of liver cells had markedly increased, which led to reconstruction of the liver parenchyma at the end of the treatment. Surprisingly, despite weekly-repeated intraperitoneal injections, MC-LR did not accumulate over time of exposure which suggests its limited uptake in the later phase of exposure. In support, mRNA expression of the membrane transport protein oatp1d was decreased at the same time as the regenerative processes were observed. Our study shows that closing of active membrane transport may serve as one defence mechanism against further MC-LR intoxication.

  2. Exposure to Green Tea Extract Alters the Incidence of Specific Cyclophosphamide-Induced Malformations

    PubMed Central

    Logsdon, Amanda L.; Herring, Betty J.; Lockard, Jarrett E.; Miller, Brittany M.; Kim, Hanna; Hood, Ronald D.; Bailey, Melissa M.

    2012-01-01

    BACKGROUND Green tea extract (GTE) has been shown to have antioxidative properties due to its high content of polyphenols and catechin gallates. Previous studies indicated that catechin gallates scavenge free radicals and attenuate the effects of reactive oxidative species (ROS). Cyclophosphamide (CP) produces ROS, which can have adverse effects on development, causing limb, digit, and cranial abnormalities. The current study was performed to determine if exposure to GTE can decrease teratogenic effects induced by CP in CD-1 mice. METHODS From gestation days (GD) 6–13, mated CD-1 mice were dosed with 400 or 800 mg/kg/d GTE; 100, 200, 400, or 800 mg/kg/d GTE + CP; CP alone, or the vehicle. GTE was given by gavage. CP (20 mg/kg) was given by intraperitoneal injection on GD 10. Dams were sacrificed on GD 17, and their litters were examined for adverse effects. RESULTS The highest GTE dose did not effectively attenuate, and in some cases exacerbated the negative effect of CP. GTE alone was also associated with an increased incidence of microblepharia. Conversely, moderate GTE doses (200 &/or 400 mg/kg/d) attenuated the effect of CP on fetal weight and (GTE 200 mg/kg/d) decreased the incidences of certain defects resulting from CP exposure. CONCLUSIONS Exposure of a developing mammal to moderate doses of GTE can modulate the effects of exposure to CP during development, possibly by affecting biotransformation, while a higher GTE dose tended to exacerbate the developmental toxicity of CP. GTE alone appeared to cause an adverse effect on eyelid development. PMID:22447743

  3. Acute Acrolein Exposure Induces Impairment of Vocal Fold Epithelial Barrier Function

    PubMed Central

    Zheng, Wei; Sivasankar, M. Preeti

    2016-01-01

    Acrolein is a ubiquitous pollutant abundant in cigarette smoke, mobile exhaust, and industrial waste. There is limited literature on the effects of acrolein on vocal fold tissue, although there are clinical reports of voice changes after pollutant exposures. Vocal folds are responsible for voice production. The overall objective of this study was to investigate the effects of acrolein exposure on viable, excised vocal fold epithelial tissue and to characterize the mechanism underlying acrolein toxicity. Vocal fold epithelia were studied because they form the outermost layer of the vocal folds and are a primary recipient of inhaled pollutants. Porcine vocal fold epithelia were exposed to 0, 50, 100, 500, 900 or 1300 μM of acrolein for 3 hours; the metabolic activity, epithelial resistance, epithelial permeability, tight junction protein (occludin and claudin 3) expression, cell membrane integrity and lipid peroxidation were investigated. The data demonstrated that acrolein exposure at 500 μM significantly reduced vocal fold epithelial metabolic activity by 27.2% (p≤0.001). Incubation with 100 μM acrolein caused a marked increase in epithelial permeability by 130.5% (p<0.05) and a reduction in transepithelial electrical resistance (TEER) by 180.0% (p<0.001). While the expression of tight junctional protein did not change in acrolein-treated samples, the cell membrane integrity was significantly damaged with a 45.6% increase of lipid peroxidation as compared to controls (p<0.05). Taken together, these data provide evidence that acute acrolein exposure impairs vocal fold epithelial barrier integrity. Lipid peroxidation-induced cell membrane damage may play an important role in reducing the barrier function of the epithelium. PMID:27643990

  4. High perfluorooctanoic acid exposure induces autophagy blockage and disturbs intracellular vesicle fusion in the liver.

