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  • 1.
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mercury and silver induce B cell activation and anti-nucleolar autoantibody production in outbred mouse stocks: are environmental factors more important than the susceptibility genes in connection with autoimmunity?2009In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 155, no 1, 117-124 p.Article in journal (Refereed)
    Abstract [en]

    Environmental and predisposing genetic factors are known to play a crucial role in the development of systemic autoimmune diseases. With respect to the role of environmental factors, it is not known how and to what extent they contribute to the initiation and exacerbation of systemic autoimmunity. In the present study, I considered this issue and asked if environmental factors can induce autoimmunity in the absence of specific susceptible genes. The development of genetically controlled mercury- and silver-induced B cell activation and anti-nucleolar autoantibodies (ANolA) production in genetically heterozygous outbred Institute of Cancer Research (ICR), Naval Medical Research Institute (NMRI) and Black Swiss mouse stocks were analysed. Four weeks of treatment with both mercury and silver induced a strong B cell activation characterized by increased numbers of splenic antibody-secreting cells of at least one or more immunoglobulin (Ig) isotype(s) in all treated stocks. The three stocks also exhibited a marked increase in the serum IgE levels in response to mercury, but not silver. More importantly, in response to mercury a large numbers of ICR (88%), NMRI (96%) and Black Swiss (100%) mice produced different levels of IgG1 and IgG2a ANolA (a characteristic which is linked strictly to the H-2 genes). Similarly, but at lower magnitudes, treatment with silver also induced the production of IgG1 and IgG2a ANolA in 60% of ICR, 75% of NMRI and 100% of Black Swiss mice. Thus, the findings of this study suggest that long-term exposure to certain environmental factors can activate the immune system to produce autoimmunity per se, without requiring specific susceptible genes.

  • 2.
    Blom, K G
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Qazi, M Rahman
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Matos, J B Noronha
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nelson, B D
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    DePierre, J W
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abedi-Valugerdi, M
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Isolation of murine intrahepatic immune cells employing a modified procedure for mechanical disruption and functional characterization of the B, T and natural killer T cells obtained.2009In: Clinical and experimental immunology, ISSN 1365-2249, Vol. 155, no 2, 320-9 p.Article in journal (Refereed)
    Abstract [en]

    Intrahepatic immune cells (IHIC) are known to play central roles in immunological responses mediated by the liver, and isolation and phenotypic characterization of these cells is therefore of considerable importance. In the present investigation, we developed a simple procedure for the mechanical disruption of mouse liver that allows efficient isolation and phenotypic characterization of IHIC. These cells are compared with the corresponding cells purified from the liver after enzymatic digestion with different concentrations of collagenase and DNase. The mechanical disruption yielded viable IHIC in considerably greater numbers than those obtained following enzymatic digestion. The IHIC isolated employing the mechanical disruption were heterogeneous in composition, consisting of both innate and adaptive immune cells, of which B, T, natural killer (NK), NK T cells, granulocytes and macrophages were the major populations (constituting 37.5%, 16.5%, 12.1%, 7.9%, 7.9% and 7.5% of the total number of cells recovered respectively). The IHIC obtained following enzymatic digestion contained markedly lower numbers of NK T cells (1.8%). The B, T and NK T cells among IHIC isolated employing mechanical disruption were found to be immunocompetent, i.e. they proliferated in vitro in response to their specific stimuli (lipopolysaccharide, concanavalin A and alpha-galactosylceramide respectively) and produced immunoglobulin M and interferon-gamma. Thus, the simple procedure for the mechanical disruption of mouse liver described here results in more efficient isolation of functionally competent IHIC for various types of investigation.

