The Effects of a Single Developmentally Entrained Pulse of Testosterone in Female Neonatal Mice on Reproductive and Metabolic Functions in Adult Life

Endocrinology. 2015 Oct;156(10):3737-46. doi: 10.1210/EN.2015-1117. Epub 2015 Jul 1.

Abstract

Early postnatal exposures to sex steroids have been well recognized to modulate predisposition to diseases of adulthood. There is a complex interplay between timing, duration and dose of endocrine exposures through environmental or dietary sources that may alter the sensitivity of target tissues to the exogenous stimuli. In this study, we determined the metabolic and reproductive programming effects of a single developmentally entrained pulse of testosterone (T) given to female mice in early postnatal period. CD-1 female mice pups were injected with either 5 μg of T enanthate (TE) or vehicle (control [CON] group) within 24 hours after birth and followed to adult age. A total of 66% of T-treated mice exhibited irregular cycling, anovulatory phenotype, and significantly higher ovarian weights than vehicle-treated mice. Longitudinal nuclear magnetic resonance measurements revealed that TE group had greater body weight, whole-body lean, and fat mass than the CON group. Adipose tissue cellularity analysis in TE group revealed a trend toward higher size and number than their littermate CONs. The brown adipose tissue of TE mice exhibited white fat infiltration with down-regulation of several markers, including uncoupling protein 1 (UCP-1), cell death-inducing DNA fragmentation factor, α-subunit-like effector A, bone morphogenetic protein 7 as well as brown adipose tissue differentiation-related transcription regulators. T-injected mice were also more insulin resistant than CON mice. These reproductive and metabolic reprogramming effects were not observed in animals exposed to TE at 3 and 6 weeks of age. Collectively, these data suggest that sustained reproductive and metabolic alterations may result in female mice from a transient exposure to T during a narrow postnatal developmental window.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / cytology
  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Animals
  • Animals, Newborn
  • Body Weight / drug effects
  • Bone Morphogenetic Protein 7 / genetics
  • Bone Morphogenetic Protein 7 / metabolism
  • Estradiol / blood
  • Estrous Cycle / drug effects
  • Female
  • Follicle Stimulating Hormone / blood
  • Gene Expression Regulation, Developmental / drug effects
  • Ion Channels / genetics
  • Ion Channels / metabolism
  • Luteinizing Hormone / blood
  • Male
  • Metabolism / drug effects*
  • Metabolism / physiology
  • Mice
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Organ Size / drug effects
  • Ovary / drug effects
  • Ovary / growth & development
  • Reproduction / drug effects*
  • Reproduction / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Testosterone / analogs & derivatives*
  • Testosterone / blood
  • Testosterone / pharmacology
  • Time Factors
  • Uncoupling Protein 1

Substances

  • Bone Morphogenetic Protein 7
  • Ion Channels
  • Mitochondrial Proteins
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • Testosterone
  • Estradiol
  • testosterone enanthate
  • Luteinizing Hormone
  • Follicle Stimulating Hormone