Biomedical subjects

R Jelínek

Publications and source records attributed to R Jelínek.

At least 19 recordsLinked to original sources

PubMed2000

Fecundability and parental exposure to ambient sulfur dioxide.

Recently it has been observed that birth rates in Teplice, a highly polluted district in Northern Bohemia, have been reduced during periods when sulfur dioxide levels were high. This study, which is based on data from 2,585 parental pairs in the same region, describes an analysis of the impact of SO(2) on fecundability in the first unprotected menstrual cycle (FUMC). We obtained detailed personal data, including time-to-pregnancy information, via maternal questionnaires at delivery. We estimated individual exposures to SO(2) in each of the 4 months before conception on the basis of continual central monitoring. Three concentration intervals were introduced: < 40 microg/m(3 )(reference level); 40-80 microg/m(3); and [greater than or equal to] 80 microg/m(3). We estimated adjusted odds ratios (AORs) of conception in the FUMC using logistic regression models. Many variables were screened for confounding. AORs for conception in the FUMC were consistently reduced only for couples exposed in the second month before conception to SO(2) levels as follows: 40-80 microg/m(3), AOR 0.57 [95% confidence interval (CI), 0.37-0.88; p < 0.011]; [greater than or equal to] 80 microg/m(3), AOR 0.49 (CI, 0.29-0.81; p < 0.006). The association was weaker in the second 2 years of the study, probably due to the gradual decrease of SO(2) levels in the region. The relationship between SO(2) and fecundability was greater in couples living close to the central monitoring station (within 3.5 km). The timing of these effects is consistent with the period of sperm maturation. This is in agreement with recent findings; sperm abnormalities originating during spermatid maturation were found in young men from Teplice region who were exposed to the increased levels of ambient SO(2). Alternative explanations of our results are also possible.

Adolescent↗

PubMed2000

Development of the ectopia cordis induced by hydrocortisone administration.

Our previous study on the development of thorax in chick embryos revealed that mechanical disturbance of the so-called membrana reuniens causes the development of the ectopia cordis (EC). To assess whether membrana reuniens disturbance was really essential for EC development, we employed hydrocortisone, a teratogen known to produce a high incidence of EC. The incidence of EC after the hydrocortisone intraamniotic application on the 4th embryonic day reached 84,8%. It was found that although in the whole course of EC development the membrana reuniens appeared very thin, it nevertheless remained continuous. The morphology of the membrana reuniens in embryos with fully developed EC, studied in classical serial histological sections, was similar to that of the amniotic membrane. Flow cytometry analysis of the cell cycle revealed that EC induced by hydrocortisone administration was associated with a significantly lowered proliferation activity of the prospective body-wall mesenchyme involved in the closure of the anterior wall of thorax. The probable mechanism of EC development is suggested.

Animals↗

PubMed1999

Genotoxicity and embryotoxicity of urban air particulate matter collected during winter and summer period in two different districts of the Czech Republic.

This study is the in vitro part of a long-term program to investigate the impact of air pollution on the health of a population in a polluted region of Northern Bohemia. In order to assess the possible health risks associated with a complex mixture of hundreds of organic compounds adsorbed to air particles, we used a biomarker-directed fractionation procedure to evaluate biological activities of different chemical compound classes. The extractable organic compounds from the air particles collected in both the polluted and the control districts during the summers and winters of 1993-1994 were investigated. The principal aim of this study was to compare the DNA binding activities of those compound classes using an in vitro acellular assay coupled with 32P-postlabeling and an embryotoxicity assay using Chick Embryotoxicity Screening Test (CHEST). In both assays, the highest activity was due to the neutral fractions from which the aromatic subfractions containing mainly polycyclic aromatic hydrocarbons (PAHs) and their methyl-derivates were the most active for both localities and seasons. A good correlation between the levels of DNA adduct formation using S9 metabolic activation and the ED50 for all different complex mixtures of organic compounds was observed (r=0.773, p<0.001). DNA adduct maps and high performance liquid chromatography (HPLC) profiles were similar for samples from both districts and seasons. The major DNA adducts resulting from the crude extracts were identical to those derived from aromatic fractions. The DNA adducts tentatively identified constituted about 50% of the total adducts formed by the crude extracts following S9-metabolic activation. Our results confirmed the similarities of the major ubiquitous emission sources of organic compounds in both districts. This is the first report in which the biological activities of complex mixtures in short-term assays with remarkably different endpoints such as DNA adduct formation and embryotoxicity have been compared.