  • 3.
    Bogdanska, Jasna
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Borg, Daniel
    Sundström, Maria
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Bergström, Ulrika
    Halldin, Krister
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Nelson, Buck
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    DePierre, Joseph
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nobel, Stefan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Tissue distribution of (35)S-labelled perfluorooctane sulfonate in adult mice after oral exposure to a low environmentally relevant dose or a high experimental dose2011In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 284, no 1-3, 54-62 p.Article in journal (Refereed)
    Abstract [en]

    The widespread environmental pollutant perfluorooctane sulfonate (PFOS), detected in most animal species including the general human population, exerts several effects on experimental animals, e.g., hepatotoxicity, immunotoxicity and developmental toxicity. However, detailed information on the tissue distribution of PFOS in mammals is scarce and, in particular, the lack of available information regarding environmentally relevant exposure levels limits our understanding of how mammals (including humans) may be affected. Accordingly, we characterized the tissue distribution of this compound in mice, an important experimental animal for studying PFOS toxicity. Following dietary exposure of adult male C57/BL6 mice for 1-5 days to an environmentally relevant (0.031 mg/kg/day) or a 750-fold higher experimentally relevant dose (23 mg/kg/day) of (35)S-PFOS, most of the radioactivity administered was recovered in liver, bone (bone marrow), blood, skin and muscle, with the highest levels detected in liver, lung, blood, kidney and bone (bone marrow). Following high daily dose exposure, PFOS exhibited a different distribution profile than with low daily dose exposure, which indicated a shift in distribution from the blood to the tissues with increasing dose. Both scintillation counting (with correction for the blood present in the tissues) and whole-body autoradiography revealed the presence of PFOS in all 19 tissues examined, with identification of thymus as a novel site for localization for PFOS and bone (bone marrow), skin and muscle as significant body compartments for PFOS. These findings demonstrate that PFOS leaves the bloodstream and enters most tissues in a dose-dependent manner.

  • 4.
    Bogdanska, Jasna
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sundström, Maria
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Bergström, Ulrika
    Borg, Daniel
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    DePierre, Joseph
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nobel, Stefan
    Tissue distribution of S-35-labelled perfluorobutanesulfonic acid in adult mice following dietary exposure for 1-5 days2014In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 98, 28-36 p.Article in journal (Refereed)
    Abstract [en]

    Perfluorobutanesulfonyl fluoride (PBSF) has been introduced as a replacement for its eight-carbon homolog perfluorooctanesulfonyl fluoride (POSF) in the manufacturing of fluorochemicals. Fluorochemicals derived from PBSF may give rise to perfluorobutanesulfonic acid (PFBS) as a terminal degradation product. Although basic mammalian toxicokinetic data exist for PFBS, information on its tissue distribution has only been reported in one study focused on rat liver. Therefore, here we characterized the tissue distribution of PFBS in mice in the same manner as we earlier examined its eight-carbon homolog perfluorooctanesulfonate (PFOS) to allow direct comparisons. Following dietary exposure of adult male C57/BL6 mice for 1,3 or 5 d to 16 mg S-35-PFBS kg(-1) d(-1), both scintillation counting and whole-body autoradiography (WBA) revealed the presence of PFBS in all of the 20 different tissues examined, demonstrating its ability to leave the bloodstream and enter tissues. After 5 d of treatment the highest levels were detected in liver, gastrointestinal tract, blood, kidney, cartilage, whole bone, lungs and thyroid gland. WBA revealed relatively high levels of PFBS in male genital organs as well, with the exception of the testis. The tissue levels increased from 1 to 3 d of exposure but appeared thereafter to level-off in most cases. The estimated major body compartments were whole bone, liver, blood, skin and muscle. This exposure to PFBS resulted in 5-40-fold lower tissue levels than did similar exposure to PFOS, as well as in a different pattern of tissue distribution, including lower levels in liver and lungs relative to blood.

  • 5.
    Bogdanska, Jasna
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sundström, Maria
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Bergström, Ulrika
    Institutionen för miljötoxikologi, Uppsala universitet.
    Borg, Daniel
    Institutet för miljömedicin, Karolinska institutet.
    Abedi-Valugerdi, Mauchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Nelson, Buck
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    DePierre, Joseph
    Institutionen för biokemi och biofysik, Department of Biochemistry and Biophysics.
    Nobel, Stefan
    Department of molecular medicin and surgery, Karolinska institutet.
    Tissue distribution of 35S-labelled perfluorobutane sulfonic acid in adult mice following dietary exposure for 1-5 daysManuscript (preprint) (Other academic)
  • 6.
    Botelho, Salomé Calado
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Saghafian, Maryam
    Pavlova, Svetlana
    Hassan, Moustapha
    DePierre, Joseph W.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Karolinska University Hospital, Sweden; ImmunoBioTox (IBT) AB, Sweden.
    Complement activation is involved in the hepatic injury caused by high-dose exposure of mice to perfluorooctanoic acid2015In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 129, no SI, 225-231 p.Article in journal (Refereed)
    Abstract [en]

