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B Wlodarczyk

Publications and source records attributed to B Wlodarczyk.

15 recordsLinked to original sources
PubMed2001

Arsenic-induced congenital malformations in genetically susceptible folate binding protein-2 knockout mice.

Arsenic is a well-known carcinogen, which has been suspected of being a human teratogen, although there is currently insufficient and inadequate supportive data to make any definitive judgments. In addition, the significance of individual genetic differences on pregnancy outcomes following in utero exposure to arsenic is currently unknown. In order to better understand the role of folate transport mechanisms in arsenic-induced neural tube defects, we examined the effect of in utero exposure to sodium arsenate in a genetically altered murine model in which the folate binding protein 2 (Folbp2) gene has been inactivated by homologous recombination. In utero sodium arsenate exposure induced exencephaly in 40.6% of Folbp2(-/-) embryos compared with 24.0% in control Folbp2(+/+) embryos. The differences in response frequencies were further exacerbated when the dams were fed a folate-deficient diet. Under these conditions, exencephaly was observed in 64.0% of Folbp2(-/-) embryos compared with 25.7% in control Folbp2(+/+) embryos. Analysis of arsenic metabolites excreted in the urine following sodium arsenate injection to Folbp2(-/-) and Folbp2(+/+) mice indicated that there were no significant differences in arsenic metabolism between the two groups. Thus, the increased susceptibility of Folbp2(-/-) mice to arsenate-induced teratogenicity may not be due to differences in biomethylation and exposure. In conclusion, the data suggest that impaired folate transport in the developing mouse embryo increases the risk for developmental defects following in utero exposure to sodium arsenate and that these differences are not due to differences in metabolism of arsenic.

Animals↗
PubMed2001

Postimplantation whole embryo culture assay for hamsters: an alternative to rat and mouse.

Postimplantation whole embryo culture (WEC) assay for rats and mice has been well established and introduced to many laboratories. Recently WEC technique for rabbits has been developed; however, information on culture of other species is very limited. Knowing the usefulness of hamsters in classical embryotoxicology, we reasoned that hamster WEC could be an alternative model for the most frequently used rat and mouse WEC. Previously we have optimized culture conditions for postimplantation hamster embryos. The aim of this study was to test the susceptibility of hamster embryos cultured in vitro to embryotoxic compounds and to compare our results with those reported by others on rat or mouse embryo culture. For that purpose we choose three known embryotoxic compounds--valproic acid, cadmium chloride, and diethylstilbestrol--and tested them using a postimplantation hamster whole embryo culture assay. Hamster embryos were cultured from 7.5 days gestation for 24 h in a medium consisting of 35% hamster serum and 65% synthetic culture medium (Iscove's or McCoy 5A). At the end of the culture period, the embryos were examined morphologically, measured with the aid of a computer image analysis system, and total protein content was assessed. All three compounds exhibited dose-related embryotoxic and teratogenic effects in hamster embryos. The malformations observed were similar to those reported on rat and mouse embryos. Comparison of the results with data reported by other authors indicates that hamster embryos cultured in vitro might be more susceptible to embryotoxic stimuli than rat and mouse embryos.

Abnormalities, Drug-Induced↗
PubMed2000

Genetic basis of susceptibility to environmentally induced neural tube defects.

Neural tube defects (NTDs) are among the most common of all human congenital defects, with multifactorial etiologies comprising both environmental and genetic components. Several murine model systems have been developed in an effort to elucidate genetic factors regulating expression of NTDs. Strain-dependent differences in susceptibility to teratogenic insults and altered patterns of gene expression observed within the neuroepithelium of affected embryos support the hypothesis that subtle genetic changes can result in NTDs. Since several affected genes are folate-regulated, transgenic knockout mice lacking a functional folate receptor were developed. Nullizygous embryos died in utero with significant morphological defects, supporting the critical role of folic acid in early embryogenesis. While epidemiological studies have not established an association between polymorphisms in the human folate receptor gene and NTDs, it is known that folate supplementation reduces infant NTD risk. Continued efforts are therefore necessary to reveal the mechanism by which folate works and the nature of the gene(s) responsible for human NTDs.

