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Abstracts / Toxicology Letters 189S (2009) S57–S273


Reproduction Toxicology


Ultra structural study of aminoglycosides (gentamicin) and fluo- roquinolone (ofloxacin) antibiotics effect on testis tissue in rats:

Light and transmission electron microscopic study

Arash Khaki 1, , Farnaz Rad saeid 1 , Mohammad Hamadeh 2

1 Islamic Azad University Tabriz Branch, Veterinary Pathology, Tabriz, Iran, Islamic Republic of Iran, 2 University of Saarland Germany, Obstetrics and Gynecology, Hamburg, Germany

Aim: The aim of this study was to investigate the comparative effects of aminoglycosides and fluoroquinolones on testis tissue in rats. Material and methods: Thirty male Wister rats were randomly divided into control (n = 10) and experimental (n = 20) groups. The experimental groups were subdivided into two groups of ten. Each received 5 mg/kg (IP) Gentamicin and 72 mg/kg (IP) Ofloxacin daily for 14 days, respectively; however, the control group just received vehicle (IP). On the fourteenth day, rats were killed and testis tissues were also prepared for light and electron microscopic study. Results: All animals exposed to drugs were seen a depletion of germ cells, germinal cells necrosis, especially in spermatogonia, and Leydig cells had an abnormal fibroblast-like appearance, Abnormal space between neighbor sertoli cells,mitochondria were lost cristae and vacuolated (none energized), lyzosome seenmore in cytoplasm of sertoli cells, nucleus of moiled cell was done heterochromatin. Conclusion: Gentamicin and Ofloxacin have negative effects on testis architecture and germinal cells damages in rats. However, these side effects are less seen in the Ofloxacin group. Therefore, it

is recommended that usage of this drug has fewer side effects on

male fertility.

Keywords: Gentamicin; Ofloxacin; Testis; Rat



Exposure assessments in nonclinical reproductive toxicology studies using toxicokinetics, including a novel approach for monitoring pre-/postnatal study exposures

Thomas Grizzle

Toxicology Services Inc., Pharmaceutical Development, Chapel Hill North Carolina, United States

The reproductive safety profile for many candidate pharmaceu- ticals is incomplete without an assessment of rat and rabbit plasma/serum concentrations of the test substance over time, along with the generation of toxicokinetic (TK) data. Developmental toxi- cology studies, where dosing typically occurs from implantation of the embryo through closure of the hard palate, utilizes TK assess- ments on the first and last days of dosing in concurrently dosed satellite dams and does. Dosing can be extended an extra day in the pregnant satellite animals for a third blood collection, this time

from fetuses, since a substance that tests negative for teratogenicity could be due to a lack of fetal exposure to the substance. For pre- /post-natal studies, additional bioanalytical assays are validated for

a new matrix, milk, and dams are milked at various intervals. A

novel approach has been developed which avoids this additional validation, and instead uses plasma from culled pups. On postna- tal day (PND)4 (birth = PND0), litter sizes are normalized within

a dose group to 4M and 4F pups/dam, a process in which culled pups are identified. A timed sacrifice is then conducted on PND4, n = 3 per time point, and a plasma concentration vs. time curve is thus constructed and TK parameters derived. Exposure data from plasma/serum of suckling pups is superior to milk concentration data because the test substance in milk might have poor bioavail- ability. In summary, TK in reproductive toxicology studies are a necessary part of safety assessments, and an improved method for assessing TK in pre-/post-natal studies is described.



Teratogenic effects of metabolically activated trimethadione in

zebrafish embryos (Danio rerio)

Stefan Weigt 1, , Nicole Hübler 1 , Friedrich von Landenberg 1 , Thomas Braunbeck 2 , Thomas Broschard 1

1 Merck KGaA, Institute of Toxicology, Darmstadt, Germany, 2 University of Heidelberg, Department of Zoology, Heidelberg, Germany

The Danio rerio embryo test with metabolic activation (mDarT) was developed to assess the teratogenic effects of proteratogens. Induced rat liver microsomes (RLM) are used as a mammalian metabolic activation system (MAS), since they contain various cytochrome P450 (CYP) isoforms in high concentrations. The human proteratogen Trimethadione (TMO) is an anticonvulsant used in the treatment of epilepsy. If administered during pregnancy, the fetal trimethadione syndrome may result causing facial dys- morphism, cardiac defects, growth and mental retardation. TMO is metabolically N-demethylated into Dimethadione, mainly by CYP 2E1. The teratogenic potential of TMO was investigated in zebrafish embryos (20 eggs/group) with RLM under moderate agitation at 32 C for 1 h, beginning at the latest 2 hpf (hours post fertilization). The negative control (TMO alone) and the vehicle control (MAS alone) were incubated in parallel. After incubation, the fish embryos were individualized in 24-well plates filled with fish medium and kept at 26 C for the next 72 h with a 12-h-light–dark cycle. Ter- atogenicity was scored at 24, 48 and 72 hpf using standardized morphological endpoints. All the controls fulfilled the acceptance criteria of 10% impaired embryos. While TMO did not show any teratogenic activity up to 15 mM, statistically significant terato- genic activity was observed in the presence of RLM. The number of embryos with teratogenic effects increased with increasing con- centrations of TMO. It is concluded that the teratogenic potential of TMO can be detected in zebrafish embryos only in the presence of a metabolic activation system.

Selected for Oral Presentation.