Prenatal arsenic exposure is associated with impaired thymic function in newborns
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Transcript of Prenatal arsenic exposure is associated with impaired thymic function in newborns
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Abstracts / Toxicology L
ere divided in four groups. In normal group, no injection andnduction of disease was occurred. In Control group, injection ofBS was performed. In pertusis toxin group, toxin of pertusis wasnjected. In safranal group, induction of EAE was performed, thenafranal was injected. EAE disease was established through immu-ization of mice with peptide MOG 35–55 with complete Freunddjuvant. After forty days of immunization, leukocyte infiltrationnto the brain was examined with a microscope. Results and conclu-ion: Results showed that in normal and pertusis toxin groups, nolinical signs were observed in the study period. Disease severityn control group compared with normal and pertusis toxin groups,rom the eleventh day after induction of disease, showed a sig-ificant increase (P ≤ 0.05). Intensity of symptoms in the groupeceived safranal compared with the control group, showed a sig-ificant reduction (P ≤ 0.05). Intensity of symptoms in the groupeceived safranal compared with normal group, did not show anyignificant difference until the thirty eighth day after the inductionf disease. These results suggest that pertusis toxin has no role inoxin-induced EAE and related lesions. Also safranal prevents thencidence of EAE.
oi:10.1016/j.toxlet.2012.03.486
20-06renatal arsenic exposure is associated with impaired thymicunction in newborns
ultan Ahmed 1, Maria Kippler 1, Yukiko Wagatsuma 2, Shamsl-Arifeen 3, Rubhana Raqib 3, Marie Vahter 1
Karolinska Institutet, Sweden, 2 University of Tsukuba, Japan,ICDDR, Bangladesh
Purpose: Arsenic exposure during pregnancy is associated withncreases infant morbidity, in particular in infectious diseases, andnfant mortality. This may be due to arsenic-related immune dys-unction, as arsenic was associated with impaired thymus size atirth. The aim of the study was to elucidate the effects of pre-atal arsenic exposure on child thymic function and potentialechanisms of action. Methods: The study included sub-sample
f 130 pregnant women, participating in a longitudinal mother-hild cohort in rural Bangladesh with wide variation to arsenicia drinking water. Arsenic exposure was assessed based on con-entrations in maternal urine, blood, placenta and cord blood,sing ICP-MS. Thymic function was estimated by Signal-joint T celleceptor-rearrangement excision circles (sjTRECs) in cord bloodononuclear cells (CBMC), and in separated CD4+ and CD8+ T-
ells. Furthermore, we assessed the expression of genes involvedn oxidative stress defense and apoptosis pathways in CBMC byCR-Array, and markers of oxidative stress in cord blood plasma (8-ydroxy-2′-deoxyguanosine by ELISA) and placenta (8-oxoguanineith immunohistochemistry). Results and conclusions: Maternal
rsenic biomarkers were highly correlated (rs > 0.62). Maternalrsenic exposure was negatively associated with sjTREC in CBMCnd separated CD4+ and CD8+ T-cells. Oxidative stress was posi-ively associated with arsenic exposure and negatively associatedith sjTRECs in T-cells. Several pro-apoptotic genes were up-
egulated at elevated arsenic exposure, while antioxidant andxidative stress responsive genes were down-regulated. In conclu-ion, prenatal arsenic exposure reduced thymic output, possibly vianduction of oxidative stress and apoptosis, resulting in inadequate
ellular immune reservoir and immunosuppression in infancy.oi:10.1016/j.toxlet.2012.03.487
211S (2012) S43–S216 S133
P20-07Establishment of humanized mouse-models to investigateinduction of DILI
Hanna Lundgren 1, Klara Martinsson 1, Frank Seeliger 1,Anna-Lena Berg 1, Jonas P. Bergström 1, Anahi Santoyo Castelazo 2,Johan Jirholt 1, Karin Cederbrant 1
1 AstraZeneca, Sweden, 2 University of Liverpool, United Kingdom
This project aims at establishing humanized mouse-models toinvestigate induction of drug-induced liver injury (DILI). In partic-ular, the models will be focused on recently identified mechanismsunderlying immune-mediated liver damage.
Ximelagatran was developed as an oral direct thrombininhibitor. None of the preclinical studies indicated hepatotoxicresponses but approximately 7% of treated patients showedincreased ALT levels. Genetic screenings suggested a contributionof HLA-DRB1*0701 and HLA-DQA1*0201 for development of DILIin response to ximelagatran. In addition, low nutritional status wasidentified as a predisposition- and also treatment-related factor.
To investigate the role of above defined HLA-molecules forthe induction of DILI following ximelagatran treatment, HLA andhCD4+ double transgenic mice were developed by the AstraZenecaTransgenics Group. The transgenic strains were phenotyped andshowed a quantitatively- and functionally intact immune system.The experimental approach was to initially determine whether dos-ing with ximelagatran on its own caused DILI in the transgenicmodel.
Dosing of transgenic mice expressing HLA-DRB1*0701/CD4+or HLA-DQA1*0201/CD4+ with ximelagatran did not increase ALTlevels or induce any pathological signs of inflammation in theliver.
However, since association with ximelagatran-induced ALT ele-vation in patients and expression of the defined HLA-type showed agenotypic odds ratio of only 4.41, it is likely that addition of an envi-ronmental factor is needed for the adverse event to occur. Ongoingstudies include introduction of different environmental factors, likespecial diets and inflammation, to this genetic background to studyif hepatotoxicity can be triggered or even augmented.
doi:10.1016/j.toxlet.2012.03.488
P20-08Mycotoxin-induced cell death and inflammatory responses inmacrophages
Jørn A. Holme 1, Anders Gammelsrud 2, Beatrice Dendelé 3, WiggoSandberg 1, Dominique Lagadic-Gossmann 3, Magne Refsnes 1,Rune Becher 1, Gunnar Eriksen 2, Anita Solhaug 2
1 Norwegian Institute of Public Health, Norway, 2 NorwegianVeterinary Institute, Norway, 3 Université de Rennes, France
The mycotoxin enniatin B (EnnB) is predominantly produced byspecies of the Fusarium genera. It is one of the emerging Fusariummycotoxins reported to be found at high concentrations in grain.The cytotoxic effect of EnnB has been suggested to be related itsability to form ionophores in cellular lipid membranes. The pur-pose of the present study was to characterise the effects of EnnB oncell death, differentiation, cell proliferation and pro-inflammatory
responses; and to explore any possible link between the responses.We exposed murine RAW 264.7 macrophages to EnnB for 24 hcaused an accumulation of cells in the G0/G1-phase with a corre-sponding decrease in cyclin D1. An increased number of cells with