Genistein inhibits proliferation and induces senescence in neonatal mouse pituitary gland explant cultures

Karen E. Weis, Lori T. Raetzman

Research output: Contribution to journalArticle

Abstract

Genistein is an isoflavone abundant in soybean and infants are exposed to high levels of genistein in soy-based formula. It is known that genistein mediates estrogen receptor (ER) signaling, and exposure during neonatal development could cause acute and long term endocrine effects. We assayed genistein's impact on the neonatal mouse pituitary gland because it is an endocrine signaling hub and is sensitive to endocrine disruption during critical periods. Pituitary explant cultures, which actively proliferate and differentiate, were exposed to 0.06 μM–36 μM genistein and assayed for mRNA and protein changes. Genistein induced mRNA expression of the ERα regulated gene, Cckar, to the same magnitude as estradiol (E2) but with less potency. Interestingly, 36 μM genistein strongly inhibited pituitary proliferation, measured by a reduction in mKi67 mRNA and phospho-Histone H3 immunostaining. Examining cell cycle dynamics, we found that 36 μM genistein decreased Ccnb1 (Cyclin B1) mRNA; while mRNA for the cyclin dependent kinase inhibitor Cdkn1a (p21) was upregulated, correlated with an apparent increase in p21 immunostained cells. Strikingly, we observed a robust onset of cellular senescence, permanent cell cycle exit, in 36 μM genistein treated pituitaries by increased senescence activated β-galactosidase staining. We also found that 36 μM genistein decreased Bcl2 mRNA levels, a gene protective against apoptosis. Taken together these data suggest that genistein exposure during the neonatal period could initiate senescence and halt proliferation during a time when the proper numbers of endocrine cells are being established for mature gland function.

Original languageEnglish (US)
Article number152306
JournalToxicology
Volume427
DOIs
StatePublished - Nov 1 2019

Fingerprint

Genistein
Pituitary Gland
Messenger RNA
Cells
Estrogen Receptors
Cell Cycle
Genes
Galactosidases
Cyclin-Dependent Kinase Inhibitor p21
Cyclin B1
Isoflavones
Endocrine Cells
Cyclin-Dependent Kinases
Cell Aging
Soybeans
Histones
Estradiol
Apoptosis
Staining and Labeling

Keywords

  • Genistein
  • Pituitary
  • Proliferation
  • Senescence

ASJC Scopus subject areas

  • Toxicology

Cite this

Genistein inhibits proliferation and induces senescence in neonatal mouse pituitary gland explant cultures. / Weis, Karen E.; Raetzman, Lori T.

In: Toxicology, Vol. 427, 152306, 01.11.2019.

Research output: Contribution to journalArticle

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