Supplemental Material for Zeiss et al., 2019

<b>S1 Fig 1</b>: 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 &lt;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. <b>S2 Fig 2:</b> 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)

<b>S3 Fig 3: </b>Hematologic parameters:<b> </b>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.<b><br></b><b><br></b><b>Supporting Table 2</b>: Statistical analysis of semi-quantitative renal
scoring.<b></b>

**补充图1（S1 Fig 1）**：10个CC品系的肾脏评分。
各品系在每周观测时间点的均值与标准误均已标注，灰色垂直线用于区分急性（A；6周）与慢性（C；12周）时间节点。上方面板展示雌性小鼠，下方为雄性小鼠。与年龄匹配的赋形剂处理对照组（蓝色组）相比，多数阿霉素处理组（红色组）动物随时间推移出现肾损伤（评分升高）。在每个品系名称上方标注星号，以标记出治疗效应（黑色星号）、治疗×性别交互效应（灰色星号）以及治疗×时间点交互效应存在p<0.05统计学显著性差异的品系。品系40极易易感，多数阿霉素处理组动物在实验结束前已死亡。

**补充图2（S2 Fig 2）**：阿霉素处理小鼠的肾脏、脾脏与睾丸病理学特征。伴严重肾脏病理学改变的动物（A）可见弥漫性肾小管-肾小球损伤。肾小球病变特征为系膜基质增多、肾小囊壁层上皮增生（B），以及节段性坏死或纤维化。肾小管损伤伴随间质淋巴-组织细胞性炎症（箭头，C）、肾小管上皮萎缩（B、C）及透明管型蓄积（C）。脾脏病理学改变范围从显著的髓外造血（星号，D）到红髓萎缩伴脾脏萎缩（星号，E），白髓则保持完整。睾丸萎缩特征为各级生精细胞完全缺失（F）。苏木精-伊红染色，标尺：A=100μm；B=20μm，C、F=50μm，D、E=1mm

**补充图3（S3 Fig 3）**：血液学参数：
红细胞计数（RBC，A）在急性时间点（橙色组）于几乎所有品系中均出现下降，仅CC051品系除外。多数品系在慢性时间点（蓝色组）恢复，但部分品系（CC001、CC011、CC042）的红细胞计数仍低于正常水平。红细胞分布宽度（RDW，B，反映红细胞直径升高的再生特征指标）在急性时间点所有品系中均升高。多数品系在慢性时间点恢复，仅CC032与CC042品系除外。研究发现，阿霉素在急性（橙色组）与慢性（蓝色组）时间点均未引起中性粒细胞减少症（或淋巴细胞减少症，数据未展示）（C）。诸多品系（CC010、CC040、CC041）在急性时间点出现中性粒细胞计数升高，该升高在部分品系（CC010、CC032、CC041）中持续至慢性时间点。部分品系（CC011、CC040）在急性时间点出现血小板计数升高（D），其余品系（CC001、CC019、CC032、CC042）则表现出性别特异性的血小板升高。该现象伴随显著的脾脏髓外造血组织学证据。多数品系在慢性时间点恢复。

**补充表2**：半定量肾脏评分的统计学分析。