Air Pollutants↗

PubMed1998

Cell-cycle alterations within chick embryonic anlagen after cyclophosphamide treatment.

With the aim of explaining a mechanism underlying the dose-dependent change in prevalence of different malformation types (shift in malformation spectra) in a population of chick embryos treated with general cytotoxic agents, we have investigated the effect of cyclophosphamide (CP) on the cell cycle in different organ rudiments. CP was administered intra-amniotically in doses of 2, 4, 8, and 16 micrograms to chick embryos on day 4. Six hours later, the embryos were removed, and limb buds, facial region, brain, and heart rudiments were dissected and treated for isolation of nuclei. The tissues were dissociated mechanically and enzymatically with collagenase-dispase, and suspensions of nuclei were prepared by a detergent and RNAase-mediated cytolysis. Ethidium bromide added to the solution allowed DNA analysis by flow cytometry, which, within the embryotoxic range of doses (4-16 micrograms), revealed a dose-dependent block of cells in the S phase, followed by a decrease of cell numbers in the G2-M phase. The effect of CP on the cell cycle was associated with the degree of damage to the embryo, and dysmorphogenesis appeared proportionate to the magnitude of mitotic inhibition. The results are consistent with the idea that the dose-dependent shift in malformation spectra is causally associated with the dose-dependent and organ-specific depression of mitotic activity.

Abnormalities, Drug-Induced↗

PubMed1998

Risk assessment of the common air pollutants in Teplice, Czech Republic.

In the framework of the systematic investigation of the environment of the district of Teplice (Northern Bohemia), one of the most polluted regions in Europe, an attempt was made to estimate health risks to the inhabitants posed by the most common air contaminants (SO2, NOx, particulate matter). A meta-analysis of data published in recent papers dealing with health effects was performed. At first we weighed the number of positive and negative findings focusing on the following health indicators: prevalence of symptoms (coughing, wheezing), decreased respiratory function, prevalence of respiratory illness, and acute mortality. Only those categories in which the positive findings prevailed were taken into consideration and median values for LOAELs were calculated from the data referring to positive dose-response relationships. The exposure assessment was based upon a series of data on daily concentrations of the air contaminants in Teplice since 1975. Due to the somatic and respiration parameters, as well as to their habits, children between the ages of 8 and 10 appeared the most heavily exposed of all age groups. It was concluded that in real concentrations the risk is posed mainly from sulphur dioxide and, above all, from particulate matter.

Adolescent↗

PubMed1998

A dose-dependent transformation of embryotoxicity manifestations in the population of chick embryos.

The world-wide and long-lasting stagnation in general incidence of inborn defects does not agree with the increasing impact of the environment. However, inborn defects alone are definitely a poor indicator of the reproductive risk being accompanied by much more frequent embryotoxicity manifestations -- death of the conceptus and growth retardation. Dose-dependent transformations of the embryotoxicity manifestations may explain both the stagnation in the incidence of inborn defects and the observed shifts in malformation spectra. An attempt was made to design a reliable experimental model to produce individual transformations resulting from the specific dose-response relationships inherited in teratogenesis. A population of chick embryos in different stages of development was exposed to increasing doses of cyclophosphamide, a model teratogen. All types of the transformations were recorded. Prenatal extinction of defective embryos, transition of single moderate defects to more severe and multiple malformations, as well as the changes in the incidence of certain types of defects exhibit a clear-cut positive dose dependence. Introducing this experimental system we will be able to study mechanisms underlying the particular transformations.

Abnormalities, Drug-Induced↗

PubMed1998

[Clinico-teratologic counseling and the Teratology Information Service].

Medical records of 1179 pregnant women counselled at the Department of Medical Genetics Klimentska during the period 1990-1995 because of exposure to medicaments during the preconception period and in the first trimester were analyzed. Women exposed to antimicrobial agents prevailed (48 per cent). Most frequent was treatment with Doxycycline, Co-trimoxazole and Metronidazole. 23 per cent of women were exposed to sex hormones, most frequently to oral contraceptives and norethisterone. The average gestational age at exposure to antimicrobial agents was 21.5 days and 30 days at exposure to sex hormones. Specific features of clinical-teratological counselling and the role of the Czech Teratologic Information Service are described.

Counseling↗

PubMed1998

Hyperthermia in the chick embryo: HSP and possible mechanisms of developmental defects.