    High-dose exposure of mice to perfluorooctanoate (PFOA) induces both hepatotoxicity and immunotoxicity. Here, we characterized the effects of TO-day dietary treatment with PFOA (0.002-0.02%, w/w) on the liver and complement system of male C57BL/6 mice. At all four doses, this compound caused hepatomegaly and reduced the serum level of triglycerides (an indicator for activation of the peroxisome proliferator-activated receptor-alpha (PPAR alpha)). At the highest dose (0.02%, w/w), this hepatomegaly was associated with the hepatic injury, as reflected in increased activity of alanine aminotranferase (ALAT) in the serum, severe hepatocyte hypertrophy and hepatocellular necrosis. PFOA-induced hepatic injury was associated with in vivo activation of the complement system as indicated by (i) significant attenuation of the serum activities of both the classical and alternative pathways; (ii) a marked reduction in the serum level of the complement factor 0; and (iii) deposition of the complement factor C3 fragment (C3a) in the hepatic parenchyma. PFOA did not activate the alternative pathway of complement in vitro. At doses lower than 0.02%, PFOA induced hepatocyte hypertrophy without causing liver injury or activating complement. These results reveal substantial involvement of activation of complement in the pathogenesis of PFOA-induced hepatotoxicity.

  • 7.
    Hansson, Monika
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mercuric chloride induces a strong immune activation, but does not accelerate the development of dermal fibrosis in tight-skin 1 (Tsk 1) mice2004In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 59, no 5, 469-477 p.Article in journal (Refereed)
    Abstract [en]

    In susceptible mice, mercuric chloride induces a systemic autoimmune disease characterized by increased serum levels of immunoglobulin (Ig) G1 and IgE, production of anti-nucleolar autoantibodies (ANolA) and formation of renal IgG deposits. We have previously hypothesized that mercury confers more adverse immunological effects on those mouse strains, which are genetically prone to develop spontaneous autoimmune diseases than on normal strains. In this study, we tested our hypothesis in tight skin 1 (Tsk1/+) mice, a murine model for human scleroderma. As a support for our hypothesis, we observed that in Tsk1/+ mice, B cells were spontaneously hyperactive and that treatment with mercury induced a strong immune/autoimmune response in these mice, but not in their non-Tsk (+/+) littermates. This response was characterized by the formation of high numbers of splenic IgG1, IgG2b and IgG3 antibody-secreting cells, increased serum levels of IgE, production of IgG1 antibodies against single-stranded DNA (ssDNA), trinitrophenol (TNP) as well as thyroglobulin and the development of renal IgG1 deposits. Neither Tsk1/+ mice nor F1 hybrid crosses between this strain, and mercury susceptible B10.S (H-2s) were able to produce IgG1-ANolA in response to mercury. Moreover, mercury-induced immune activation in Tsk1/+ was not able to potentiate the progression of skin fibrosis in this strain. Thus, exposure to mercury accelerates the immune dysregulation, but not the development of skin fibrosis in Tsk1/+ mice.

  • 8.
    Qazi, Mousumi R
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Bogdanska, Jasna
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Butenhoff, John L
    Nelson, B Dean
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    DePierre, Joseph W
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    High-dose, short-term exposure of mice to perfluorooctanesulfonate (PFOS) or perfluorooctanoate (PFOA) affects the number of circulating neutrophils differently, but enhances the inflammatory responses of macrophages to lipopolysaccharide (LPS) in a similar fashion.2009In: Toxicology, ISSN 1879-3185, Vol. 262, no 3, 207-14 p.Article in journal (Refereed)
    Abstract [en]

