Epigenetic Effects of a Single Developmentally-Entrained Testosterone Pulse on Body Composition and Muscle Mass are Associated with Global Changes in DNA Methylation

Presentation Number: SAT-390
Date of Presentation: June 15th, 2013

Hyeran Jang*1, James Costello2, Gianluca Toraldo3, Carlo Serra1, Sang-Woon Choi4, Shalender Bhasin1 and Ravi Jasuja1
1Brigham & Women's Hospital, Boston, MA, 2Boston University, 3Boston University Medical Center, MA, 4JM-USDA-HNRCA at Tufts University

Abstract

Background: The neonatal transient surge of testosterone (T) in male mammals that occurs shortly after birth (<72 hours in mice; <6 months in humans) is important for the organizational effects on gender dimorphic reproductive, mating and non-mating behaviors, and neural development. While these organizational effects of neonatal testosterone exposure are well known, the underlying mechanisms are poorly understood. In this study, we tested the hypothesis that neonatal transient exposure to T alters the adult phenotype through epigenetic alterations that are sustained through adult lifespan.

Methods: CD-1 male mice pups were injected with either 5µg of testosterone enanthate or vehicle within 24 hours after birth. After insertions of tattoos for group segregation, the mouse pups  were mixed and then given back to lactating mothers to eliminate maternal effects and followed to adult age.

Results: Bi-weekly NMR scanning showed neonatally T injected mice had significantly higher percent lean body mass (LBM) than their litter-mate controls (72.7±1.8% vs 67.5±1.0; p<0.05 at 20w). These pro-myogenic organizational effects were particularly pronounced in the androgen sensitive levator ani whose wet weight was significantly greater in mice given a single pulse of testosterone than in mice given vehicle (206.8±9.9mg vs. 172.1±8.5; p<0.05). Immunoblot analysis showed a significant increase in androgen receptor protein expression in the levator ani muscle of T injected mice than in vehicle-injected mice.  Injections of a single testosterone pulse at 20 or 40 days of age had no significant effect on LBM or levator ani mass in adulthood. Using LC/MS, we found that the increase in levator animuscle by a single neonatal T injection was accompanied by significantly increase in genomic DNA methylation (3.4±0.2% vs. 3.7±0.1; p<0.001).

Conclusion: A single pulse of testosterone administered during a specific developmental window in immediate postnatal life results in epigenetic programming of muscle mass and AR expression in adult life and is associated with global changes in DNA methylation. The mechanisms of these epigenetic effects need further investigation.

 

Nothing to Disclose: HJ, JC, GT, CS, SWC, SB, RJ