In utero and lactational exposure to a mixture of environmental contaminants detected in canadian arctic human populations alters retinoid levels in rat offspring with low margins of exposure

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Arctic inhabitants are highly exposed to persistent organic pollutants (POP), which may produce adverse health effects. This study characterized alterations in tissue retinoid (vitamin A) levels in rat offspring and their dams following in utero and
  This article was downloaded by: [Lubna Elabbas]On: 08 March 2014, At: 13:27Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,37-41 Mortimer Street, London W1T 3JH, UK Journal of Toxicology and Environmental Health, PartA: Current Issues Publication details, including instructions for authors and subscription information: In Utero and Lactational Exposure to a Mixture ofEnvironmental Contaminants Detected in CanadianArctic Human Populations Alters Retinoid Levels in RatOffspring with Low Margins of Exposure Lubna E. Elabbas a  , Javier Esteban a   b  , Xavier Barber c  , Gerd Hamscher d   e  , Heinz Nau d  ,Wayne J. Bowers f   i  , Jamie S. Nakai f  , Maria Herlin a  , Agneta Åkesson a  , Matti Viluksela g   h , Daniel Borg a  & Helen Håkansson aa  Institute of Environmental Medicine , Karolinska Institutet , Stockholm , Sweden b  Instituto de Bioingeniería , Universidad Miguel Hernández de Elche , Elche (Alicante) ,Spain c  Centro de Investigación Operativa, Universidad Miguel Hernández de Elche , Elche(Alicante) , Spain d  Institute for Food Toxicology and Analytical Chemistry , University of Veterinary Medicine ,Hannover , Germany e  Institute for Food Chemistry and Food Biotechnology , Justus Liebig University , Giessen ,Germany f  Neurotoxicology Laboratory , Environmental Health Sciences and Research Bureau, HealthCanada , Ottawa , Canada g  Department of Environmental Health , National Institute for Health and Welfare , Kuopio ,Finland h  Department of Environmental Science , University of Eastern Finland , Kuopio , Finland i  Department of Neuroscience , Carleton University , Ottawa , CanadaPublished online: 03 Mar 2014. To cite this article:  Lubna E. Elabbas , Javier Esteban , Xavier Barber , Gerd Hamscher , Heinz Nau , Wayne J. Bowers , JamieS. Nakai , Maria Herlin , Agneta Åkesson , Matti Viluksela , Daniel Borg & Helen Håkansson (2014) In Utero and LactationalExposure to a Mixture of Environmental Contaminants Detected in Canadian Arctic Human Populations Alters Retinoid Levelsin Rat Offspring with Low Margins of Exposure, Journal of Toxicology and Environmental Health, Part A: Current Issues, 77:5,223-245, DOI: 10.1080/15287394.2013.861776 To link to this article: PLEASE SCROLL DOWN FOR ARTICLETaylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) containedin the publications on our platform. However, Taylor & Francis, our agents, and our licensors make norepresentations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of theContent. Any opinions and views expressed in this publication are the opinions and views of the authors, andare not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon andshould be independently verified with primary sources of information. Taylor and Francis shall not be liable forany losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever  or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use ofthe Content.This article may be used for research, teaching, and private study purposes. Any substantial or systematicreproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in anyform to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://    D  o  w  n   l  o  a   d  e   d   b  y   [   L  u   b  n  a   E   l  a   b   b  a  s   ]  a   t   1   3  :   2   7   0   8   M  a  r  c   h   2   0   1   4   Journal of Toxicology and Environmental Health, Part A , 77:223–245, 2014Copyright © 2014 Crown copyrightISSN: 1528-7394 print / 1087-2620 onlineDOI: 10.1080/15287394.2013.861776 