title: The rate of 2,5-hexanedione intoxication, not total dose, determines the extent of testicular injury and altered microtubule assembly in the rat.
abstract: Charles River CD rats (220 g) were intoxicated with 1.0, 0.5, or 0.25% 2,5-hexanedione (2,5-HD) in the drinking water for a total of 21, 35, or 69 days, respectively. All rats received a total dose of 131 +/- 2 mmol/kg 2,5-HD at dose rates ranging from 1.9 to 6.1 mmol/kg/day. Rats were sacrificed 4 weeks after ending intoxication to evaluate the extent of testicular injury. An exposure rate of 6.1 mmol 2,5-HD/kg/day produced uniformally low testis weights (49% of control) and severe germ cell depletion, while exposure at 1.9 mmol/kg/day gave normal testis weights and histology. Exposure at the intermediate dose rate of 3.8 mmol 2,5-HD/kg/day produced an intermediate degree of testicular injury. In a separate experiment, testis pyrrole content and microtubule assembly behavior were measured in rats exposed to 2,5-HD at the various dose rates for 3 weeks. The rate of intoxication determined the extent of biochemical abnormality. Rats exposed to 1.0, 0.5, or 0.25% 2,5-HD had microtubule nucleation times 55, 63, and 72% of control and pyrrole contents equivalent to 2.14, 1.40, and 1.18 nmol 2,5-dimethylpyrrole/mg testis protein. These data demonstrate that 2,5-HD-induced testicular injury, unlike the nervous system toxicity, is dependent upon the rate of intoxication independent of total dose.
authors: Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 02912.
authors: K
authors: K
authors: Boekelheide
authors: J
authors: J
authors: Eveleth
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006588:Hexanones / Q000633:toxicity*; D007659:Ketones / Q000633:toxicity*; D008297:Male; D008870:Microtubules / Q000187:drug effects*; D009929:Organ Size / Q000187:drug effects; D011758:Pyrroles / Q000378:metabolism; D051381:Rats; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: D006588:Hexanones; D007659:Ketones; D011758:Pyrroles; C011269:2,5-hexanedione