    PubMed

    Yan, Shengmin; Zhang, Hongxia; Guo, Xuejiang; Wang, Jianshe; Dai, Jiayin

    2017-01-01

    Perfluorooctanoic acid (PFOA) has been shown to cause hepatotoxicity and other toxicological effects. Though PPARα activation by PFOA in the liver has been well accepted as an important mechanism of PFOA-induced hepatotoxicity, several pieces of evidence have shown that the hepatotoxic effects of PFOA may not be fully explained by PPARα activation. In this study, we observed autophagosome accumulation in mouse livers as well as HepG2 cells after PFOA exposure. Further in vitro study revealed that the accumulation of autophagosomes was not caused by autophagic flux stimulation. In addition, we observed that PFOA exposure affected the proteolytic activity of HepG2 cells while significant dysfunction of lysosomes was not detected. Quantitative proteomic analysis of crude lysosomal fractions from HepG2 cells treated with PFOA revealed that 54 differentially expressed proteins were related to autophagy or vesicular trafficking and fusion. The proteomic results were further validated in the cells in vitro and livers in vivo after PFOA exposure, which implied potential dysfunction at the late stage of autophagy. However, in HepG2 cells, it seemed that further inhibition of autophagy did not significantly alter the effects of PFOA on cell viability. Although these findings demonstrate that PFOA blocked autophagy and disturbed intracellular vesicle fusion in the liver, the changes in autophagy were observed only at high cytotoxic concentrations of PFOA, suggesting that autophagy may not be a primary target or mode of toxicity. Furthermore, since altered liver autophagy was not observed at concentrations of PFOA associated with human exposures, the relevance of these findings must be questioned.

  5. Vanadium Exposure Induces Olfactory Dysfunction in an Animal Model of Metal Neurotoxicity

    PubMed Central

    Ngwa, Hilary Afeseh; Kanthasamy, Arthi; Jin, Huajun; Anantharam, Vellareddy; Kanthasamy, Anumantha G.

    2014-01-01

    Epidemiological evidence indicates chronic environmental exposure to transition metals may play a role in chronic neurodegenerative conditions such as Parkinson’s disease (PD). Chronic inhalation exposure to welding fumes containing metal mixtures may be associated with development of PD. A significant amount of vanadium is present in welding fumes, as vanadium pentoxide (V2O5), and incorporation of vanadium in the production of high strength steel has become more common. Despite the increased vanadium use in recent years, the neurotoxicological effects of this metal are not well characterized. Recently, we demonstrated that V2O5 induces dopaminergic neurotoxicity via protein kinase C delta (PKCδ)-dependent oxidative signaling mechanisms in dopaminergic neuronal cells. Since anosmia (inability to perceive odors) and non-motor deficits are considered to be early symptoms of neurological diseases, in the present study, we examined the effect of V2O5 on the olfactory bulb in animal models. To mimic the inhalation exposure, we intranasally administered C57 black mice a low-dose of 182 µg of V2O5 three times a week for one month, and behavioral, neurochemical and biochemical studies were performed. Our results revealed a significant decrease in olfactory bulb weights, tyrosine hydroxylase (TH) levels, levels of dopamine (DA) and its metabolite, 3, 4-dihydroxyphenylacetic acid (DOPAC) and increases in astroglia of the glomerular layer of the olfactory bulb in the treatment groups relative to vehicle controls. Neurochemical changes were accompanied by impaired olfaction and locomotion. These findings suggest that nasal exposure to V2O5 adversely affects olfactory bulbs, resulting in neurobehavioral and neurochemical impairments. These results expand our understanding of vanadium neurotoxicity in environmentally-linked neurological conditions. PMID:24362016

  6. Evaluation of genotoxicity induced by exposure to antineoplastic drugs in lymphocytes of oncology nurses and pharmacists.