IN UTERO AND LACTATIONAL EXPOSURE TO A MIXTURE OF ENVIRONMENTALCONTAMINANTS DETECTED IN CANADIAN ARCTIC HUMAN POPULATIONS ALTERS RETINOID LEVELS IN RAT OFFSPRING WITH LOW MARGINS OF EXPOSURE Lubna E. Elabbas 1 , Javier Esteban 1,2 , Xavier Barber 3 , Gerd Hamscher 4,5 , Heinz Nau 4 ,Wayne J. Bowers 6,9 , Jamie S. Nakai 6 , Maria Herlin 1 , Agneta Åkesson 1 , Matti Viluksela 7,8 ,Daniel Borg 1 , Helen Håkansson 1 1 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden 2 Instituto de Bioingeniería, Universidad Miguel Hernández de Elche, Elche (Alicante), Spain 3 Centro de Investigación Operativa, Universidad Miguel Hernández de Elche, Elche (Alicante),Spain 4 Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine,Hannover, Germany 5 Institute for Food Chemistry and Food Biotechnology, Justus Liebig University,Giessen, Germany 6 Neurotoxicology Laboratory, Environmental Health Sciences and Research Bureau, HealthCanada, Ottawa, Canada 7 Department of Environmental Health, National Institute for Health and Welfare,Kuopio, Finland 8 Department of Environmental Science, University of Eastern Finland, Kuopio, Finland 9 Department of Neuroscience, Carleton University, Ottawa, Canada  Arctic inhabitants are highly exposed to persistent organic pollutants (POP), which mayproduce adverse health effects. This study characterized alterations in tissue retinoid (vita-min A) levels in rat offspring and their dams following in utero and lactational exposureto the Northern Contaminant Mixture (NCM), a mixture of 27 contaminants includ-ing polychlorinated biphenyls (PCB), organochlorine (OC) pesticides, and methylmercury(MeHg), present in maternal blood of the Canadian Arctic Inuit population. Further, effectlevels for retinoid system alterations and other endpoints were compared to the Arctic Inuitpopulation exposure and their interrelationships were assessed. Sprague-Dawley rat damswere dosed with NCM from gestational day 1 to postnatal day (PND) 23. Livers, kidneys andserum were obtained from offspring on PND35, PND77, and PND350 and their dams onPND30 for analysis of tissue retinoid levels, hepatic cytochrome P-450 (CYP) enzymes, andserum thyroid hormones. Benchmark doses were established for all endpoints, and a partialleast-squares regression analysis was performed for NCM treatment, hepatic retinoid levels,CYP enzyme induction, and thyroid hormone levels, as well as body and liver weights. Hepaticretinoid levels were sensitive endpoints, with the most pronounced effects at PND35 thoughstill apparent at PND350. The effects on tissue retinoid levels and changes in CYP enzymeactivities, body and liver weights, and thyroid hormone levels were associated and likelydriven by dioxin-like compounds in the mixture. Low margins of exposure were observedfor all retinoid endpoints at PND35. These findings are important for health risk assessmentof Canadian Arctic populations and further support the use of retinoid system analyses intesting of endocrine-system-modulating compounds. Received 27 August 2013; accepted 30 October 2013. Address correspondence to Helen Håkansson, Institute of Environmental Medicine, Karolinska Institutet, PO Box 210, SE-171 77Stockholm, Sweden. E-mail: 223    D  o  w  n   l  o  a   d  e   d   b  y   [   L  u   b  n  a   E   l  a   b   b  a  s   ]  a   t   1   3  :   2   7   0   8   M  a  r  c   h   2   0   1   4  224 L. E. ELABBAS ET AL. Persistent organic pollutants (POP), heavymetals, and hydrocarbon contaminants aretransported to the Arctic marine environment where they bioaccumulate and biomagnifyin biota (Borgå et al., 2004; Macdonaldet al., 2000). Concerns regarding adverseeffects on the health of Canadian Arcticinhabitants from environmental contaminantsincluding polychlorinated biphenyls (PCB) andmethylmercury (MeHg) have been raised(Bjerregaard et al., 2001; Van Oostdam et al.,1999; Welfinger-Smith et al., 2011) based ontheir consumption of fish and marine mam-mals in their traditional diet. In