Doxorubicin treatment in male rats caused persistent testicular atrophy at 6 weeks post-treatment compared to saline (normalized testis mass 0.0039 vs 0.0074 g; p<0.05), alongside elevated TNF-α.
Doxorubicin induces persistent systemic toxicity, including testicular atrophy, splenomegaly, and sustained inflammation and oxidative stress, even 6 weeks after treatment cessation in a rat model.
Absolute Event Rate: 0.0039% vs 0.0074%
p-value: p=< 0.05
Doxorubicin (DOX) is an effective chemotherapeutic agent that induces systemic toxicity, yet its long-term effects after treatment cessation remain poorly understood. The purpose of this study was to evaluate the long-term effects of DOX on reproductive and immune organs six weeks after treatment cessation. We hypothesize that DOX-induced systemic oxidative stress and inflammation persist following treatment cessation and contribute to lasting alterations in reproductive and immune organ mass. Thirty-five male Wistar rats at 10 weeks old received either DOX (4 weekly I.P. injections of 2.5mg/Kg; D, n=18) or equal volume of saline solution (C, n=17). Rats were evaluated after DOX treatment – baseline timepoint (CB or DB) and following 6 weeks of recovery – recovery timepoint (CR or DR). Rats received food and water ad libitum, and average daily food intake was recorded. Blood plasma, spleen, and testis were collected during euthanasia, and tissue mass was normalized by body mass. Differences between groups were analyzed using two-way ANOVA or the Kruskal–Wallis test, followed by Tukey’s or Dunn’s post hoc test when appropriate. Statistical significance was set at p < 0.05. DOX treatment reduced food intake, with both time (p < 0.0001) and treatment effects (p = 0.0039) observed but not significant interaction, and values were lower at the recovery timepoint. Final body mass differed between groups at the end of the study, with DR showing lower mass than CR, while CR showed higher mass than its time control (CB: 415.9±29.03, DB: 402.5±19.88, CR: 483.7±32.48, DR: 424.7±27.97g; p < 0.05). Tibia length increased over time in all groups (time effect, p = 0.0003). Testis mass normalized to body mass decreased in DR group compared with DB and CR, indicating persistent gonadal atrophy (CB: 0.0087±0.0015, DB: 0.0075±0.0007, CR: 0.0074±0.0015, DR: 0.0039±0.0008g; p < 0.05). Spleen mass normalized to body mass was higher in DOX-treated rats (treatment effect, p = 0.0041). Consistently with enlarged spleen, systemic inflammation persisted during recovery from DOX; TNF-α was elevated in DR compared to CR (CB: 12.78±1.98, DB: 18.22±5.82, CR: 12.69±2.54, DR: 18.41±3.98pg/mL; p < 0.05), whereas IL-6 levels were unchanged. Plasma malondialdehyde (MDA), an oxidative stress marker, was also elevated in DR compared to CR (CB: 96.05 ± 25.55, DB: 117.2 ± 12.02, CF: 80.54 ± 22.58, DF: 195.6 ± 106.8μg/mL; p=0.001 CF x DF). Conclusions: DOX-induced systemic alterations persist after treatment cessation, including reduced food intake and body mass, testicular atrophy, and splenomegaly. Elevated plasma TNF-α and MDA levels during recovery indicate sustained activation of inflammatory and oxidative stress pathways, implicating TNF-α-associated signaling as a potential contributor to DOX-induced hypogonadism and systemic toxicity. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Pigg et al. (Fri,) conducted a other in Doxorubicin-induced systemic toxicity (n=35). Doxorubicin vs. Saline solution was evaluated on Testis mass normalized to body mass at recovery (p=< 0.05). Doxorubicin treatment in male rats caused persistent testicular atrophy at 6 weeks post-treatment compared to saline (normalized testis mass 0.0039 vs 0.0074 g; p<0.05), alongside elevated TNF-α.