    PubMed

    El-Ebiary, Ahmad A; Abuelfadl, Arwa A; Sarhan, Naglaa I

    2013-03-01

    The hazards of handling antineoplastic drugs have been raised and discussed in several studies. Introduction of new antineoplastics together with abuse of safety standards have contributed to the exposure risk for personnel who handle these substances. Interactions of antineoplastic drugs with biological structures vary according to the drug(s) and the individual's genetic susceptibility. This study was carried out to evaluate the genome damage induced by exposure to antineoplastic drugs in nurses (n = 20) and pharmacists (n = 18) working in the Oncology Department of Tanta Cancer Center. Thirty subjects matched in age, gender and smoking habit were selected as controls. Both chromosomal aberration analysis and micronucleus assay were used to evaluate genome damage in peripheral blood lymphocytes of the study subjects. The numbers of aberrant lymphocytes, as well as chromosomal aberration and micronuclei frequencies, were significantly increased in exposed personnel in comparison to matched controls. Compared with pharmacists, nurses showed notably higher level of chromosome damage. On the other hand, no significant difference in micronuclei frequency was observed between nurses and pharmacists. Correlation analyses pointed to the influence of age and duration of occupational exposure on the level of chromosome damage among exposed subjects. The results of this study confirmed that handling antineoplastic drugs without appropriate precautions imposed a genotoxic risk for exposed healthcare workers. These results address the need for regular biomonitoring of exposed personnel. In addition, they call attention to the need for proper implementation of intervention measures aiming to eliminate or significantly reduce worker exposure and prevent untoward biological effects. Copyright © 2011 John Wiley & Sons, Ltd.

  7. Vanadium exposure induces olfactory dysfunction in an animal model of metal neurotoxicity.

    PubMed

    Ngwa, Hilary Afeseh; Kanthasamy, Arthi; Jin, Huajun; Anantharam, Vellareddy; Kanthasamy, Anumantha G

    2014-07-01

    Epidemiological evidence indicates chronic environmental exposure to transition metals may play a role in chronic neurodegenerative conditions such as Parkinson's disease (PD). Chronic inhalation exposure to welding fumes containing metal mixtures may be associated with development of PD. A significant amount of vanadium is present in welding fumes, as vanadium pentoxide (V2O5), and incorporation of vanadium in the production of high strength steel has become more common. Despite the increased vanadium use in recent years, the neurotoxicological effects of this metal are not well characterized. Recently, we demonstrated that V2O5 induces dopaminergic neurotoxicity via protein kinase C delta (PKCδ)-dependent oxidative signaling mechanisms in dopaminergic neuronal cells. Since anosmia (inability to perceive odors) and non-motor deficits are considered to be early symptoms of neurological diseases, in the present study, we examined the effect of V2O5 on the olfactory bulb in animal models. To mimic the inhalation exposure, we intranasally administered C57 black mice a low-dose of 182μg of V2O5 three times a week for one month, and behavioral, neurochemical and biochemical studies were performed. Our results revealed a significant decrease in olfactory bulb weights, tyrosine hydroxylase (TH) levels, levels of dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and increases in astroglia of the glomerular layer of the olfactory bulb in the treatment groups relative to vehicle controls. Neurochemical changes were accompanied by impaired olfaction and locomotion. These findings suggest that nasal exposure to V2O5 adversely affects olfactory bulbs, resulting in neurobehavioral and neurochemical impairments. These results expand our understanding of vanadium neurotoxicity in environmentally-linked neurological conditions.

