Archives of Toxicology

, Volume 93, Issue 7, pp 1979–1992 | Cite as

Novel insight in estrogen homeostasis and bioactivity in the ACI rat model of estrogen-induced mammary gland carcinogenesis

  • Daniela Pemp
  • Harald L. Esch
  • René Hauptstein
  • Frank J. Möller
  • Oliver Zierau
  • Maarten C. Bosland
  • Leo N. Geppert
  • Carolin Kleider
  • Katharina Schlereth
  • Günter Vollmer
  • Leane LehmannEmail author
Organ Toxicity and Mechanisms


Despite being widely used to investigate 17β-estradiol (E2)-induced mammary gland (MG) carcinogenesis and prevention thereof, estrogen homeostasis and its significance in the female August Copenhagen Irish (ACI) rat model is unknown. Thus, levels of 12 estrogens including metabolites and conjugates were determined mass spectrometrically in 38 plasmas and 52 tissues exhibiting phenotypes ranging from normal to palpable tumor derived from a representative ACI study using two different diets. In tissues, 40 transcripts encoding proteins involved in estrogen (biotrans)formation, ESR1-mediated signaling, proliferation and oxidative stress were analyzed (TaqMan PCR). Influence of histo(patho)logic phenotypes and diet on estrogen and transcript levels was analyzed by 2-way ANOVA and explanatory variables influencing levels and bioactivity of estrogens in tissues were identified by multiple linear regression models. Estrogen profiles in tissue and plasma and the influence of Hsd17b1 levels on intra-tissue levels of E2 and E1 conclusively indicated intra-mammary formation of E2 in ACI tumors by HSD17B1-mediated conversion of E1. Proliferation in ACI tumors was influenced by Egfr, Igf1r, Hgf and Met levels. 2-MeO-E1, the only oxidative estrogen metabolite detected above 28–42 fmol/g, was predominately observed in hyperplastic tissues and intra-tissue conversion of E1 seemed to contribute to its levels. The association of the occurrence of 2-MeO-E1 with higher levels of oxidative stress observed in hyperplastic and tumor tissues remained equivocal. Thus, the present study provides mechanistic explanation for previous and future results observed in the ACI model.


ACI rat Mammary estrogen profile Estrogen activity Tumorigenesis Multiple linear regression 



This work is part of the joint research project, IsoCross, entitled “Isoflavones: Cross-species comparison of metabolism, estrogen sensitivity, epigenetics and carcinogenesis”, which was supported in whole by grants from the German Research Foundation to L. Lehmann (DFG LE 1329/10–1) and G. Vollmer (DFG VO410/12-1).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Supplementary material 1 (PDF 126 kb)
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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institute of Pharmacy and Food ChemistryUniversity of WürzburgWürzburgGermany
  2. 2.Chair of Molecular Cell Physiology and EndocrinologyUniversity of DresdenDresdenGermany
  3. 3.Department of Pathology, College of MedicineUniversity of Illinois at ChicagoChicagoUSA
  4. 4.Chair of Mathematical Statistics with Applications in BiometricsTU Dortmund UniversityDortmundGermany

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