Animals↗
PubMed1997

Developmental expression of morphoregulatory genes in the mouse embryo: an analytical approach using a novel technology.

The molecular techniques of in situ transcription and antisense RNA amplification (IST/aRNA) have allowed for the monitoring of coordinate changes in the expression of multiple genes simultaneously. However, the analysis of their concurrent behavior during murine embryogenesis has been problematic. Studies involving the investigation of temporal and spatial gene expression during embryogenesis have focused solely on the analysis of isolated, single gene events. Such an approach has failed to provide an integrative picture of genetic control over the varied and complicated cellular processes governing embryogenesis. In order to interpret the enormous amount of gene expression data generated by these procedures, we have attempted to develop an analytical framework by employing the statistical concepts of principal components analysis (PCA). For the current study, we performed IST/aRNA on neural tubes dissected from the highly inbred LM/Bc murine strain collected during four gestational time periods. A subset of these genes, representing a partial signaling pathway in the developing neuroepithelium, was then subjected to PCA. Here, we report that PCA highlighted the transcriptional interplay among the genes p53, wee-1, Tgf beta-2, and bcl-2 such that the combined reciprocal regulation of their gene products is suggestive of a predominant proliferative state for the developing neuroepithelium. The application of PCA to the gene expression data has elucidated previously unknown interrelationships among cell cycle genes, growth, and transcription factors on a transcriptional level during critical stages of neurulation. The information gleaned from this analysis, while not definitive, suggests distinct hypotheses to guide future research.

Analysis of Variance↗
PubMed1996

Teratogenicity of carbamazepine-10, 11-epoxide and oxcarbazepine in the SWV mouse.

The mechanism of carbamazepine (CBZ)-related teratogenicity was investigated in the SWV mouse by contrasting the effects of CBZ-10, 11-epoxide (CBZE) and oxcarbazepine (OXC) treatments. Dietary CBZE administration was initiated 2 weeks before mating and continued through day 18 of gestation. OXC was administered to pregnant dams by gavage on day 6 of gestation and continued through day 18 of gestation. Maternal plasma concentrations of CBZE ranged from 1.4 to 17.7 micrograms/ml and OXC ranged from 6.1 to 15.9 micrograms/ml. In comparison, clinical plasma concentrations of CBZE ranged from 1 to 2 micrograms/ml and OXC plasma concentrations were 1 microgram/ml or less. The incidence of malformation were 14%, 27% and 26% after daily CBZE doses of 300, 600 and 1000 mg/kg, respectively, compared with a 6% incidence in no-drug control mice, P < .05. The incidence of malformation was 8% after exposure at the highest tolerable dose of OXC (1100 mg/kg/day), compared with a 5% incidence in no-drug controls, P > .05. Phenobarbital cotreatment (45 mg/kg/day) with OXC (1100 mg/kg/day) did not lead to changes in the incidence of malformation when compared with OXC (1100 mg/kg/day) dosed alone. These data are consistent with a teratogenic CBZ metabolite, possibly CBZE, or with oxidation of CBZE or CBZ at positions on the aromatic ring leading to the formation of reactive intermediates such as arene oxides or quinones.

Animals↗
PubMed1992

Teratological evaluation of Ukrain in hamsters and rats.

The compound Ukrain, containing thiophosphoric acid alkaloid derivatives from the plant Chelidonium majus L., was given intramusculary (i.m.) on days 6-11 of gestation to hamsters and on days 6-15 of gestation to rats in doses of 0.1, 1.67 and 28 mg/kg daily. No clinical signs of toxicity were found in treated animals and no teratogenic effect could be noted in either species. Such parameters as the number of corpora lutea, implantation sites, pre and post-implantation losses, number of live foetuses per litter, placental weight, foetal weight and crown-rump length were not significantly different between the Ukrain treated rats and the controls. Slight embryotoxic effects (increased post-implantation losses) and in consequence decreased number of average litter size were noted in hamsters exposed to Ukrain at doses which were otherwise not embryotoxic to rats.

Alkaloids↗
PubMed1985

[A new technic of cutaneous suture. The SAFE technic (Suture, Assisted by adhesive Film, for Esthetic results)].