  8. Chronic dietary exposure to environmental organochlorine contaminants induces thyroid gland lesions in Arctic foxes (Vulpes lagopus).

    PubMed

    Sonne, Christian; Wolkers, Hans; Leifsson, Pall S; Iburg, Tine; Jenssen, Bjørn Munro; Fuglei, Eva; Ahlstrøm, Oystein; Dietz, Rune; Kirkegaard, Maja; Muir, Derek C G; Jørgensen, Even H

    2009-08-01

    The impact of dietary organochlorine (OC) exposure on thyroid gland pathology was studied in farmed male Arctic foxes (Vulpes lagopus). The exposed group (n=16) was fed a diet based on wild minke whale (Balaenoptera acutorostrata) blubber as a main fat source in order to mimic the exposure to OC cocktails in the Artic environment. This resulted in an exposure of approximately 17 microg Sigma OC/kg day and a Sigma OC residue adipose tissue and liver concentration of 1700 and 4470 ng/gl.w., respectively, after 16 months of exposure. Control foxes (n=13) were fed a diet with pork (Sus scrofa) fat as a main fat source containing significantly lower OC concentrations. The food composition fed to the control and exposed group was standardized for nutrient contents. Four OC-related histopathological changes were found: (1) flat-epithelial-cell true thyroid cysts (TC) characterized by neutral content; (2) remnants of simple squamous epithelial-cell embryonic ducts containing neutral debris (EDN); (3) remnants of stratified squamous epithelial-cell embryonic ducts containing acid mucins often accompanied with debris of leukocyte inflammatory nature (EDM) and (4) disseminated thyroid C-cell hyperplasia (HPC). Of these, the prevalence of TC, EDN and HPC was significantly highest in the exposed group (chi(2) test: all p<0.04). The study shows that the OC mixture in minke whale blubber may cause development of thyroid gland cysts, C-cell hyperplasia and increase the prevalence of cystic remnants of embryonic ducts. The mechanism causing these effects could include endocrine disruption of the hypothalamus-pituitary-thyroid (HPT) axis, a disturbance of the calcium homeostasis/metabolism or energy metabolism or immune suppression. Because concentrations of OCs are higher in wild Arctic foxes, it is likely that these animals could suffer from similar OC-induced thyroid gland pathological and functional changes.

  9. Alternaria alternata allergens: Markers of exposure, phylogeny and risk of fungi-induced respiratory allergy.

    PubMed

    Gabriel, Marta F; Postigo, Idoia; Tomaz, Cândida T; Martínez, Jorge

    2016-01-01

    Alternaria alternata spores are considered a well-known biological contaminant and a very common potent aeroallergen source that is found in environmental samples. The most intense exposure to A. alternata allergens is likely to occur outdoors; however, Alternaria and other allergenic fungi can colonize in indoor environments and thereby increase the fungal aeroallergen exposure levels. A consequence of human exposure to fungal aeroallergens, sensitization to A. alternata, has been unequivocally associated with increased asthma severity. Among allergenic proteins described in this fungal specie, the major allergen, Alt a 1, has been reported as the main elicitor of airborne allergies in patients affected by a mold allergy and considered a marker of primary sensitization to A. alternata. Moreover, A. alternata sensitization seems to be a triggering factor in the development of poly-sensitization, most likely because of the capability of A. alternata to produce, in addition to Alt a 1, a broad and complex array of cross-reactive allergens that present homologs in several other allergenic sources. The study and understanding of A. alternata allergen information may be the key to explaining why sensitization to A. alternata is a risk factor for asthma and also why the severity of asthma is associated to this mold. Compared to other common environmental allergenic sources, such as pollens and dust mites, fungi are reported to be neglected and underestimated. The rise of the A. alternata allergy has enabled more research into the role of this fungal specie and its allergenic components in the induction of IgE-mediated respiratory diseases. Indeed, recent research on the identification and characterization of A. alternata allergens has allowed for the consideration of new perspectives in the categorization of allergenic molds, assessment of exposure and diagnosis of fungi-induced allergies.

