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Supplemental Material for Zeiss et al., 2019

posted on 01.07.2019 by Caroline J. Zeiss, Daniel M. Gatti, Olga Toro-Salazar, Crystal Davis, Cathleen M. Lutz, Francis Spinale, Timothy Stearns, Milena B. Furtado, Gary A. Churchill

S1 Fig 1: Renal scores across all 10 CC strains. Means and standard error at each weekly time point are shown for each strain, with a vertical gray line delineating acute (A; 6 weeks) and chronic (C; 12 week) time points. Females are shown on the top panel and males beneath. The majority of doxorubicin-treated animals (red) demonstrate renal injury (increased scores) over time compared to age matched vehicle treated controls (blue). Strains with p values <0.05 for treatment effect (black asterisk), treatment*sex (gray asterisk), and treatment*timepoint (white asterisk) interactions are indicated with asterisks located above each strain name. Strain 40 is very susceptible, with most doxorubicin-treated animals dying before the end of the study.

S2 Fig 2: Renal, splenic and testicular pathology in doxorubicin -treated mice. Animals with severe renal pathology (A) experienced diffuse tubuloglomerular injury. Glomerular pathology was characterized by increased mesangial matrix, proliferation of parietal epithelium of Bowman’s capsule (B), and segmental necrosis or fibrosis. Tubular injury was accompanied by interstitial lympho-histiocytic inflammation (arrow, C), tubular epithelial atrophy (B, C) and accumulation of hyaline casts (C). Splenic pathology varied from marked extramedullary hematopoiesis (asterisk, D) to collapse of red pulp and splenic atrophy (asterisk, E). White pulp remained intact. Testicular atrophy was characterized by loss of the entire spermatogenic series (F).

Hematoxylin and eosin, Bar = 100µm (A); 20µm (B), 50µm (C, F), 1mm (D, E)

S3 Fig 3: Hematologic parameters: Red blood cell counts (RBC, A) decreased at the acute time point (orange) in almost all strains, except CC051. Most strains recovered by the chronic time point (blue), but some strains (CC001, CC011, CC042) still had decreased RBC. Red blood cell distribution width (RDW, B, an indicator of increased red cell diameter characteristic of regeneration) was increased in all strains at the acute time point. Most strains had recovered by the chronic time point, except for CC032 and CC042. We found that DOX did not cause neutropenia (or lymphopenia, data not shown) at either the acute (orange) or chronic (blue) time points (C). Many strains (CC010, CC040, CC041) showed increased neutrophil counts at the acute time point. This increase persisted at the chronic time point in some strains (CC010, CC032, CC041). Some strains (CC011, CC040) showed increased platelets at the acute time point (D), with other strains (CC001, CC019, CC032, CC042) showed sex-specific increases. This was accompanied by histologic evidence of marked splenic extramedullary hematopoeisis. Most strains had recovered by the chronic time point.

Supporting Table 2: Statistical analysis of semi-quantitative renal scoring.


Article title

Doxorubicin-Induced Cardiotoxicity in Collaborative Cross (CC) Mice Recapitulates Individual Cardiotoxicity in Humans

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