Reproductive cytotoxicity is predicted by magnetic resonance microscopy and confirmed by ubiquitin-proteasome immunohistochemistry in a theophylline-induced model of rat testicular and epididymal toxicity.
This study investigated the testicular changes in the rat induced by the nonspecific phosphodiesterase inhibitor, theophylline using magnetic resonance microscopy (MRM) and ubiquitin immunostaining techniques. In vivo T1- and T2-weighted images were acquired at 2 T under anesthesia. Increased signal observed in the theophylline-treated rats suggests that leakage of MRM contrast was occurring. In vivo MRM results indicate that day 16 testis displayed an increased T1-weighted water signal in the area of the seminiferous tubule that decreased by day 32. These findings were validated by histopathology, suggesting that in vivo MRM has the sensitivity to predict changes in testis and epididymal tissues. The participation of the ubiquitin system was investigated, using probes for various markers of the ubiquitin-proteasome pathway. MRM can be used to detect subtle changes in the vascular perfusion of organ systems, and the up-regulation/mobilization of ubiquitin-proteasome pathway may be one of the mechanisms used in theophylline-treated epididymis to remove damaged cells before storage in the cauda epididymis. The combined use of in vivo MRM and subsequent tissue or seminal analysis for the presence of ubiquitin in longitudinal studies may become an important biomarker for assessing testis toxicities drug studies.
Tengowski
M W
MW
Safety Sciences Groton, Pfizer Global Research and Development, Groton, CT 06340, USA. mark_w_tengowski@groton.pfizer.com
Sutovsky
P
P
Hedlund
L W
LW
Guyot
D J
DJ
Burkhardt
J E
JE
Thompson
W E
WE
Sutovsky
M
M
Johnson
G A
GA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004822:Epididymis / Q000737:chemistry / Q000187:drug effects*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008853:Microscopy; D009929:Organ Size / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013737:Testis / Q000737:chemistry / Q000187:drug effects*; D013806:Theophylline / Q000633:toxicity*; D025801:Ubiquitin / Q000378:metabolism*
D025801:Ubiquitin; D013806:Theophylline; D046988:Proteasome Endopeptidase Complex