Evaluation de l'embryotoxicité d'agents chimiques par le système de culture in vitro d'embryons de souris après l'implantation

Diss. Doct

Pesticides et cancers - Apports de l\u27expertise Inserm

Le premier objectif de l\u27expertise a été d\u27évaluer un lien entre une exposition professionnelle aux pesticides, en particulier dans le secteur agricole, et la survenue d\u27une pathologie chronique. Le deuxième a été d\u27évaluer les effets sanitaires d\u27une exposition précoce chez le foetus et le jeune enfant. Le troisième objectif a été d\u27identifier des familles ou substances actives pouvant être impliquées d\u27après les études disponible

Exposition professionnelle des parents aux pesticides et cancers chez l\u27enfant

Les données épidémiologiques concernant le lien entre pesticides et cancers de l\u27enfant sont nombreuses et leurs résultats sont souvent controversés. Les revues systématiques (RS) et méta-analyses (MA) offrent des synthèses de données scientifiques aussi objectives que possible et aident aussi à comprendre les controverses de la littérature en explorant les liens entre les effets observés et des caractéristiques d\u27études

Prostate cancer among pesticide applicators: a meta-analysis.

OBJECTIVES: To analyse data from peer-reviewed, case-referent and cohort studies, studying the occurrence of prostate cancer in pesticide applicators and in some other, related, occupational categories, in order to determine a possible relationship of cancer of the prostate with pesticide exposure; to calculate a meta-rate ratio and to compare it with the meta-rate ratios obtained in a previous meta-analysis performed over a shorter time (1995-2001) in a broader exposure category, including many pesticide-related agricultural and non-agricultural occupations. METHODS: Medline was searched for the years between 1966 and 2003, and relevant studies were identified from 1986 on. We conducted a meta-analysis of 22 studies complying with the inclusion criteria in order to pool their relative risk (RR) estimates. Studies were summarised and assessed for homogeneity and publication bias. RESULTS: The meta-rate ratio, based on 22 estimates of RR, is 1.24 [95% confidence interval (95% CI) 1.06-1.45]. This pooled risk estimate for the occupational categories selected is higher than the one previously calculated for farmers in general over a shorter period of publication. Substantial heterogeneity of rate ratios exists between the different studies. The major source of heterogeneity identified is geographic location. Increased meta-rate ratios are observed for studies derived from North America as well as from Europe, the meta-rate ratios from Europe being lower than those from North America. There is no obvious indication of publication bias. CONCLUSION: The increased meta-rate ratio for prostate cancer in agricultural pesticide applications provides additional evidence for a possible relationship between pesticide exposure and prostate cancer. The homogeneity observed between the individual rate ratios, after we had regrouped the data according to geographic location, tends to increase the consistency of the association. However, the data available from the individual studies do not provide sufficient exposure information for firm conclusions to be drawn about pesticide exposure as the cause of prostate cancer, independently from other factors

Evaluation of the embryotoxic potential of ten chemicals in the whole mouse embryo culture.

Ten widely different chemicals, actinomycin D, mithramycin, podophyllotoxin, vincristine sulfate, triaziquone, chlorambucil, mercaptopurine riboside, methyl-mercaptopurine riboside, dimethylsulfoxide, and L-lysine were tested in the whole mouse embryo culture system. The highest concentration was always the concentration that induced 100% lethality (ELC100). The lowest concentration varied from 1/2 to 1/10 of the ELC100. The chemicals that had the most noxious effect on embryonic growth and differentiation were actinomycin D, triaziquone, and mercaptopurine riboside. Podophyllotoxin, methyl-mercaptopurine riboside, and L-lysine were the less embryotoxic. As a whole, no significant discrepancies were observed between the results and the teratological data obtained from the literature. These observations support the assumption that the whole murine embryo culture system can give valuable information on the teratogenicity of chemicals

All-trans-retinoic acid upregulates the expression of COUP-TFI in early-somite mouse embryos cultured in vitro

Exposure of embryos to an excess of retinoic acid (RA) modifies the spatio-temporal pattern of expression of developmental genes. RA regulates the expression of target genes through binding of the retinoid nuclear receptors (RARs and RXRs), as heterodimers, to regulatory cis-acting elements. COUP-TF factors, which are able to dimerize with the RXRs and to compete with the retinoid receptors for their DNA binding sites, are suspected to modulate the retinoid signal transduction pathway. Therefore, COUP-TF factors may be involved in the regulation of the expression of developmental genes and/or in the modifications induced by an excess of RA in the expression of these genes. The aim of this work is to assess whether RA-induced modifications in the expression of Krox-20 and Hox genes correlate with alterations of the expression of COUP-TF genes. In addition to spatial modifications in the expression patterns of Krox-20 and Hox genes, we report here an upregulation of the expression level of COUP-TFI after RA exposure. However, this abnormality did not spatially overlap with the modifications observed in the expression of Krox-20 and Hox genes. These data suggest an involvement of COUP-TFI in the generation of RA-induced abnormalities, but do not support the hypothesis of an involvement of this factor in the regulation of the expression of Hox or Krox-20 genes. (C) 1998 Elsevier Science Inc

Retinoic acid induces a tissue-specific deletion in the expression domain of Otx2

The expression domain of Otx2, a gene essential for the development of the fore- and midbrain, has previously been shown to be affected by exposure to all-trans-retinoic acid (AT-RA). However, morphological abnormalities of the fore- and midbrain induced by exposure of early somite-stage embryos to AT-RA were not associated with abnormal Otx2 expression. To identify abnormal expression of developmental genes induced by exposure at early somite-stages, we performed a fine analysis of the expression domains of Otx2, Otx1, Emx2, and Pax-6 by combining in situ hybridization (ISH) with computer-assisted superpositions and three-dimensional reconstructions of these expression domains. No alteration in the relative location of the caudal boundaries of the expression domains of these genes was observed. The only abnormality was a deletion of the most cranial portion of the neural folds (NF)

Defects in the development of branchial nerves and ganglia induced by in vitro exposure of mouse embryos to mercuric chloride

The embryotoxic and dysmorphogenic effects of mercuric chloride (HgCl2) have been studied in mouse embryos cultured in vitro. In addition, the alterations induced in the developing branchial nerves and ganglia were analyzed. Mouse embryos with 6-8 pairs of somites were exposed for 26 hr to increasing concentrations (0, 12.5, 25, 50 microM) of HgCl2. After this period, a first set of embryos was removed and a second set of embryos transferred to culture medium without HgCl2 and remained in culture for an additional 22 hr. Both sets of embryos were examined for (1) survival, (2) presence of external dysmorphogenesis, (3) growth, and (4) differentiation. Dose-related alterations of these parameters were observed. The main target was the cephalic neural tube (mainly the forebrain), but several other systems were also affected (e.g., the turning of the embryos, the optic system). The 48-hr cultured embryos were immunostained using a monoclonal antineurofilament antibody to visualize defects in the development of branchial nerves and ganglia. HgCl2 induced a pronounced retardation in the differentiation of ganglion/nerve V and a slight retardation in the differentiation of ganglia/nerves VII and IX. The ganglia/nerves VIII and X were not retarded. In addition, hight percentages of abnormalities of ganglion/nerve V and fusions between ganglia/nerves IX and X were observed in these embryos. Disorganized fibers between ganglia/nerves VII-VIII and IX and between ganglia/nerves IX and X were also more frequently observed. At the highest concentration, asymmetric defects were induced by HgCl2 with a more pronounced effect observed on the right side of the embryos. These results demonstrate the usefulness of this approach in evaluating the susceptibility of the developing branchial nerves to the adverse effects of developmental toxicants