Reference SummarySnyder JM, Geroscience 2026 Apr;48(2):1787-1797

Title

 End-of-life pathology in UM-HET3 mice treated with 16 alphahydroxyestradiol or latestart canagliflozin.

Authors

 Snyder JM; Harrison DE; Korstanje R; Ginsburg B; Reifsnyder PC; Nelson J; Leiser S; Kaczorowski C; Imai DM; Salmon AB; Strong R; Ladiges W; Miller RA

Journal

 Geroscience

Volume

 48

Issue

 2

Year

 2026

Pages

 1787-1797

Abstract

 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.

Links

 J:385467 – MGI References
40601216 – National Library of Medicine/PubMed

Strain Notes

Strain Note
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 "Briefly, these UM-HET3 mice are the progeny of CByB6F1 mothers (JAX stock 100009) and C3D2F1 fathers (JAX stock 100004)."

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Adrenal gland - Cortex neoplasia Adrenal gland - Cortex

0 - 38.5
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Adrenal gland - Cortex neoplasia
  • 16alpha-hydroxyestradiol (OH_Est)
 Adrenal gland - Cortex

7.7 - 11.1
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Adrenal gland - Cortex neoplasia
  • canagliflozin (Cana)
 Adrenal gland - Cortex

6.9 - 20.7
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Blood vessel hemangiosarcoma Blood vessel

0
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Blood vessel hemangiosarcoma
  • 16alpha-hydroxyestradiol (OH_Est)
 Blood vessel

13.8
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Blood vessel hemangiosarcoma
  • canagliflozin (Cana)
 Blood vessel

6.5 - 16.7
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Bone lesion - fibro-osseous Bone

0 - 7.1
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Bone lesion - fibro-osseous
  • 16alpha-hydroxyestradiol (OH_Est)
 Bone

59.3 - 60.9
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Bone lesion - fibro-osseous
  • canagliflozin (Cana)
 Bone

observed
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Liver adenoma Liver

3.6 - 28.6
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Liver adenoma
  • 16alpha-hydroxyestradiol (OH_Est)
 Liver

0 - 6.9
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Liver adenoma
  • canagliflozin (Cana)
 Liver

3.3 - 6.9
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Liver hepatocellular carcinoma Liver

7.1 - 13
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Liver hepatocellular carcinoma
  • 16alpha-hydroxyestradiol (OH_Est)
 Liver

0 - 10
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Liver hepatocellular carcinoma
  • canagliflozin (Cana)
 Liver

0 - 30
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Lung adenocarcinoma Lung

13.3 - 28.6
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Lung adenocarcinoma
  • 16alpha-hydroxyestradiol (OH_Est)
 Lung

3.4 - 7.1
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Lung adenocarcinoma
  • canagliflozin (Cana)
 Lung

10 - 40
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Lung carcinoma Lung

6.7
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Lung carcinoma
  • 16alpha-hydroxyestradiol (OH_Est)
 Lung

3.4 - 6.9
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Lung carcinoma
  • canagliflozin (Cana)
 Lung

6.7 - 22.6
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Mammary gland carcinoma Mammary gland

0 - 3.3
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Mammary gland carcinoma
  • 16alpha-hydroxyestradiol (OH_Est)
 Mammary gland

0 - 10.3
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Mammary gland carcinoma
  • canagliflozin (Cana)
 Mammary gland

0 - 16.7
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Mammary gland neoplasm Mammary gland

11.1
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Pituitary gland neoplasm Pituitary gland

6.7
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Pituitary gland neoplasm
  • 16alpha-hydroxyestradiol (OH_Est)
 Pituitary gland

3.6 - 29.6
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Pituitary gland neoplasm
  • canagliflozin (Cana)
 Pituitary gland

0 - 10
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Thyroid gland hyperplasia Thyroid gland

0 - 17.4
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Thyroid gland hyperplasia
  • 16alpha-hydroxyestradiol (OH_Est)
 Thyroid gland

0 - 22.2
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Uterus - Endometrium hyperplasia - cystic Uterus - Endometrium

observed
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 Uterus - Endometrium hyperplasia - cystic
  • 16alpha-hydroxyestradiol (OH_Est)
 Uterus - Endometrium

observed
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 (Unspecified organ) neoplasia (Unspecified organ)

6.7 - 50
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 (Unspecified organ) neoplasia Head

0 - 13.3
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 (Unspecified organ) neoplasia Uterus

37.9
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 (Unspecified organ) neoplasia Liver

15.4 - 40.7
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 (Unspecified organ) neoplasia
  • 16alpha-hydroxyestradiol (OH_Est)
 (Unspecified organ)

20.7 - 44.8
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 (Unspecified organ) neoplasia
  • 16alpha-hydroxyestradiol (OH_Est)
 Head

0 - 7.1
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 (Unspecified organ) neoplasia
  • 16alpha-hydroxyestradiol (OH_Est)
 Uterus

14.8
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 (Unspecified organ) neoplasia
  • canagliflozin (Cana)
 (Unspecified organ)

20 - 22.6
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 (Unspecified organ) neoplasia
  • canagliflozin (Cana)
 Uterus

13.8
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 (Unspecified organ) neoplasia
  • canagliflozin (Cana)
 Liver

16.7 - 30
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 (Unspecified organ) squamous cell carcinoma (Unspecified organ)

0
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 (Unspecified organ) squamous cell carcinoma
  • 16alpha-hydroxyestradiol (OH_Est)
 (Unspecified organ)

0 - 6.9
(BALB/cByJ x C57BL/6J)F1 x (C3H/HeJ x DBA/2J)F1 (Unspecified organ) squamous cell carcinoma
  • canagliflozin (Cana)
 (Unspecified organ)

0 - 3.3