کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
8551239 1562107 2018 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
An innovative investigative approach to characterize the effects observed in a combined fertility study in male and female rats
ترجمه فارسی عنوان
یک رویکرد تحقیق نوآورانه برای مشخص کردن اثرات مشاهده شده در یک مطالعه ترکیب باروری در موش های صحرایی نر و ماده
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
چکیده انگلیسی
This paper describes the characterization of male- and female-mediated effects in a standard ICH rat fertility and early embryonic development study with a discontinued clinical small molecule. In the standard study, the test item had no effect on the number of treated females becoming pregnant, but litter sizes were reduced at the high dose level. In the treated male rats, increased incidences of abnormal sperm, decreases in average sperm path and straight line velocities, and minimal retention of mature sperm in the seminiferous tubules were observed at all dose-levels tested. These findings were unexpected in view of a lack of histopathological changes in the reproductive organs of either gender in 4-week repeat dose studies in rats and monkeys. A follow-up fertility study was conducted using an innovative flexible study design and a single high-dose level. In the first instance, treated male rats were mated with untreated females, followed by necropsy of a subset of males. The intention was then to re-mate the males after an 8-week wash-out period with either treated or untreated females depending on the outcome of the first mating. On this occasion, litter sizes were not affected, but the testicular effects were reproduced. A second mating with treated females reproduced the reduced litter sizes due to increased pre- and post-implantation loss, demonstrating that the effect on fecundity was female-mediated. The testicular changes in males were shown to be reversible after a 12-week recovery period.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Regulatory Toxicology and Pharmacology - Volume 95, June 2018, Pages 339-347
نویسندگان
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