    Having found previously that high-dose, short-term dietary exposure of mice to perfluorooctanesulfonate (PFOS) or perfluorooctanoate (PFOA) suppresses adaptive immunity, in the present study we characterize the effects of these fluorochemicals on the innate immune system. Male C57BL/6 mice receiving 0.02% (w/w) PFOS or PFOA in their diet for 10 days exhibited a significant reduction in the numbers of total white blood cells (WBC), involving lymphopenia in both cases, but neutropenia only in response to treatment with PFOA. Moreover, both compounds also markedly reduced the number of macrophages (CD11b(+) cells) in the bone marrow, but not in the spleen or peritoneal cavity. The ex vivo production of tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) by peritoneal macrophages isolated from animals treated with PFOA or PFOS was increased modestly. Moreover, both fluorochemicals markedly enhanced the ex vivo production of these same cytokines by peritoneal and bone marrow macrophages stimulated either in vitro or in vivo with lipopolysaccharide (LPS); whereas there was no such effect on splenic macrophages. The serum levels of these inflammatory cytokines observed in response to in vivo stimulation with LPS were elevated substantially by prior exposure to PFOA, but not by PFOS. None of these parameters of innate immunity were altered in animals receiving a dietary dose of these compounds that was 20-fold lower (0.001%, w/w). These findings reveal that in addition to suppressing adaptive immunity, high-dose, short-term exposure of mice to either PFOS or PFOA augments inflammatory responses to LPS, a potent activator of innate immunity.

  • 9.
    Qazi, Mousumi Rahman
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abedi, M. R.
    Nelson, Buck Dean
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    DePierre, J. W.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Characterization of the Hepatic and Splenic Immune Status and Immunoglobulin Synthesis in Aged Male Mice Lacking the Peroxisome Proliferator-Activated Receptor-Alpha (PPAR alpha)2011In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 73, no 3, 198-207 p.Article in journal (Refereed)
    Abstract [en]

    It is now well established that the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR alpha) is expressed in different types of immune cells and plays a pivotal role in the regulation of age-related production of inflammatory cytokines. However, the role(s) of this receptor in the regulation of immune cell homoeostasis in ageing non-lymphoid and lymphoid organs has not yet been resolved. We examine this issue here by evaluating the hepatic and splenic immune status and immunoglobulin (Ig) production in male PPAR alpha-null mice and their wild-type littermates at one and 2 years of age. In comparison with the age-matched control animals, PPAR alpha-null mice exhibited age-related elevations in the numbers of total, as well as of phenotypically distinct subpopulations of intrahepatic immune cells (IHIC) and splenocytes. Moreover, at 2 years of age, these alterations in hepatic immune cells were accompanied by significant increases in hepatic levels of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interferon-gamma (IFN-gamma), in combination with the development of hepatic inflammatory loci containing mixtures of leucocytes. Alterations in splenocytes of old PPAR alpha-null mice were also accompanied by increases in cellularity of both white and red pulps of the spleen. Furthermore, these same animals exhibited pronounced increases in the numbers of splenic plasma cells and enhanced production of Ig of different isotypes, including IgG1, IgG2a and IgE. Thus, our findings indicate that upon ageing, PPAR alpha plays a crucial role in regulating the total numbers, compositions and functions of immune cells in both lymphoid and non-lymphoid immune organs of mice.

  • 10.
    Qazi, Mousumi Rahman
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abedi, Mohammad R
    Nelson, B Dean
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    DePierre, Joseph W
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Dietary exposure to perfluorooctanoate or perfluorooctane sulfonate induces hypertrophy in centrilobular hepatocytes and alters the hepatic immune status in mice2010In: International Immunopharmacology, ISSN 1567-5769, E-ISSN 1878-1705, Vol. 10, no 11, 1420-7 p.Article in journal (Refereed)
    Abstract [en]

