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Comparative 90-day dietary study of paraffin wax in Fischer-344 and Sprague-Dawley rats
L C Griffis1, L E Twerdok, S Francke-Carroll
1Toxicology Consulting, 116 Chalk Creek Ct, Martinez, CA, USA. larrygriffis@comcast.net
Abstract:
Highly refined mineral hydrocarbons (MHCs) such as low melting point paraffin wax (LMPW) and low viscosity white oils can cause inflammatory changes in the liver and mesenteric lymph nodes (MLNs) of the Fischer-344 (F-344) rat. In contrast, only minimal MLN changes are seen in the Sprague-Dawley (S-D) rat with no changes in the liver. In this study, the response of female F-344 and S-D rats was compared after 90days dietary treatment with 0%, 0.2% or 2% LMPW. Effects in the F-344 rats were significantly greater than in the S-D rats: increased liver and splenic weights and inflammatory changes (hepatic microgranulomas) in these tissues were observed only in the F-344 rats. Microgranulomas in the MLNs were observed in both strains but the effects were substantially greater in the F-344 rats. Cellular markers of inflammation were examined in a subset of rats from each group using immunohistochemical staining. An increase in staining for CD3 (T-cells), CD8a (suppresser/cytotoxic T-cells) and CD4 (helper T-cells) correlated with an increase in lymphoid cells in the livers of treated F-344 rats. The majority of macrophages in the hepatic microgranulomas of treated F-344 rats were negative for the ED2 marker, indicating a likely origin from non-resident macrophages. Electron microscopy showed Kupffer cell hypertrophy and hyperplasia in treated F-344 rats. However, lysozyme staining (indicating activation of epithelioid macrophages) decreased with increasing granuloma size. Non-ED2 expressing cells may have been recruited but not sufficiently activated to be lysozyme positive. Inflammatory changes in the cardiac mitral valve noted in previous studies of LMPW were also seen in the F-344 rats in this study but not in the S-D rats. Chemical analysis showed that MHC accumulated in livers from treated F-344 but not S-D rats and the concentration was more than 2-fold greater in MLNs from the F-344 than from the S-D rats. The F-344 appears to be more immunologically sensitive to a number of agents than other rat strains and the results of this study suggest that this may contribute, along with pharmacokinetic differences, to the inflammatory response of F-344 rats to dietary MHCs.
Insights
Fischer-344 rats show greater inflammatory responses to mineral hydrocarbon exposure than Sprague-Dawley rats, with significant liver and lymph node changes. This highlights strain-specific sensitivity to dietary mineral hydrocarbons (MHCs).
Area of Science:
- Toxicology and Pharmacology
- Immunology
- Comparative Pathology
Background:
- Highly refined mineral hydrocarbons (MHCs), including low melting point paraffin wax (LMPW), can induce inflammatory changes in Fischer-344 (F-344) rat livers and mesenteric lymph nodes (MLNs).
- Sprague-Dawley (S-D) rats exhibit minimal MLN changes and no liver alterations when exposed to MHCs.
Purpose of the Study:
- To compare the inflammatory response of female F-344 and S-D rats to dietary low melting point paraffin wax (LMPW) over 90 days.
- To investigate the cellular mechanisms and strain-specific differences in the response to MHCs.
Main Methods:
- Dietary administration of 0%, 0.2%, or 2% LMPW to female F-344 and S-D rats for 90 days.
- Assessment of organ weights (liver, spleen), histopathological examination (hepatic microgranulomas, MLN changes), immunohistochemical staining (CD3, CD8a, CD4, ED2), and electron microscopy.
- Chemical analysis of MHC accumulation in tissues and examination of cardiac mitral valve inflammation.
Main Results:
- F-344 rats showed significantly greater effects than S-D rats, including increased liver and splenic weights, hepatic microgranulomas, and MLN microgranulomas.
- Immunohistochemistry revealed increased T-cells (CD3, CD8a, CD4) and non-resident macrophages in F-344 rat livers. Kupffer cell hypertrophy/hyperplasia was observed, but lysozyme staining decreased.
- MHCs accumulated in F-344 rat livers and MLNs, and inflammatory changes in the cardiac mitral valve were noted only in F-344 rats.
Conclusions:
- F-344 rats exhibit a heightened inflammatory and pharmacokinetic response to dietary MHCs compared to S-D rats, likely due to greater immunological sensitivity.
- The findings suggest that F-344 rats are a more sensitive model for studying MHC-induced inflammation, with non-resident macrophages playing a role in granuloma formation.
- Strain-specific differences in immune sensitivity and pharmacokinetics are critical factors in the toxicological response to dietary mineral hydrocarbons.