  10. Bioeffects induced by exposure to microwaves are mitigated by superposition of ELF noise.

    PubMed

    Litovitz, T A; Penafiel, L M; Farrel, J M; Krause, D; Meister, R; Mullins, J M

    1997-01-01

    We have previously demonstrated that microwave fields, amplitude modulated (AM) by an extremely low-frequency (ELF) sine wave, can induce a nearly twofold enhancement in the activity of ornithine decarboxylase (ODC) in L929 cells at SAR levels of the order of 2.5 W/kg. Similar, although less pronounced, effects were also observed from exposure to a typical digital cellular phone test signal of the same power level, burst modulated at 50 Hz. We have also shown that ODC enhancement in L929 cells produced by exposure to ELF fields can be inhibited by superposition of ELF noise. In the present study, we explore the possibility that similar inhibition techniques can be used to suppress the microwave response. We concurrently exposed L929 cells to 60 Hz AM microwave fields or a 50 Hz burst-modulated DAMPS (Digital Advanced Mobile Phone System) digital cellular phone field at levels known to produce ODC enhancement, together with band-limited 30-100 Hz ELF noise with root mean square amplitude of up to 10 microT. All exposures were carried out for 8 h, which was previously found to yield the peak microwave response. In both cases, the ODC enhancement was found to decrease exponentially as a function of the noise root mean square amplitude. With 60 Hz AM microwaves, complete inhibition was obtained with noise levels at or above 2 microT. With the DAMPS digital cellular phone signal, complete inhibition occurred with noise levels at or above 5 microT. These results suggest a possible practical means to inhibit biological effects from exposure to both ELF and microwave fields.

  11. DNA damage induced by occupational and environmental exposure to miscellaneous chemicals.

    PubMed

    da Silva, Juliana

    Epidemiological studies for hazardous situations resulting from the risk of environmental and/or occupational exposure to miscellaneous chemicals present several difficulties. Biomonitoring of human populations can provide an early detection system for the initiation of cell dysregulation in the development of cancer, which would help develop an efficient prevention program. Recently, the cytokinesis-block micronucleus (CBMN) assay in lymphocyte cells has become an important tool for assessing DNA damage in exposed populations. This is the method of choice for population-based studies of occupational and/or environmental exposure to different agents. In this review, human populations exposed to coal, dyes, paints, organic solvents in a complex mixture, and others miscellaneous chemicals were analyzed. Data from 28 studies was evaluated in relation to the effect of complex mixture exposition on micronucleus (MN) frequency. Other biomarkers and the background factors were evaluated as well, such as gender, age, or smoking habit. Most of these studies (75%) showed a significant increase of micronucleated cells to exposed groups in relation to the control groups, besides chromosomal aberrations (CA), sister chromatid exchanging (SCE) and comet cells (comet assay). The studies from this review about miscellaneous chemicals exposures using CBMN assay have indicated some time and dose-dependent effects. Overall, the findings suggest that the responses resulting from exposure to complex mixtures are varied and complicated. However, they are also an important mechanism of DNA damage concerning disruption of metal ion homeostasis that may lead to oxidative stress, a state where increased formation of reactive oxygen species (ROS) overwhelms body antioxidant protection and subsequently could induce cancer.