    It is well established that exposure of mice to perfluorooctanoate (PFOA) or perfluorooctane sulfonate (PFOS) induces hepatomegaly and, concurrently, immunotoxicity. However, the effects of these perfluorochemicals on the histology and immune status of the liver have not been yet investigated and we have examined these issues here. Dietary treatment of male C57BL/6 mice with 0.002% (w/w) PFOA or 0.005% (w/w) PFOS for 10 days resulted in significant reductions in serum levels of cholesterol and triglycerides, a moderate increase in the serum activity of alkaline phosphatase (ALP) and hepatomegaly, without affecting other immune organs. This hepatomegaly was associated with marked hypertrophy of the centrilobular hepatocytes, with elevated numbers of cytoplasmic acidophilic granules and occasional mitosis. Furthermore, dietary exposure to PFOA or PFOS altered the hepatic immune status: whereas exposure to PFOA enhanced the numbers of total, as well as of phenotypically distinct subpopulations of intrahepatic immune cells (IHIC), and in particular the presumptive erythrocyte progenitor cells, treatment with PFOS enhanced only the numbers of hepatic cells that appear immunophenotypically to be erythrocyte progenitors, without affecting other types of IHIC. In addition, exposure to these compounds attenuated hepatic levels of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and interleukin-4 (IL-4). Furthermore, the exposed animals exhibited a significant increase in hepatic levels of erythropoietin, a hormone required for erythropoiesis. Thus, in mice, PFOA- and PFOS-induced hepatomegaly is associated with significant alterations in hepatic histophysiology and immune status, as well as induction of hepatic erythropoiesis.

  • 11. Qazi, Mousumi Rahman
    et al.
    Hassan, Moustapha
    Nelson, B. Dean
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    DePierre, Joseph W.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Both sub-acute, moderate-dose and short-term, low-dose dietary exposure of mice to perfluorooctane sulfonate exacerbates concanavalin A-induced hepatitis2013In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 217, no 1, 67-74 p.Article in journal (Refereed)
    Abstract [en]

    Exposure of rodents to perfluorooctane sulfonate (PFOS) induces pronounced hepatomegaly associated with significant alterations in hepatic histophysiology and immune status. The present investigation was designed to evaluate the effects of this perfluorochemical on immune-mediated liver damage. Accordingly, the influence of both sub-acute (10 days), moderate-dose (0.004%, w/w = 6 +/- 1.3 mg/kg body weight/day) or short-term (28 days), low-dose (0.0001%, w/w = 144 +/- 4 mu g/kg body weight/day) dietary pretreatment with PFOS on the development of concanavalin A (Con A)-induced liver damage in mice was examined. With either regimen of exposure, PFOS exacerbated the acute liver damage caused by Con A, i.e., elevated serum levels of transaminases and led to more pronounced damage of hepatic tissue. This exacerbation was associated with either reduced (moderate dose) or unaltered (low dose) hepatic levels of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma). Moreover, hepatic DNA fragmentation was enhanced, particularly following short-term exposure to a low-dose. Our findings suggest that exposure to PFOS may sensitize hepatic parenchymal cells to other insults that activate the hepatic immune system and thereby exacerbate liver damage during acute inflammation.

  • 12.
    Qazi, Mousumi Rahman
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hassan, Moustapha
    Nelson, B. Dean
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    DePierre, Joseph W.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Karolinska Institutet.
    Sub-acute, moderate-dose, but not short-term, low-dose dietary pre-exposure of mice to perfluorooctanoate aggravates concanavalin A-induced hepatitis2013In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 219, no 1, 1-7 p.Article in journal (Refereed)
    Abstract [en]

    Exposure of mice to perfluorooctanoate (PFOA) evokes pronounced hepatomegaly along with significant alterations in both the histological structure and immune status of the liver. The present study was designed to evaluate the effects of this perfluorochemical on immune-mediated liver damage. In this connection, the influence of both sub-acute (10 days), moderate-dose (0.002% w/w = 3 +/- 0.7 mg/kg body weight/day) and short-term (28 days), low-dose (0.00005% w/w = 70 +/- 2 mu g/kg body weight/day) dietary pretreatment with PFOA on the development of concanavalin A (Con A)-induced liver damage in mice was examined. With sub-acute, moderate, but not short-term, low-dose exposure, PFOA aggravated the acute liver damage caused by Con A, i.e., elevated serum levels of transaminases and led to more pronounced damage of hepatic tissue. This aggravation was associated with significantly enhanced hepatic level of interleukin-6 (IL-6), but unaltered hepatic levels of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and interleukin-4 (IL-4). Moreover, hepatic DNA fragmentation was not changed by subacute exposure to the moderate-dose. Our findings imply that exposure to PFOA may sensitize hepatic parenchymal cells to other toxicants that activate the hepatic immune system and thereby aggravate liver injury during acute inflammation. 

