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- Amirhosseini, Mehdi, et al.
(författare)
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Autoantibodies in outbred Swiss Webster mice following exposure to gold and mercury
- 2021
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Ingår i: Toxicology and Applied Pharmacology. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0041-008X .- 1096-0333. ; 412
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to heavy metals may have toxic effects on several human organs causing morbidity and mortality. Metals may trigger or exacerbate autoimmunity in humans. Inbred mouse strains with certain H-2 haplotypes are susceptible to xenobiotic-induced autoimmunity; and their immune response to metals such as mercury, gold, and silver have been explored. Serum antinuclear antibodies (ANA), polyclonal B-cell activation, hypergammaglobulinemia and tissue immune complex deposition are the main features of metal-induced autoimmunity in inbred mice. However, inbred mouse strains do not represent the genetic heterogeneity in humans. In this study, outbred Swiss Webster (SW) mice exposed to gold or mercury salts showed immune and autoimmune responses. Intramuscular injection of 22.5 mg/kg.bw aurothiomalate (AuTM) induced IgG ANA in SW mice starting after 5 weeks that persisted until week 15 although with a lower intensity. This was accompanied by elevated serum levels of total IgG antibodies against chromatin and total histones. Exposure to gold led to development of serum IgG autoantibodies corresponding to H1 and H2A histones, and dsDNA. Both gold and mercury induced polyclonal B-cell activation. Eight mg/L mercuric chloride (HgCl2) in drinking water, caused IgG antinucleolar antibodies (ANoA) after 5 weeks in SW mice accompanied by immune complex deposition in kidneys and spleen. Serum IgG antibodies corresponding to anti-fibrillarin, and anti-PM/Scl-100 antibodies, were observed in mercury-exposed SW mice. Gold and mercury trigger systemic autoimmune response in genetically heterogeneous outbred SW mice and suggest them as an appropriate model to study xenobiotic-induced autoimmunity.
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| 2. |
- Dubbelboer, Ilse R., et al.
(författare)
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Systematic review of physiologically based kinetic lactation models for transfer of xenobiotic compounds to milk
- 2023
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier. - 0041-008X .- 1096-0333. ; 467
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Forskningsöversikt (refereegranskat)abstract
- Lactational elimination has been described mathematically for nearly 50 years. Over 40 published articles, containing >50 physiologically based kinetic (PBK) lactation models were included in the systematic review. These PBK models described the lactational elimination of xenobiotic compounds in humans, rats, mice, and dairy cows and goats. A total of 78 compounds have been modelled, ranging from industrial chemicals, pesticides, to pain medication, antibiotics, and caffeine. Few models included several species or compounds, and models were thus generally not translational or generic. Three dairy cow models mechanistically described the intramammary disposition of pharmaceuticals after intramammary administration, including volume changes caused by milking, while empirically describing the remaining pharmacokinetics. The remaining models were semi- or whole body PBK models, describing long-term exposure of environmental pollutants, or short-term exposure of pharmaceuticals. The absolute majority described the disposition to the mammary gland or milk with perfusion limited compartments, but permeability limited models were available as well. With long-term exposure, models often included changes in milk volume and/or consumption by the offspring, and changes in body weight of offspring. Periodic emptying of the mammary gland, as with feeding or milking, was sparsely applied. Rodent models used similar physiological parameters, while values of physiological parameters applied in human models could range widely. When milk composition was included in the models, it most often included the fat content. The review gives an extensive overview of the applied functions and modelling strategies of PBK lactation models.
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| 3. |
- Schlezinger, J. J., et al.
(författare)
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Perfluorooctanoic acid induces liver and serum dyslipidemia in humanized PPAR α mice fed an American diet
- 2021
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Ingår i: Toxicology and Applied Pharmacology. - : Academic Press. - 0041-008X .- 1096-0333. ; 426
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Tidskriftsartikel (refereegranskat)abstract
- Per- and polyfluoroalkyl substances (PFAS) are pervasive in the environment resulting in nearly universal detection in people. Human serum PFAS concentrations are strongly associated with increased serum low-density lipoprotein cholesterol (LDL-C), and growing evidence suggests an association with serum triacylglycerides (TG). Here, we tested the hypothesis that perfluorooctanoic acid (PFOA) dysregulates liver and serum triacylglycerides in human peroxisome proliferator activated receptor α (hPPARα)-expressing mice fed an American diet. Mice were exposed to PFOA (3.5 mg/L) in drinking water for 6 weeks resulting in a serum concentration of 48 ± 9 μg/ml. In male and female hPPARα mice, PFOA increased total liver TG and TG substituted with saturated and monounsaturated fatty acids. Lack of expression of PPARα alone also increased total liver TG, and PFOA treatment had little effect on liver TG in PPARα null mice. In hPPARα mice, PFOA neither significantly increased nor decreased serum TG; however, there was a modest increase in TG associated with very low-density cholesterol particles in both sexes. Intriguingly, in female PPARα null mice, PFOA significantly increased serum TG, with a similar trend in males. PFOA also modified fatty acid and TG homeostasis-related gene expression in liver, in a hPPARα-dependent manner, but not in adipose. The results of our study and others reveal the importance of context (serum concentration and genotype) in determining the effect of PFOA on lipid homeostasis.
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