A new cutaneous suture technique is described. It is designed for tegumental closing of rectilinear incisions in nonseptic surgery. The technique involves intradermal overcasting with monofilament non-resorbable suture covered with a double adhesive film which reduces strain and provides a therapeutic pressure; after ablation of the first film, it is replaced with adhesive films continuously for 2 months. This technique provides the following advantages: rapidity of suture, simplification of postoperative care, improvement in patient comfort, major reduction in duration of the inflammatory cicatricial period, improvement in final aesthetic results, spectacular in the case of zones under high mechanical tension (arms and legs, scapular belt, etc.), reduction in total cost: suture + postoperative dressing. This technique has been studied for 1 1/2 years in more than 400 patients undergoing various procedures, both for immediate suture and for resuture of the trunk and extremities; postoperative cicatrization appears to be optimal from the standpoints of both the surgeon and the patient, and in our experience, there have been only two minor allergic reactions which did not compromise normal cicatrization. This technique is presented in detail, with a summary of indications and results.

Cicatrix↗
PubMedDate not supplied

Effect of stiripentol dose on phenytoin-induced teratogenesis in a mouse model.

PURPOSE: Previous studies have suggested that polytherapy by design may aid in the management of human pregnancies complicated by epilepsy. However, mechanistic parallels must be drawn between the models of teratogenesis and human pregnancies, and doses of the second agent given to minimize side-effects must be justified. This study sought to determine the lowest dosage of stiripentol (STP) protective against phenytoin-induced teratogenesis in a mouse model, and to determine mechanistically if inhibition of oxidative metabolism by STP in vitro decreased production of reactive phenytoin (PHT) metabolites. METHODS: Pregnant SWV mice were assigned to control or treatment groups of STP alone, PHT alone, or PHT with ascending doses of STP coadministration. Treatments continued from Day 6 to Day 18 of gestation when fetuses were examined for developmental anomalies. [14C]PHT was incubated in mouse liver microsomes with and without NADPH and in the presence or absence of STP or piperonyl butoxide. Covalent binding of [14C] was measured. RESULTS: There were no dose-related differences in the frequency of fetal malformations per litter among groups treated with STP alone. However, STP (all doses) reduced the frequency of PHT-induced malformations. Covalent binding of [14C]PHT was NADPH-dependent and was inhibited by either piperonyl butoxide or STP. CONCLUSIONS: The beneficial effects of STP occurred at concentrations below the therapeutic range for its anticonvulsant effects. These results support the concept of polytherapy by design to reduce the risk of teratogenesis associated with PHT.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Valproic acid-induced alterations in growth and neurotrophic factor gene expression in murine embryos [corrected].

Although the teratogenicity of valproic acid (VPA) has been well established, the mechanism(s) by which this anticonvulsant drug induces malformations remains controversial. Using the combined molecular techniques of in situ-transcription (IST) and antisense RNA (aRNA) amplification we analyzed VPA-induced alterations in the gene expression for 10 genes within the neural tubes of embryos from two murine strains that have been shown to differ in their susceptibility to VPA-induce neural tube defects (NTD). Pregnant dams from both SWV (susceptible) and LM/Bc (resistant) strains were either treated with saline (control) or VPA (600 mg/kg) on gestational day (GD) 8:12 (day:hour). Neural tubes were isolated from control or VPA exposed embryos at three gestational time points, which represented the beginning (GD 8:18), middle (GD 9:00), and end (GD 9:12) of neural tube closure (NTC) in both of these murine strains. Using univariant statistics we demonstrated that in LM/Bc embryos with NTDs, the expression of bdnf, ngf, and trk, ngf-R were significantly elevated at all three time points, and the cytokine, cntf was significantly decreased at GD 9:00. In contrast, the major gene alterations observed in SWV embryos were a significant increase in tfgalpha and tgfbeta1-3 at GD 9:00. In an effort to better define the more intricate interactions between VPA exposure and the expression of these genes, we analyzed our data using Principal Component Analysis. The results from this analysis demonstrated that embryos from these two stains behaved differently, not only in response to a VPA exposure, but also under control conditions, which may explain the multifactorial nature of NTDs in these mice.

Analysis of Variance↗