  • 13.
    Qazi, Mousumi Rahman
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nelson, B. Dean
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    DePierre, Joseph W.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    28-Day dietary exposure of mice to a low total dose (7 mg/kg) of perfluorooctanesulfonate (PFOS) alters neither the cellular compositions of the thymus and spleen nor humoral immune responses: Does the route of administration play a pivotal role in PFOS-induced immunotoxicity?2010In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 267, no 03-jan, 132-139 p.Article in journal (Refereed)
    Abstract [en]

    Short-term exposure of mice to high doses of perfluorooctanesulfonate (PFOS), an ubiquitous and highly persistent environmental contaminant, induces various metabolic changes and toxic effects, including immunotoxicity. However, extrapolation of these findings to the long-term, low-dose exposures to which humans are subject is highly problematic. In this connection, recent studies have concluded that sub-chronic (28-day) exposure of mice by oral gavage to doses of PFOS that result in serum levels comparable to those found in general human populations suppress adaptive immunity. Because of the potential impact of these findings on environmental research and monitoring, we have examined here whether sub-chronic dietary exposure (a major route of human exposure) to a similarly low-dose of PFOS also suppress adaptive immune responses. Dietary treatment of male B6C3F1 mice for 28 days with a dose of PFOS that resulted in a serum concentration of 11 mu g/ml (ppm) significantly reduced body weight gain and increased liver mass. However, this treatment did not alter the cellular compositions of the thymus and spleen; the number of splenic cells secreting IgM antibodies against sheep red blood cell (SRBC); serum levels of IgM and IgG antibodies specifically towards SRBC; or circulating levels of IgM antibodies against the T-cell-independent antigen trinitrophenyl conjugated to lipopolysaccharide (TNP-LPS). These findings indicate that such sub-chronic dietary exposure of mice to PFOS resulting in serum levels approximately 8-85-fold greater than those observed in occupationally exposed individuals does not exert adverse effects on adaptive immunity.

  • 14.
    Qazi, Mousumi Rahman
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nelson, Buck Dean
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    DePierre, Joseph W.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    High-dose dietary exposure of mice to perfluorooctanoate or perfluorooctane sulfonate exerts toxic effects on myeloid and B-lymphoid cells in the bone marrow and these effects are partially dependent on reduced food Consumption2012In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 50, no 9, 2955-2963 p.Article in journal (Refereed)
    Abstract [en]

    It is well established that exposure of mice to perfluorooctanoate (PFOA) or perfluorooctane sulfonate (PFOS) exerts adverse effects on the thymus and spleen. Here, we characterize the effects of a 10-day dietary treatment with these compounds (0.001-0.02%, w/w) on the bone marrow (BM) of mice. At a dose of 0.02%, both compounds reduced food consumption and caused atrophy of the thymus and spleen. At this same dose, histopathological and flow cytometric analysis revealed that (i) the total numbers of BM as well as the numbers of myeloid, pro/pre B, immature B and early mature B cells were all reduced significantly; and (ii) these adverse effects were reversed either partially or completely 10 days after withdrawal of these compounds. At the lower dose of 0.002%, only PFOA reduced the B-lymphoid cell population. Finally, mice fed an amount of diet equivalent to that consumed by the animals exposed to 0.02% PFOA also exhibited atrophy of the thymus and spleen, and a reduction in the number of B-lymphoid population, without affecting myeloid cells. Thus, in mice, immunotoxic doses of PFOA or PFOS induce adverse effects on the myeloid and B-lymphoid cells in the BM, in part as a consequence of reduced food consumption.

