title: Selective inhibition of PDE4 in Wistar rats can lead to dilatation in testis, efferent ducts, and epididymis and subsequent formation of sperm granulomas.
abstract: Testicular tubular dilatation and degeneration and epididymal sperm granulomas were frequently seen in 4-week toxicity studies using different phosphodiesterase-4 (PDE4) inhibitors in Wistar rats, including the prototypic PDE4 inhibitor BYK169171. To investigate the pathogenesis of testicular and epididymal lesions, a time course study with BYK169171 was conducted with sequential necropsies after 7, 14, 21, and 28 days of treatment. After 7 days, a dilatation of efferent ducts and of the initial segment of the epididymis and a subacute interstitial inflammation were seen followed by a diffuse dilatation of seminiferous tubules in the testis. Dilatation and inflammation were most pronounced after 14 days. Single animals also exhibited vascular necrosis in the inflamed interstitium. Although dilatation decreased later in the study, the incidence and severity of tubular degeneration increased from 14 days onward. Sperm granulomas developed in efferent ducts and in the caput and cauda of the epididymis after 14 days. Our results demonstrate a clear time course of PDE4 inhibition-induced lesions, with dilatation preceding sperm granuloma formation. We conclude that the most likely mechanism of toxicity is a disturbance of fluid homeostasis in efferent and epididymal ducts resulting in abnormal luminal fluid and sperm contents, epithelial damage at specific sites of the excurrent duct system, sperm leakage, and granuloma formation.
authors.affiliation: Institute for Pharmacology and Preclinical Drug Safety (IPAS), Nycomed GmbH (Nycomed: A Takeda Company), Barsbüttel, Germany. anke.heuser@takeda.com
authors.forename: Anke
authors.initials: A
authors.lastname: Heuser
authors.forename: Lars
authors.initials: L
authors.lastname: Mecklenburg
authors.forename: Deborah
authors.initials: D
authors.lastname: Ockert
authors.forename: Manfred
authors.initials: M
authors.lastname: Kohler
authors.forename: Jörg
authors.initials: J
authors.lastname: Kemkowski
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D004108:Dilatation, Pathologic / Q000139:chemically induced* / Q000473:pathology; D004822:Epididymis / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D005832:Genital Diseases, Male / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D006099:Granuloma / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D006651:Histocytochemistry; D008297:Male; D009929:Organ Size / Q000187:drug effects; D058988:Phosphodiesterase 4 Inhibitors / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013737:Testis / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4