particular,fetuses and infants are considered suscepti-ble population groups to chemical exposuredue to the possibility of interference with crit-ical periods of development (Makri et al.,2004). Indeed, studies on the Arctic Inuit population, as well as on other populationswith similar traditional diets, observed asso-ciations between prenatal exposure to POPand MeHg and neurological disturbances suchas cognitive impairment and neurobehavioralchanges, immunodeficiency, and cardiovascu-lar and metabolic disorders (Arctic Monitoringand Assessment Programme [AMAP], 2009).These findings have been confirmed in exper-imental studies in rodents showing that expo-sure to mixtures of organochlorine (OC) con-taminantsaffectsgrowth,cellularandmolecularprocesses, immune competence, neurobehav-ioral development, liver and thyroid function,and reproductive development and perfor-mance (Anas et al., 2005; Bowers et al., 2004;Chu et al., 2001, 2005; Desaulniers et al.,2005). Since no apparent study had been con-ducted using environmentally relevant expo-sure to mixtures of contaminants proportionalto those found in the blood of Arctic humanpopulations, this study was undertaken whererat dams were exposed during gestation andlactation to the Northern Contaminant Mixture(NCM) (Chu et al., 2008). The NCM is a recon-stituted mixture of 27 contaminants, includingPCB, OC pesticides, and MeHg, based onthe blood profile of contaminants in maternalblood of the Arctic Inuit population (Muckleet al., 2001, 2003), yielding blood levels of the different constituents in the rats similar tothose in the human population (Chu et al.,2008). Observed effects in rat offspring con-sisted of suppressed growth, changes in organweights, and biochemical and histopathologicalalterations in liver, thyroid, and spleen. One of the most sensitive and persistent effects identi-fied in offspring was decreased hepatic retinoid(vitamin A) levels. Due to the vital role of thisnonsteroidal hormone system over the entirelife span, this finding warrants further investi-gation with regard to possible adverse healthconsequences as well as underlying mode-of-action (MOA) information.Retinoids are essential for normal embry-onic growth and development, vision, repro-duction, immune function, and tissue home-ostasis (Blomhoff and Blomhoff, 2006). Whilederived from food, retinoids are stored in stel-late cells in liver and other target tissues asretinyl esters, mainly retinyl palmitate, and mayupon physiological request be converted toretinol, retinal, or retinoic acid (RA), as needed(Balmer and Blomhoff, 2002). Transcriptionalretinoid functions are mediated via the nuclearretinoic acid receptor (RAR) and retinoid Xreceptor (RXR) families, which are activatedby all- trans -RA and its metabolite 9- cis -RA,respectively (Balmer and Blomhoff, 2002; Tateet al., 1994). All- trans -RA alone is involveddirectly or indirectly in the regulation of hun-dreds of genes. A metabolite of RA, 9- cis -4-oxo-13,14-dihydroretinoic acid (9c-4o-13,14-dh-RA), also an agonist of RAR (Schuchardt et al., 2009), was shown to be a sensitivemarker of dioxin exposure (Schmidt et al.,2003a; Fletcher et al., 2005). Studies in ratsdemonstrated that alterations in tissue retinoidlevels, i.e., reduction of hepatic retinoids andincrease of renal retinoids, is one of the most sensitive endpoints following exposure to arylhydrocarbon receptor (AhR) ligands such asdioxins and dioxin-like (DL) PCB (Chen et al.,1992; Chu et al., 2001; Fletcher et al., 2001,2005; Håkansson et al., 1991a, 1991b; VanBirgelen et al., 1994a, 1994b), as well as topolybrominated diphenyl ethers (PBDE) (Ellis-Hutchins et al., 2006, 2009; Van der Venet al., 2008a, 2008b) and other brominated    D  o  w  n   l  o  a   d  e   d   b  y   [   L  u   b  n  a   E   l  a   b   b  a  s   ]  a   t   1   3  :   2   7   0   8   M  a  r  c   h   2   0   1   4  CONTAMINANT MIXTURE MODULATES RETINOID METABOLISM 225 compounds (Van der Ven et al., 2008c, 