Although hyperthermia is an established teratogen in all species studied and the cellular heat shock response is well known, the mechanisms of developmental deviation remain obscure. We have used a chick model system in which fertilized eggs containing embryos at presomite and/or early somite stages (HH 4-10) were exposed to 45 degrees C for 180 min. Six hours following treatment we did not observe any overt morphological disturbance, but at twelve hours following exposure (when controls reached HH 11-13) embryos exposed at late streak stages (HH 4-6) exhibited severe malformation of the head. Embryos exposed later (HH 6-9) manifested spina bifida at the thoracic and lumbosacral levels. Mirror image heart looping was also observed in 20% of these embryos. Paraxial mesoderm was apparently unaffected. Changes in cell proliferation and induced cell death preceded morphological changes. We used acridine orange and confocal laser microscopy to demonstrate that hyperthermia induced cell death in neural folds starting 6 h following treatment. To assess cell proliferation, we used BrdU incorporation for 4 h. Immunodetection on paraffin sections demonstrated that proliferation was inhibited 6 h after treatment. Heat-exposed embryos exhibited the heat shock response, with protein expression reaching a maximum 4-6 h following heat treatment. Malformed embryos showed an intense heat shock response for a further 6 h. The levels of induced heat shock proteins were similar in the affected neural tube and in the heart, where neither induced cell death nor malformations were observed.

Animals↗

PubMed1996

Interaction between quercetin and heat shock. A preliminary study on the chick embryo.

A hyperthermic shock (43 degrees C/30 min) enhances in somite stages of the chick embryo development the activity of the caudal morphogenetic system, manifested by intensive growth of the embryonic trunk. The exposure also induced the synthesis of heat shock proteins (HSP 70). A single administration of a bioflavonoid quercetin dissolved in DMSO to chick embryos in stages HH 10-11 (10-14 somites) prior to heat exposure inhibited both the growth acceleration and the HSP induction.

Animals↗

PubMed1994

Embryotoxicity in chick embryo of thalidomide hydrolysis products following metabolic activation by rat liver homogenate.

Three and four-day-old chick embryos were exposed to thalidomide as well as to its hydrolysis products before and after in vitro biotrasformation of these compounds with rat liver homogenate. Significant embryotoxic effects of 30 and 100 micrograms doses per embryo encountered only in the case when the products of alkaline hydrolysis of thalidomide were pretreated with rat liver homogenate.

Animals↗

PubMed1994

Validation of the Chick Embryotoxicity Screening Test (CHEST). A comparative study.

With the aim of investigating the predictive value of the Chick Embryotoxicity Screening Test (CHEST) with respect to regulatory rat-rabbit procedures, we compared the results of testing 50 chemicals of different pharmacological properties. Besides all being tested in the alternative technique, 27 substances were tested both in rats and rabbits, 22 only in the rat, and one only in the rabbit, respectively. The predictive value of CHEST with respect to the both official whole-animal procedures was found satisfactory, exhibiting about 80% consistent results. It is argued that the purpose of alternative testing methods is not in replacing the official routine procedures, but in contributing to the development of new predictive systems based on recent teratological knowledge.

Animals↗

PubMed1994

Teratogenic effects of bilirubin--a study using chick embryotoxicity screening test (CHEST).

Using the Chick Embrotoxicity Screening Test (CHEST), two samples of bilirubin of different commercial origin were tested on 2, 3 and 4- day old chick embryos. Water soluble Bilirubin Lachema (containing 20 mg albumin per 1 ml) had no teratogenic effect. On the opposite, Bilirubin Merck (containing 8 mg albumin per 1 ml) manifested an apparent teratogenic potential when single doses 0.2 and 0.6 micrograms were administered intraamniotically on day 4. Dose-dependent malformations of brain and eyes, cleft beak and reduction deformities of limbs were observed. No such effects could be produced by administration of Bilirubin Merck on either day 2 and 3. A tentative explanation of the difference between teratogenic properties of Merck and Lachema bilirubin preparations may be sougth in the different proportion of the free and albumin bound fractions.

Abnormalities, Drug-Induced↗

PubMed1993

Antimitotic and teratogenic effects of acyclic nucleotide analogues 1-(S)-(3-hydroxy-2-phosphonomethoxyethyl)cytosine (HPMPC) and 9-(2-phosphonomethoxyethyl) adenine (PMEA).

The acyclic nucleotide analogues, HPMPC and PMEA, differ in their in vitro effect on the genetic material of eukaryotic cells. While HPMPC exerts a cytostatic effect on eukaryotic cells in vitro, PMEA has a genotoxic activity. These results correspond with the mode of embryotoxic action of these compounds: HPMPC exhibits a general embryolethal effect, whereas PMEA is apparently teratogenic and interacts with the mutant allele producing preaxial polydactyly of the hind limbs.

