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Immunomodulatory effects of domoic acid differ between in vivo and in vitro exposure in mice.

Levin M, Leibrecht H, Ryan J, Van Dolah F, De Guise S - Mar Drugs (2008)

Bottom Line: Differences between in vitro and in vivo results suggest that DA may exert its immunotoxic effects both directly and indirectly.Modulation of cytosolic calcium suggests that DA exerts its effects through ionotropic glutamate subtype surface receptors at least on monocytes.This study is the first to identify DA as an immunotoxic chemical in a mammalian species.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology and Veterinary Science, University of Connecticut, Storrs, CT 06269, USA. Milton.Levin@uconn.edu

ABSTRACT
The immunotoxic potential of domoic acid (DA), a well-characterized neurotoxin, has not been fully investigated. Phagocytosis and lymphocyte proliferation were evaluated following in vitro and in vivo exposure to assay direct vs indirect effects. Mice were injected intraperitoneally with a single dose of DA (2.5 microg/g b.w.) and sampled after 12, 24, or 48 hr. In a separate experiment, leukocytes and splenocytes were exposed in vitro to 0, 1, 10, or 100 microM DA. In vivo exposure resulted in a significant increase in monocyte phagocytosis (12-hr), a significant decrease in neutrophil phagocytosis (24-hr), a significant decrease in monocyte phagocytosis (48-hr), and a significant reduction in T-cell mitogen-induced lymphocyte proliferation (24-hr). In vitro exposure significantly reduced neutrophil and monocyte phagocytosis at 1 muM. B- and T-cell mitogen-induced lymphocyte proliferation were both significantly increased at 1 and 10 microM, and significantly decreased at 100 microM. Differences between in vitro and in vivo results suggest that DA may exert its immunotoxic effects both directly and indirectly. Modulation of cytosolic calcium suggests that DA exerts its effects through ionotropic glutamate subtype surface receptors at least on monocytes. This study is the first to identify DA as an immunotoxic chemical in a mammalian species.

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Changes in peripheral blood neutrophil (top), monocyte (middle), and lymphocyte (bottom) cytosolic calcium upon exposure to increasing concentrations of domoic acid. Data are expressed as the % of the unexposed control over time (T-1: 1 min prior to exposure, T0: time of exposure to agonists, T2: 2 min after exposure, T4: 4 min after exposure, T6: 6 min after exposure). For each time point, data are presented as the average of 3 mice. (100% indicated by dotted line)
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f8-md-06-00636: Changes in peripheral blood neutrophil (top), monocyte (middle), and lymphocyte (bottom) cytosolic calcium upon exposure to increasing concentrations of domoic acid. Data are expressed as the % of the unexposed control over time (T-1: 1 min prior to exposure, T0: time of exposure to agonists, T2: 2 min after exposure, T4: 4 min after exposure, T6: 6 min after exposure). For each time point, data are presented as the average of 3 mice. (100% indicated by dotted line)

Mentions: Mouse mean peripheral blood neutrophil, monocyte and lymphocyte fluorescence increased by 407%, 408%, and 408%, respectively, 1 min following exposure to ionomycin (data not shown), suggesting appropriate cell loading with the probe. The results for calcium mobilization upon exposure to increasing concentrations of DA are shown in Figure 8. For all three sub-populations of leukocytes, 1 μM DA consistently reduced cytosolic calcium, as measured by a reduction of cell fluorescence compared to baseline fluorescence. For neutrophils and lymphocytes, 10 μM DA also reduced cytosolic calcium, while calcium was moderately increased in monocytes. 100 μM DA moderately increased cytosolic calcium in monocytes, while calcium was modestly increased in neutrophils and lymphocytes.


Immunomodulatory effects of domoic acid differ between in vivo and in vitro exposure in mice.

Levin M, Leibrecht H, Ryan J, Van Dolah F, De Guise S - Mar Drugs (2008)

Changes in peripheral blood neutrophil (top), monocyte (middle), and lymphocyte (bottom) cytosolic calcium upon exposure to increasing concentrations of domoic acid. Data are expressed as the % of the unexposed control over time (T-1: 1 min prior to exposure, T0: time of exposure to agonists, T2: 2 min after exposure, T4: 4 min after exposure, T6: 6 min after exposure). For each time point, data are presented as the average of 3 mice. (100% indicated by dotted line)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2630849&req=5

f8-md-06-00636: Changes in peripheral blood neutrophil (top), monocyte (middle), and lymphocyte (bottom) cytosolic calcium upon exposure to increasing concentrations of domoic acid. Data are expressed as the % of the unexposed control over time (T-1: 1 min prior to exposure, T0: time of exposure to agonists, T2: 2 min after exposure, T4: 4 min after exposure, T6: 6 min after exposure). For each time point, data are presented as the average of 3 mice. (100% indicated by dotted line)
Mentions: Mouse mean peripheral blood neutrophil, monocyte and lymphocyte fluorescence increased by 407%, 408%, and 408%, respectively, 1 min following exposure to ionomycin (data not shown), suggesting appropriate cell loading with the probe. The results for calcium mobilization upon exposure to increasing concentrations of DA are shown in Figure 8. For all three sub-populations of leukocytes, 1 μM DA consistently reduced cytosolic calcium, as measured by a reduction of cell fluorescence compared to baseline fluorescence. For neutrophils and lymphocytes, 10 μM DA also reduced cytosolic calcium, while calcium was moderately increased in monocytes. 100 μM DA moderately increased cytosolic calcium in monocytes, while calcium was modestly increased in neutrophils and lymphocytes.

Bottom Line: Differences between in vitro and in vivo results suggest that DA may exert its immunotoxic effects both directly and indirectly.Modulation of cytosolic calcium suggests that DA exerts its effects through ionotropic glutamate subtype surface receptors at least on monocytes.This study is the first to identify DA as an immunotoxic chemical in a mammalian species.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology and Veterinary Science, University of Connecticut, Storrs, CT 06269, USA. Milton.Levin@uconn.edu

ABSTRACT
The immunotoxic potential of domoic acid (DA), a well-characterized neurotoxin, has not been fully investigated. Phagocytosis and lymphocyte proliferation were evaluated following in vitro and in vivo exposure to assay direct vs indirect effects. Mice were injected intraperitoneally with a single dose of DA (2.5 microg/g b.w.) and sampled after 12, 24, or 48 hr. In a separate experiment, leukocytes and splenocytes were exposed in vitro to 0, 1, 10, or 100 microM DA. In vivo exposure resulted in a significant increase in monocyte phagocytosis (12-hr), a significant decrease in neutrophil phagocytosis (24-hr), a significant decrease in monocyte phagocytosis (48-hr), and a significant reduction in T-cell mitogen-induced lymphocyte proliferation (24-hr). In vitro exposure significantly reduced neutrophil and monocyte phagocytosis at 1 muM. B- and T-cell mitogen-induced lymphocyte proliferation were both significantly increased at 1 and 10 microM, and significantly decreased at 100 microM. Differences between in vitro and in vivo results suggest that DA may exert its immunotoxic effects both directly and indirectly. Modulation of cytosolic calcium suggests that DA exerts its effects through ionotropic glutamate subtype surface receptors at least on monocytes. This study is the first to identify DA as an immunotoxic chemical in a mammalian species.

Show MeSH
Related in: MedlinePlus