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Different cytotoxic response to gadolinium between mouse and rat alveolar macrophages
Y Kubota1, S Takahashi, I Takahashi
1Environmental and Toxicological Sciences Research Group, National Institute of Radiological Sciences, Chiba, Japan. y_kubota@nirs.go.jp
Abstract:
The cytotoxicity of gadolinium (Gd) chloride was investigated in alveolar macrophages (AM) cultured in vitro. A marked difference in the cytotoxic response to Gd was found between mouse and rat AM. The viability of rat AM was decreased by exposure to Gd at doses more than 3 microM, while mouse AM appeared to be resistant even up to 1000 microM Gd exposure. The decrease in the viability of rat AM exposed to Gd at doses up to 1000 microM was mitigated by centrifugation and filtration of the culture medium containing Gd, or by the treatment of AM with lysosomotropic agents such as NH(4)Cl or chloroquine, suggesting that the cytotoxic response of rat AM to Gd at doses up to 1000 microM was dependent on the intracellular uptake and subsequent dissolution of Gd present in the culture medium in colloidal form. The phagocytic activity of mouse AM, evaluated by the uptake of latex particles, was higher than that of rat AM. Furthermore, quantitative analysis of Gd with inductively coupled plasma-mass spectrometry revealed that mouse AM took up a larger amount of Gd than rat AM. Therefore, the marked difference in the cytotoxic response to Gd between mouse and rat AM could not be attributed to the phagocytic activities for the colloidal form of Gd. The cytotoxic sensitivity of AM to Gd present in non-colloidal form was almost the same between mouse and rat AM. Therefore, it is suggested that the extent to which Gd-colloid phagocytosed is dissolved in the phago-lysosome or the subsequent process to exhibit the cytotoxicity may be different between mouse and rat AM.
Insights
Gadolinium chloride exhibits different toxicity in mouse and rat alveolar macrophages (AM). Rat AM are sensitive to gadolinium chloride, while mouse AM are resistant, suggesting species-specific cellular mechanisms influence gadolinium toxicity.
Area of Science:
- Toxicology
- Cell Biology
- Immunology
Background:
- Gadolinium (Gd) chloride is used in various applications, but its cytotoxicity, particularly in immune cells like alveolar macrophages (AM), requires detailed investigation.
- Understanding species-specific differences in cellular responses to toxic agents is crucial for accurate risk assessment and developing targeted interventions.
Purpose of the Study:
- To investigate the in vitro cytotoxicity of gadolinium (Gd) chloride in mouse and rat alveolar macrophages (AM).
- To elucidate the mechanisms underlying the observed species-specific differences in Gd-induced cytotoxicity.
Main Methods:
- Primary cultures of mouse and rat alveolar macrophages (AM) were exposed to varying concentrations of gadolinium (Gd) chloride.
- Cell viability was assessed, and experiments involving medium manipulation (centrifugation, filtration) and lysosomotropic agents (NH(4)Cl, chloroquine) were conducted.
- Phagocytic activity was measured using latex particle uptake, and Gd uptake was quantified using inductively coupled plasma-mass spectrometry (ICP-MS).
Main Results:
- Rat AM viability decreased at Gd doses >3 microM, whereas mouse AM remained resistant up to 1000 microM.
- Gd-induced cytotoxicity in rat AM was reduced by medium treatment and lysosomotropic agents, indicating dependence on intracellular uptake and dissolution of colloidal Gd.
- Despite higher phagocytic activity and Gd uptake in mouse AM, their resistance suggests mechanisms beyond phagocytosis influence Gd toxicity.
Conclusions:
- The marked difference in Gd cytotoxicity between mouse and rat AM is not solely due to phagocytic capacity for colloidal Gd.
- Species-specific differences in the intracellular processing of phagocytosed Gd, potentially involving lysosomal dissolution or downstream events, dictate the cytotoxic response.
- Further research into the intracellular fate of Gd within AM is warranted to fully understand these species-specific toxicological profiles.