  12. DNA strand breaks in human nasal respiratory epithelium are induced upon exposure to urban pollution.

    PubMed Central

    Calderon-Garciduenas, L; Osnaya-Brizuela, N; Ramirez-Martinez, L; Villarreal-Calderon, A

    1996-01-01

    All organisms have the ability to respond and adapt to a myriad of environmental insults. The human respiratory epithelium, when exposed to oxidant gases in photochemical smog, is at risk of DNA damage and requires efficient cellular adaptative responses to resist the environmentally induced cell damage. Ozone and its reaction products induce in vitro and in vivo DNA single strand breaks (SSBs) in respiratory epithelial cells and alveolar macrophages. To determine if exposure to a polluted atmosphere with ozone as the main criteria pollutant induces SSBs in nasal epithelium, we studied 139 volunteers, including a control population of 19 children and 13 adult males who lived in a low-polluted Pacific port, 69 males and 16 children who were permanent residents of Southwest Metropolitan Mexico City (SWMMC), and 22 young males newly arrived to SWMMC and followed for 12 weeks. Respiratory symptoms, nasal cytology and histopathology, cell viabilities, and single-cell gel electrophoresis were investigated. Atmospheric pollutant data were obtained from a fixed-site monitoring station. SWMMC volunteers spent >7 hr/day outdoors and all had upper respiratory symptoms. A significant difference in the numbers of DNA-damaged nasal cells was observed between control and chronically exposed subjects, both in children (p<0.00001) and in adults (p<0.01). SSBs in newly arrived subjects quickly increased upon arrival to the city, from 39.8 +/- 8.34% in the first week to 67.29 +/- 2.35 by week 2. Thereafter, the number of cells with SSBs remained stable in spite of the continuous increase in cumulative ozone, suggesting a threshold for cumulative DNA nasal damage. Exposure to a polluted urban atmosphere induces SSBs in human nasal respiratory epithelium, and nasal SSBs could serve as a biomarker of ozone exposure. Further, because DNA strand breaks are a threat to cell viability and genome integrity and appear to be a critical lesion responsible for p53 induction, nasal SSBs should be

  13. DNA strand breaks in human nasal respiratory epithelium are induced upon exposure to urban pollution.

    PubMed

    Calderon-Garciduenas, L; Osnaya-Brizuela, N; Ramirez-Martinez, L; Villarreal-Calderon, A

    1996-02-01

    All organisms have the ability to respond and adapt to a myriad of environmental insults. The human respiratory epithelium, when exposed to oxidant gases in photochemical smog, is at risk of DNA damage and requires efficient cellular adaptative responses to resist the environmentally induced cell damage. Ozone and its reaction products induce in vitro and in vivo DNA single strand breaks (SSBs) in respiratory epithelial cells and alveolar macrophages. To determine if exposure to a polluted atmosphere with ozone as the main criteria pollutant induces SSBs in nasal epithelium, we studied 139 volunteers, including a control population of 19 children and 13 adult males who lived in a low-polluted Pacific port, 69 males and 16 children who were permanent residents of Southwest Metropolitan Mexico City (SWMMC), and 22 young males newly arrived to SWMMC and followed for 12 weeks. Respiratory symptoms, nasal cytology and histopathology, cell viabilities, and single-cell gel electrophoresis were investigated. Atmospheric pollutant data were obtained from a fixed-site monitoring station. SWMMC volunteers spent >7 hr/day outdoors and all had upper respiratory symptoms. A significant difference in the numbers of DNA-damaged nasal cells was observed between control and chronically exposed subjects, both in children (p<0.00001) and in adults (p<0.01). SSBs in newly arrived subjects quickly increased upon arrival to the city, from 39.8 +/- 8.34% in the first week to 67.29 +/- 2.35 by week 2. Thereafter, the number of cells with SSBs remained stable in spite of the continuous increase in cumulative ozone, suggesting a threshold for cumulative DNA nasal damage. Exposure to a polluted urban atmosphere induces SSBs in human nasal respiratory epithelium, and nasal SSBs could serve as a biomarker of ozone exposure. Further, because DNA strand breaks are a threat to cell viability and genome integrity and appear to be a critical lesion responsible for p53 induction, nasal SSBs should be

  14. Subchronic Arsenic Exposure Induces Anxiety-Like Behaviors in Normal Mice and Enhances Depression-Like Behaviors in the Chemically Induced Mouse Model of Depression.