  • 15.
    Qazi, Mousumi Rahman
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Xia, Zhenlei
    Bogdanska, Jasna
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Chang, Shu-Ching
    Ehresman, Dave J
    Butenhoff, John L
    Nelson, B Dean
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    DePierre, Joseph W
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The atrophy and changes in the cellular compositions of the thymus and spleen observed in mice subjected to short-term exposure to perfluorooctanesulfonate are high-dose phenomena mediated in part by peroxisome proliferator-activated receptor-alpha (PPARalpha).2009In: Toxicology, ISSN 1879-3185, Vol. 260, no 1-3, 68-76 p.Article in journal (Refereed)
    Abstract [en]

    We have previously shown that short-term, high-dose exposure of mice to the environmentally persistent perfluorooctanoate (PFOA) results in thymic and splenic atrophy and the attenuation of specific humoral immune responses. Here we characterize the effects of a 10-day treatment with different dietary doses (1-0.001%, w/w) of perfluorooctanesulfonate (PFOS), a similar fluorochemical, on the immune system of male C57BL/6 mice. At doses greater than 0.02%, PFOS induced clinical signs of toxicity in the animals, whereas at the concentration of 0.02%, this compound caused weight loss, hepatomegaly and atrophy of the thymus, spleen and adipose tissue without toxicity. With this latter dose, histopathological and flow-cytometric analysis revealed that (i) the thymic cortex was virtually depleted of cells; (ii) the total numbers of thymocytes and splenocytes were reduced by 84 and 43%, respectively; (iii) although all populations of thymocytes and splenocytes were smaller, the thymic CD4(+)CD8(+) cells and the splenic B-lymphocytes were most decreased. These alterations resembled those evoked by analogous exposure to PFOA, but were less pronounced. At lower doses (less than 0.02%), PFOS induced hepatomegaly without affecting the thymus or spleen. Finally, comparison of male wild-type 129/Sv mice and the corresponding knock-outs lacking peroxisome proliferator-activated receptor-alpha (PPARalpha) indicated that these effects of PFOS are not strain-dependent. More importantly, hepatomegaly is independent of PPARalpha, the thymic changes are partially dependent on this receptor, and splenic responses are largely eliminated in its absence. Thus, immunomodulation caused by PFOS is a high-dose phenomenon partially dependent on PPARalpha.

  • 16. Sadeghi, B.
    et al.
    Aghdami, N.
    Hassan, Z.
    Forouzanfar, M.
    Rozell, B.
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hassan, M.
    GVHD after chemotherapy conditioning in allogeneic transplanted mice2008In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 42, no 12, 807-818 p.Article in journal (Refereed)
    Abstract [en]

    GVHD is a major complication in allogeneic SCT. Available GVHD models are mainly based on radio-therapy-conditioning and/or immune deficient mice. GVHD models based on chemotherapy-based regimens remain poorly studied, despite 50% of all transplantations being chemotherapy based. Our aim was to develop a GVHD model using chemotherapy as conditioning. Female BALB/c (H-2Kd) were conditioned with BU-CY and transplanted with 2 x 10(7) BM and 3 x 10(7) spleen cells from either C57BL/6 (H-2Kb) mice ( allogeneic setting) or from male BALB/c to serve as a control group for regimen-related toxicity and engraftment. GVHD manifestations and histopathological changes were evaluated. Chimerism and donor T cells presence in skin, intestine and liver were studied using FACS-, FISH analysis and immunohistochemistry. Allogeneic transplanted mice developed lethal GVHD starting from day+7 with both histological and clinical signs. Donor T cells accumulated in recipient skin and intestine with GVHD progression. BM-failure, apoptosis and T-lymphocyte infiltration into target organs were significantly higher in allogeneic when compared with the syngeneic group. No toxicity or GVHD signs were observed in the syngeneic setting. We report a mouse model of GVHD using BU-CY conditioning that represents the most common myeloablative-conditioning regimen in clinical SCT. This model can be utilized to study the role of conditioning on mechanisms underlying GVHD.

  • 17. Sadeghi, B.
    et al.
    Al-Chaqmaqchi, H.
    Al-Hashmi, S.
    Brodin, D.
    Hassan, Z.
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Moshfegh, A.
    Hassan, M.
    Early-phase GVHD gene expression profile in target versus non-target tissues: kidney, a possible target?2013In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 48, no 2, 284-293 p.Article in journal (Refereed)
    Abstract [en]