Adenine↗

PubMed1992

Embryotoxicity of T-2 toxin and secalonic acid in embryonic chicks varies with the site of administration.

A crucial role of the site of administration in the sensitivity of the alternative system using chick embryo for testing embryotoxicity was demonstrated by morphological evaluation of the effects of T-2 toxin and secalonic acid D, and by incorporation of [14C]sodium acetate radioactivity. Secalonic acid D, administered to 2-, 3-, and 4-day-old embryos in doses higher than 1 microgram produced mostly malformations of the face (bilateral cleft beak, microphthalmia) while the teratogenic effects of T-2 toxin were being limited to the embryonic trunk of 2-day-old embryos (rumplessness) after administering doses higher than 0.001 microgram. In case of subgerminal and intraamniotic injections, the doses of both mycotoxins needed for producing embryotoxic effects comparable to those obtained with the more commonly used yolk sac injections appeared to be lower by one and two orders of magnitude, respectively. The results stress the need of using the shortest transport channel of test substances from the site of application to the target tissues of the embryo, when the maximum sensitivity and reproducibility of the test system are to be expected.

Age Factors↗

PubMed1992

Embryotoxicity of 25 psychotropic drugs: a study using CHEST.

Twenty five psychotropic drugs were ranked according to the embryotoxicity dose ranges estimated by the Chick Embryotoxicity Screening Test (CHEST). The chick results were compared with some data for common laboratory mammals. In 17 psychotropic drugs a deleterious dose-dependent effect upon the embryonic cardiovascular system was disclosed, terminating in immediate cardiac arrest.

Animals↗

PubMed1991

Observations on the biological activity of epitestosterone.

Epitestosterone, a 17 alpha-epimer of testosterone is a normal constituent of body fluids in many species including man. It has long been believed that it is devoid of any biological significance. However, it is now demonstrated that in in vivo experiments on castrated male mice it counteracts the action of testosterone on androgen-dependent organs. In vitro experiments show that on the overall antiandrogenicity of epitestosterone participate true antiandrogenic action due to the binding to androgen receptors, strong 5 alpha-reductase inhibiting activity as well as a weak antigonadotropic activity. Epitestosterone is devoid of any embryotoxicity as checked by chick embryo-toxicity screening test.

5-alpha Reductase Inhibitors↗

PubMed1991

Experimental models for drug teratogenicity.

Teratogenicity a specific manifestation of embryotoxicity, is explored in the course of the preclinical phase of drug testing. The official routine rat-rabbit procedures employ an integral experimental model--the whole animal with its species-specific metabolism. Although it has been widely accepted that pharmaco-kinetics of drugs represents the most important source of interspecies differences in teratology, the official procedure is still considered satisfactory. The reason why a new thalidomide affair has not occurred can be explained by the extremely low expression of teratogenic potential at the human population level--a condition inherent in the principles of teratogenesis. On the other hand, many partial experimental models have been developed that use mainly suborganismic objects (i.e. isolated morphogenetic systems, explanted tissues and cell populations). These objects possess many limitations disgracing their use as candidates for replacing the whole-animal experiments. Nevertheless, some of the partial models can be used and must be used in deeper analysis of the teratogenic potential of drugs with the aim of improving the predictive power of embryotoxicity risk assessment. (Fig. 1, Ref. 7.)

Animals↗

PubMed1990

Mutagenic and teratogenic effects of cyclophosphamide on the chick embryo: chromosomal aberrations and cell proliferation in affected and unaffected tissues.

Chromosomal aberrations and cell proliferation were analyzed in the chick embryo blood, limb bud, and facial tissues 12 and 24 hours after cyclophosphamide (CP) administration on day 3. The cytogenic findings were compared with teratogenic effects evaluated on incubation day 8. Low dose (0.3 micrograms) resulting in heart defects exclusively, increased the frequency of aberrant cells with simultaneous depression of cell proliferation in blood only. High dose of CP (6 micrograms), besides the heart defects, also induced facial clefts and limb malformations, and strong clastogenic effects associated with mitotic inhibition were observed in all tissues investigated. The results support the idea that the consequences of mutagenic action of cyclophosphamide--cell cycle delay and excessive death of cells with unstable aberrations--result in abnormal morphogenesis.

Animals↗