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<p>Canagliflozin (Cana) started&#xa0; at 16&#xa0;months of age and 16-hydroxy-estradiol (OH_Est) started at 12&#xa0;months each led to significant increases in lifespan in male UM-HET3 mice but significant decreases in female lifespan. To seek insights into the basis for these sex-specific effects, we performed end-of-life histopathological analyses of control and treated mice for all three interventions testing program sites. There were no significant drug-induced alterations in inferred cause of death, although statistical power was low for such comparisons. Tabulation of incidental lesions (i.e., combining lethal and non-lethal lesions) revealed a complex set of significant and near-significant changes caused by each of the two agents, in some cases absent, or even opposite in direction, in one of the two sexes. The analysis did not, however, reveal a clear pattern that would explain the selective sex-specific effects of either agent on lifespan. It is plausible that the female-specific harm induced by each of these agents could reflect harmful or toxic effects that are not easily detectable by histopathological examination.</p>

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End-of-life pathology in UM-HET3 mice treated with 16 α‑hydroxyestradiol or late‑start canagliflozin

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月2日

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  • Jessica M. Snyder,
  • David E. Harrison,
  • Ron Korstanje,
  • Brett Ginsburg,
  • Peter C. Reifsnyder,
  • James Nelson,
  • Scott Leiser,
  • Catherine Kaczorowski,
  • Denise M. Imai,
  • Adam B. Salmon,
  • Randy Strong,
  • Warren Ladiges,
  • Richard A. Miller

摘要

Canagliflozin (Cana) started  at 16 months of age and 16-hydroxy-estradiol (OH_Est) started at 12 months each led to significant increases in lifespan in male UM-HET3 mice but significant decreases in female lifespan. To seek insights into the basis for these sex-specific effects, we performed end-of-life histopathological analyses of control and treated mice for all three interventions testing program sites. There were no significant drug-induced alterations in inferred cause of death, although statistical power was low for such comparisons. Tabulation of incidental lesions (i.e., combining lethal and non-lethal lesions) revealed a complex set of significant and near-significant changes caused by each of the two agents, in some cases absent, or even opposite in direction, in one of the two sexes. The analysis did not, however, reveal a clear pattern that would explain the selective sex-specific effects of either agent on lifespan. It is plausible that the female-specific harm induced by each of these agents could reflect harmful or toxic effects that are not easily detectable by histopathological examination.