The problem of maternal toxicity in developmental toxicity studies

Guidelines for developmental toxicity studies require that the highest dose(s) should induce some signs of maternal toxicity. However, the interpretation of the results is often difficult when developmentally toxic effects are recorded only at maternotoxic doses, as it is impossible to ascertain whether the developmental effects are maternally mediated or not. In order to avoid this source of misinterpretation we suggest to use in developmental toxicity tests for environmental chemicals the maximum dose unable to produce maternal toxic effects extrapolated by previous short term toxicity studies

Microtubule alterations occur early in experimental Parkinsonism and the microtubule stabilizer epothilone D is neuroprotective

The role of microtubule (MT) dysfunction in Parkinson\u2019s disease is emerging. It is still unknown whether it is a cause or a consequence of neurodegeneration. Our objective was to assess whether alterations of MT stability precede or follow axonal transport impairment and neurite degeneration in experimental parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57Bl mice. MPTP induced a time- and dose-dependent increase in fibres with altered mitochondria distribution, and early changes in cytoskeletal proteins and MT stability. Indeed, we observed significant increases in neuron-specific betaIII tubulin and enrichment of deTyr tubulin in dopaminergic neurons. Finally, we showed that repeated daily administrations of the MT stabilizer Epothilone D rescued MT defects and attenuated nigrostriatal degeneration induced by MPTP. These data suggest that alteration of MTs is an early event specifically associated with dopaminergic neuron degeneration. Pharmacological stabilization of MTs may be a viable strategy for the management of parkinsonism

Gene-teratogen interactions in chemically induced congenital malformations

Exposure of the embryo to environmental chemicals can result in congenital malformations or abortion. Although experimental teratology data are considered sufficient for risk assessment, only knowledge of their mechanisms of action permits a justifiable extrapolation of animal data to humans. Mechanistic studies of some teratogenic agents such as retinoic acids, valproic acid, diethylstilbestrol, and cyclopamine provided evidence of interference with regulation of genes controlling the embryonic development. The new genomic technologies are important tools in this field and may represent a real improvement in understanding the mechanisms of action of chemical teratogens

Teratogenic activity of HDAC inhibitors

Modification of the terminal tails of histones is considered one of the documented mechanism for epigenetic control of gene expression. Histone deacetylase inhibitors (HDACi) lead to a state of hyperacetylation of histone, a condition that can affect normal gene transcription. Furthermore, HDACi have many other protein targets involved in regulation of gene expression, cell proliferation and cell death. For these properties some HDACi are nowadays used as anticancer drugs with promising results. Several molecules with HDACi properties (valproic acid, trichostatin A, apicidin, MS-275, sodium butyrate, boric acid, salicylic acid) have been found to induce congenital malformations associated with hyperacetylation of histones in the target organs. Cell death is the major event in the target organs a few hours after embryonic exposure to HDACi. Gene deregulation, oxidative stress, DNA demethylation, and/or retinoic acid imbalance are the modes of action postulated for HDACi-induced teratogenesis

Biomarkers of teratogenesis : suggestions from animal studies

Biomarkers of effect are measurable biochemical, physiological or other alterations within an organism that can be recognized as causing an established or potential impairment of embryo-fetal development. They may be identified studying the mechanisms of action of teratogens. Hyperacetylation of histones, oxidative stress, cholesterol and retinoic acid unbalance are some of the identified mechanisms of action of some known teratogens. Nevertheless, their use is not currently applicable in human pregnancy because of the difficulty of the choice of biological material, the time when the material must be obtained, and the invasivity of methods. Furthermore, before using them in human pregnancy studies, biomarkers should be validated in experimental animals and in epidemiologic studies. On the contrary, some biomarkers could be useful in the screening of developmental toxicity of chemicals and drugs, comparing molecules of the same chemical class or with the similar pharmacologic activity, and using adequate in vitro tests, in order to reduce the use of experimental animals

Are Azole fungicides a teratogenic risk for human conceptus?

Azole fungicides are widely used in agriculture and in human mycosis. Their antifungal activity is based on their ability to inhibit CYP51, a key enzyme in the formation of fungal wall. Several azole fungicides tested in laboratory animals have been found to possess a common teratogenic potential to induce facial, axial skeleton, and limb defects. The mechanism of the teratogenic effect has been hypothesized to be related to the capability of these substances to alter embryonic retinoic acid catabolism. Although a number of human epidemiological studies were unable to demonstrate a definite relationship between azole exposure during pregnancy and birth defects, some case reports indicate a possible teratogenic effect of high doses of azoles in humans. Because of their common mechanism of action, azole fungicides should be regarded with caution for use in pregnant women