The bovine oocyte in vitro maturation model: A potential tool for reproductive toxicology screening

Reproductive toxicity testing according to the present guidelines requires a high number of animals. Therefore, the development of alternative in vitro methods is urgently required. The aim of the present study was to investigate the applicability domain of the bovine oocyte in vitro maturation assay (bIVM) to study female reproductive toxicology. Therefore, bovine oocytes were exposed to a broad set of chemicals of two distinct biological function groups: (a) affecting female fertility and (b) affecting embryonic development and having a broad range of physical and chemical properties. The endpoints evaluated were the oocyte nuclear maturation (progression of meiosis) and general cytotoxicity. The oocyte nuclear maturation was negatively affected by all compounds tested and the effect was observed at concentrations lower than the cytotoxic ones. The bIVM assay correctly predicted the classification of compounds between those predefined groups. Additionally, the bIVM model contributes significantly for the 3R principle, since no test animals are used in this assay. In conclusion, the bIVM is a sensitive and valuable alternative assay to identify potential chemical hazard on female fertility. © 2012 Elsevier Inc

A category approach to predicting the developmental (neuro) toxicity of organotin compounds: The value of the zebrafish (Danio rerio) embryotoxicity test (ZET).

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Zebrafish embryotoxicity test for developmental (neuro)toxicity: Demo case of an integrated screening approach system using anti-epileptic drugs

To improve the predictability of the zebrafish embryotoxicity test (ZET) for developmental (neuro)toxicity screening, we used a multiple-endpoints strategy, including morphology, motor activity (MA), histopathology and kinetics. The model compounds used were antiepileptic drugs (AEDs): valproic acid (VPA), carbamazepine (CBZ), ethosuximide (ETH) and levetiracetam (LEV). For VPA, histopathology was the most sensitive parameter, showing effects already at 60. μM. For CBZ, morphology and MA were the most sensitive parameters, showing effects at 180. μM. For ETH, all endpoints showed similar sensitivity (6.6. mM), whereas MA was the most sensitive parameter for LEV (40. mM). Inclusion of kinetics did not alter the absolute ranking of the compounds, but the relative potency was changed considerably. Taking all together, this demo-case study showed that inclusion of multiple-endpoints in ZET may increase the sensitivity of the assay, contribute to the elucidation of the mode of toxic action and to a better definition of the applicability domain of ZET. © 2014 Elsevier Inc. Molecular Sequence Numbers: GENBANK: NM_131146, NM_131850; Chemicals/CAS: carbamazepine, 298-46-4, 8047-84-5; ethosuximide, 77-67-8; etiracetam, 102767-28-2, 33996-58-6; valproic acid, 1069-66-5, 99-66-1 Manufacturers: Sigma Aldrich, United State

Bisphenol A exposure in utero disrupts early oogenesis in the mouse

Estrogen plays an essential role in the growth and maturation of the mammalian oocyte, and recent studies suggest that it also influences follicle formation in the neonatal ovary. In the course of studies designed to assess the effect of the estrogenic chemical bisphenol A (BPA) on mammalian oogenesis, we uncovered an estrogenic effect at an even earlier stage of oocyte development--at the onset of meiosis in the fetal ovary. Pregnant mice were treated with low, environmentally relevant doses of BPA during mid-gestation to assess the effect of BPA on the developing ovary. Oocytes from exposed female fetuses displayed gross aberrations in meiotic prophase, including synaptic defects and increased levels of recombination. In the mature female, these aberrations were translated into an increase in aneuploid eggs and embryos. Surprisingly, we observed the same constellation of meiotic defects in fetal ovaries of mice homozygous for a targeted disruption of ERbeta, one of the two known estrogen receptors. This, coupled with the finding that BPA exposure elicited no additional effects in ERbeta null females, suggests that BPA exerts its effect on the early oocyte by interfering with the actions of ERbeta. Together, our results show that BPA can influence early meiotic events and, importantly, indicate that the oocyte itself may be directly responsive to estrogen during early oogenesis. This raises concern that brief exposures during fetal development to substances that mimic or antagonize the effects of estrogen may adversely influence oocyte development in the exposed female fetus