    GVHD is a major complication after allo-SCT. In GVHD, some tissues like liver, intestine and skin are infiltrated by donor T cells while others like muscle are not. The mechanism underlying targeted tropism of donor T cells is not fully understood. In the present study, we aim to explore differences in gene expression profile among target versus non-target tissues in a mouse model of GVHD based on chemotherapy conditioning. Expression levels of JAK-signal transducers and activators of transcription (STAT), CXCL1, ICAM1 and STAT3 were increased in the liver and remained unchanged (or decreased) in the muscle and kidney after conditioning. At the start of GVHD the expression levels of CXCL9, ITGb2, SAA3, MARCO, TLR and VCAM1 were significantly higher in the liver or kidney compared with the muscle of GVHD animals. Moreover, biological processes of inflammatory reactions, leukocyte migration, response to bacterium and chemotaxis followed the same pattern. Our data show that both chemotherapy and allogenicity exclusively induce expression of inflammatory genes in target tissues. Moreover, gene expression profile and histopathological findings in the kidney are similar to those observed in the liver of GVHD mice. Bone Marrow Transplantation (2013) 48, 284-293; doi:10.1038/bmt.2012.120; published online 23 July 2012

  • 18. Sadeghi, B.
    et al.
    Jansson, M.
    Hassan, Z.
    Mints, M.
    Hagglund, H.
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hassan, M.
    The effect of administration order of BU and CY on engraftment and toxicity in HSCT mouse model2008In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 41, no 10, 895-904 p.Article in journal (Refereed)
    Abstract [en]

    Conditioning regimens are an important issue determining the outcome of hematopoietic stem cell transplantation (HSCT). Less toxicity, early engraftment and no relapse are the aims of efficient conditioning. Our objective was to investigate the long-term effects of BU-CY and their administration order on the toxicity and chimerism in a mouse model of HSCT. Female BALB/c mice were treated with either BU (15 mg/kg/day x 4)-CY (100 mg/kg/day x 2) or CY-BU. Treated mice were transplanted with Sca-1+ cells from male BALB/c mice. Until 90 days after HSCT, the animals were monitored for body weight and analyzed for cellular phenotype of the thymus, spleen and BM, total chimerism, the spleen chimerism of DCs and T regulatory (Treg) cells, and hepatotoxicity. BU-CY and CY-BU treatments exerted comparable myeloablative and immunosuppressive effects. The long-term engraftment of donor cells in the BM and thymus regeneration showed the same features in both groups. However, the two regimens differed; in general, hepatotoxicity and chimerism of DC and Treg cells. In the long term, BU-CY, but not CY-BU caused a marked decrease in body weight and a significant increase in the activities of the liver enzymes, particularly aspartate amino transferase (AST). We conclude that the alteration of the administration order of BU-CY to CY-BU not only gives the same level of engraftment but also reduces the toxicity of the conditioning regimen that might be valuable specially in young patients who are undergoing HSCT.

  • 19. Sadeghi, Behnam
    et al.
    Al-Hashmi, Suleiman
    Hassan, Zuzana
    Rozell, Bjorn
    Concha, Hernan
    Lundmark, Carin
    Grönvik, Kjell-Olov
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hassan, Moustapha
    Expansion and Activation Kinetics of Immune Cells during Early Phase of GVHD in Mouse Model Based on Chemotherapy Conditioning2010In: Clinical & Developmental Immunology, ISSN 1740-2522, E-ISSN 1740-2530, 142943- p.Article in journal (Refereed)
    Abstract [en]

    In the present paper, we have investigated early pathophysiological events in graft-versus-host disease (GVHD), a major complication to hematopoietic stem cell transplantation (HSCT). BLLB/c female mice conditioned with busulfan/cyclophosphamide (Bu-Cy) were transplanted with allogeneic male C57BL/6. Control group consisted of syngeneic transplanted Balb/c mice. In allogeneic settings, significant expansion and maturation of donor dendritic cells (DCs) were observed at day +3, while donor T-cells CD8+ were increased at day +5 (230%) compared to syngeneic HSCT. Highest levels of inflammatory cytokines IL-2, IFN-gamma, and TNF-alfa at day +5 matched T-cell activation. Concomitantly naive T-cells gain effecr-memory phenotype and migrated from spleen to peripheral lymphoid organs. Thus, in the very early phase of GHVD following Bu-Cy conditioning donor, DCs play an important role in the activation of donor T cells. Subsequently, donor naive T-cells gain effector-memory phenotype and initiate GVHD.

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