    PubMed

    Chang, Chia-Yu; Guo, How-Ran; Tsai, Wan-Chen; Yang, Kai-Lin; Lin, Li-Chuan; Cheng, Tain-Junn; Chuu, Jiunn-Jye

    2015-01-01

    Accumulating evidence implicates that subchronic arsenic exposure causes cerebral neurodegeneration leading to behavioral disturbances relevant to psychiatric disorders. However, there is still little information regarding the influence of subchronic exposure to arsenic-contaminated drinking water on mood disorders and its underlying mechanisms in the cerebral prefrontal cortex. The aim of this study is to assess the effects of subchronic arsenic exposure (10 mg/LAs2O3 in drinking water) on the anxiety- and depression-like behaviors in normal mice and in the chemically induced mouse model of depression by reserpine pretreatment. Our findings demonstrated that 4 weeks of arsenic exposure enhance anxiety-like behaviors on elevated plus maze (EPM) and open field test (OFT) in normal mice, and 8 weeks of arsenic exposure augment depression-like behaviors on tail suspension test (TST) and forced swimming test (FST) in the reserpine pretreated mice. In summary, in this present study, we demonstrated that subchronic arsenic exposure induces only the anxiety-like behaviors in normal mice and enhances the depression-like behaviors in the reserpine induced mouse model of depression, in which the cerebral prefrontal cortex BDNF-TrkB signaling pathway is involved. We also found that eight weeks of subchronic arsenic exposure are needed to enhance the depression-like behaviors in the mouse model of depression. These findings imply that arsenic could be an enhancer of depressive symptoms for those patients who already had the attribute of depression.

  15. Subchronic Arsenic Exposure Induces Anxiety-Like Behaviors in Normal Mice and Enhances Depression-Like Behaviors in the Chemically Induced Mouse Model of Depression

    PubMed Central

    Chang, Chia-Yu; Guo, How-Ran; Tsai, Wan-Chen; Yang, Kai-Lin; Lin, Li-Chuan

    2015-01-01

    Accumulating evidence implicates that subchronic arsenic exposure causes cerebral neurodegeneration leading to behavioral disturbances relevant to psychiatric disorders. However, there is still little information regarding the influence of subchronic exposure to arsenic-contaminated drinking water on mood disorders and its underlying mechanisms in the cerebral prefrontal cortex. The aim of this study is to assess the effects of subchronic arsenic exposure (10 mg/LAs2O3 in drinking water) on the anxiety- and depression-like behaviors in normal mice and in the chemically induced mouse model of depression by reserpine pretreatment. Our findings demonstrated that 4 weeks of arsenic exposure enhance anxiety-like behaviors on elevated plus maze (EPM) and open field test (OFT) in normal mice, and 8 weeks of arsenic exposure augment depression-like behaviors on tail suspension test (TST) and forced swimming test (FST) in the reserpine pretreated mice. In summary, in this present study, we demonstrated that subchronic arsenic exposure induces only the anxiety-like behaviors in normal mice and enhances the depression-like behaviors in the reserpine induced mouse model of depression, in which the cerebral prefrontal cortex BDNF-TrkB signaling pathway is involved. We also found that eight weeks of subchronic arsenic exposure are needed to enhance the depression-like behaviors in the mouse model of depression. These findings imply that arsenic could be an enhancer of depressive symptoms for those patients who already had the attribute of depression. PMID:26114099

  16. DNA damage induced by Strontium-90 exposure at low concentrations in mesenchymal stromal cells: the functional consequences

    PubMed Central

    Musilli, S.; Nicolas, N.; El Ali, Z.; Orellana-Moreno, P.; Grand, C.; Tack, K.; Kerdine-Römer, S.; Bertho, J. M.

    2017-01-01

    90Sr is one of the radionuclides released after nuclear accidents that can significantly impact human health in the long term. 90Sr accumulates mostly in the bones of exposed populations. P