2009). A similar response was also seen in exper-imental studies in other mammalian species(Brunström et al., 1991; Fletcher et al., 2001)and in various wildlife species (Brouwer et al.,1989; Doyon et al., 1998; Grasman et al.,1996; Kirkegaard et al., 2010; Murk et al.,1998; Skaare et al., 2001). Consequences of amodulated retinoid system are expected to beadverse and wide-ranging due to their numer-ous physiological functions, and hence it wasproposed that effects on the retinoid systemneed to be incorporated into existing stan-dard guidelines for testing of chemicals withpotential endocrine-system-modulating prop-erties (Organization for Economic Cooperationand Development [OECD], 2012).This study further elucidates the impact of NCM exposure on hepatic retinoid levels in rat offspring and their dams. Effect levels of thesechanges and of other toxicological endpointswere established using benchmark dose (BMD)analysis, their interrelationships were assessedusing an orthogonal partial least-squares anal-ysis (PLS), and the findings were analyzed inrelation to possible adverse effects on the highlyexposed Arctic Inuit population. In addition,to what extent DL components were produc-ing the observed effects was determined usingthe toxic equivalency (TEQ) concept approach(Van den Berg et al., 2006). This is the first study to investigate the effects of a mixture of OC of direct human relevance on the profileof individual retinoid forms in rat offspring andtheir dams following in utero and lactationalexposure. MATERIALS AND METHODSChemicals Details of chemical constituents and prepa-ration of the NCM were previously described(Chu et al., 2008). Briefly, the NCM is com-posed of 14 PCB congeners, 12 OC pesti-cides, and MeHg, and is based on the pro-file of chemicals found in maternal blood of Canadian Arctic populations (Muckle et al.,2001, 2003). For retinoid analyses by high-performance liquid chromatography (HPLC),chemicals were used according to Nilsson et al.(2000) and Schmidt et al. (2003b). For analysisof cytochrome P-450  ( CYP) enzymes, chem-icals were used as described in Chu et al.(2008).  Animals and Experimental Design  All animals were maintained and usedin accordance with the Canadian Council Animal Care guidelines and Health Canada’sInstitutional Animal Care Committee. Details of animal housing and experimental design werereported earlier in Chu et al. (2008). In brief,pregnant Sprague-Dawley rats were adminis-tered corn oil (vehicle) or the NCM via thediet at daily doses of 0.05, 0.5, or 5 mg / kgbody weight (bw) from gestation day (GD)1 until weaning on postnatal day (PND) 23(Chu et al., 2008). Following sacrifice by decap-itation, organs from dams were collected onPND30 and from male and female offspringon PND35, PND77, and PND350, respectively,and stored at –80 ◦ C until analyzed.  Analyses of Retinoids, CYP Activities,and Thyroid Hormones Retinyl palmitate and retinol in liver andkidney were analyzed in all dose groups of offspring and dams by HPLC as described inNilsson et al. (2000). Briefly, retinoids wereextracted from the tissues using diisopropylether and separated on a Nucleosil C18 5- µ m HPLC column (Macherey-Nagel, GmbH,Germany) using an ethanol:water mobilephase. Retinol and retinyl palmitate weredetected with a JASCO821-FP fluorescencedetector ( λ ex  =  325 nm,  λ em  =  475 nm).The limit of detection (LOD) for retinol andretinyl palmitate was 60 and 70 ng / g tissue,respectively. All- trans -RA and its metabolite 9c-4o-13,14-dh-RA were analyzed in all dose groupsin liver and in control and high-dose groupsin kidneys in offspring and dams by HPLC aspreviously described (Schmidt et al., 2003b).In brief, retinoids were extracted from thetissues using isopropanol, and all- trans -RA    D  o  w  n   l  o  a   d  e   d   b  y   [   L  u   b  n  a   E   l  a   b   b  a  s   ]  a   t   1   3  :   2   7   0   8   M  a  r  c   h   2   0   1   4
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