1
Risk AssessmentSymposium, Pilsen, Czechoslovakia 179 reaction and changes of proliferative responses of spleen cells and thymocytes were more intensive in the offspring of females treated on days 11 through 17 of pregnancy than in the offspring of females treated from day 4 of pregnancy. A possible explanation could be seen in the fact that effects of the solvent ofTBTO (Tween 80 : ethanol : saline - 1 : 2:97) on the immune responses were, in some aspects, opposite to the effects of TBTO. Prenatally induced deviations of the postnatal development of the immune response are a fre- quent finding with various chemicals and drugs. The above effects of TBTO in a dose as low as 0. l mg/kg body weight of a female on day 1 of pregnancy are another example of an extreme sensitivity of the developing immune system to toxicants. Prenatal screening for Down's syndrome J. Caesar,* B. Bockel,* M. Krawczak,t M. Thiele,* B. Hoppe-Sievert,* I. Bartels* *Institute for Humangenetik, Universitat Gottingen, fln- stitut for Humangenetik der medizinische Hochschule, Hannover, Germany Several antenatal screening programs on the detection of Down's syndrome pregnancies have been proposed. Using maternal serum concentrations of alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), and unconjugated oestriol (UE3) with or without inclusion of the maternal age, about 80% of affected pregnancies can be found. The detection rate and the false positive rate correspond to the cutofflevel of the determined risk and to the maternal age if included in the calculation. Since the concentrations of pregnancy- specific proteins are dependent on the gestation week, an event determination, possibly by ultrasound, is recommended. Application of a complex serum screening test to a large collective of pregnant women requires careful counselling before any test and an assisted interpretation of the results. Contribution of spontaneous abortions examination to un- derstanding of genetic and developmental anomalies etiology J. Dejmek, J. Vojtassak, J. Malova Institute of Preventive and Clinical Medicine, Bratislava, CSFR Evaluation of the population reproduction quality based on newborn data only may be deceptive, omitting the fact that a considerable proportion of pathologic fetuses are elimi- nated long before birth. Original frequency of chromo- somal (ChA) and developmental anomalies (DA) is not known, but may be very high. About 30% to 50% of spon- taneously aborted (SAb) fetuses are ChA, and roughly 70% suffer from DA. Only about 20% of abortuses are without any pathologic finding. From data of ChA and DA distribution in newborns and those in abortuses, together with knowledge about abortion rates in various gestation phases, the prenatal pop- ulation structure may be estimated. From this reconstruc- tion, it followed that in the pregnancy establishment phase (4th to 6th week) about 7% ChA and 10% to 15% DA con- ceptuses remain in the population of surviving fetuses. Pre- natal selection decreases the frequency of anomalies grad- ually to values found at term. The disappearance of particular types of anomaly is nonrandom, changing the malformation spectrum continually. However, risk of pre- natal elimination of the anomaly is not invariably propor- tional to the degree ofphenotype damage of fetus. The par- adox mentioned evokes the idea that some specific selection mechanism is operating. Warkany assumes that under- standing and exploitation of such a mechanism in the fu- ture would replace the use of therapeutic abortions. In the last several years, valuable knowledge concern- ing some etiologic connection has been assembled as a re- sult of the studies of SAb. For example, significant associa- tion of the risk oftrisomies and triploidies in aborted fetuses with gonadal x-ray doses above 10 mGy has been found. In aborted fetuses of females using salicylates, a significant ex- cess of polyploidies and trisomies was established. Similar connections between penicillin use and X-monosomic abortions also have been found. Further interesting etio- logic connections were proved for alcohol drinking of male and female progenitors and severe developmental malfor- mations of aborted fetuses. High prevalence of pathology in SAb increases the sta- tistical power of etiologic studies considerably. Therefore, the chance of valid evaluation of particular exposure/effect relation increases significantly. Study of this hidden portion of the prenatal population makes it possible to cover a considerably greater fraction of the whole reproduction output, supplementing the knowl- edge that currently derives mostly from the study of neo- natal populations. Developmental Immunotoxicology Miroslav Dostal Institute of Experimental Medicine, Czechoslovak Acad- emy of Sciences, Prague, Czechoslovakia In a manner similar to structural congenital defects induced by exposure of the maternal organism to embryotoxic drugs or chemicals during the period oforganogenesis, functional defects can be induced by exposures in the fetal and/or peri- natal period. An important field of functional teratology is developmental immunotoxicology (Roberts and Chap- man, 1981). The immune system is, compared to other systems, ex- tremely sensitive to toxicants, as both its development and functions are carried out by cooperation of continuously proliferating and differentiating cell subpopulations. There is evidence that some toxicants can selectively target the im- mune system at doses below those that produce manifesta- tions of toxic damage to other tissues. Also, it has been found that the developing immune system is more sensitive to toxicants and, moreover, that with some chemicals it is possible to affect only the developing, and not the adult, im- mune system. At present, results of numerous studies of prenatal and perinatal effects of xenobiotics on the postnatal functional development of the immune system are available. These studies were performed with laboratory rodents by means of functional assays used in experimental and diagnostic immunology. Functional immune parameters have been found to be altered by prenatal exposure to heavy metals (cadmium, lead, methylmercury), pesticides, polychlori- nated hydrocarbons, carcinogens, cytostatics (busulfan, cy- clophosphamide), hormones, immunomodulators, vita-

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Page 1: Contribution of spontaneous abortions examination to understanding of genetic and developmental anomalies etiology

Risk Assessment Symposium, Pilsen, Czechoslovakia 179

reaction and changes of proliferative responses of spleen cells and thymocytes were more intensive in the offspring of females treated on days 11 through 17 of pregnancy than in the offspring of females treated from day 4 of pregnancy. A possible explanation could be seen in the fact that effects of the solvent ofTBTO (Tween 80 : ethanol : saline - 1 : 2:97) on the immune responses were, in some aspects, opposite to the effects of TBTO. Prenatally induced deviations of the postnatal development of the immune response are a fre- quent finding with various chemicals and drugs. The above effects of TBTO in a dose as low as 0. l mg/kg body weight of a female on day 1 of pregnancy are another example of an extreme sensitivity of the developing immune system to toxicants.

Prenatal screening for Down's syndrome J. Caesar,* B. Bockel,* M. Krawczak,t M. Thiele,* B. Hoppe-Sievert,* I. Bartels* *Institute for Humangenetik, Universitat Gottingen, fln- stitut for Humangenetik der medizinische Hochschule, Hannover, Germany

Several antenatal screening programs on the detection of Down's syndrome pregnancies have been proposed. Using maternal serum concentrations of alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), and unconjugated oestriol (UE3) with or without inclusion of the maternal age, about 80% of affected pregnancies can be found. The detection rate and the false positive rate correspond to the cutofflevel of the determined risk and to the maternal age if included in the calculation. Since the concentrations of pregnancy- specific proteins are dependent on the gestation week, an event determination, possibly by ultrasound, is recommended. Application of a complex serum screening test to a large collective of pregnant women requires careful counselling before any test and an assisted interpretation of the results.

Contribution of spontaneous abortions examination to un- derstanding of genetic and developmental anomalies etiology J. Dejmek, J. Vojtassak, J. Malova Institute of Preventive and Clinical Medicine, Bratislava, CSFR

Evaluation of the population reproduction quality based on newborn data only may be deceptive, omitting the fact that a considerable proportion of pathologic fetuses are elimi- nated long before birth. Original frequency of chromo- somal (ChA) and developmental anomalies (DA) is not known, but may be very high. About 30% to 50% of spon- taneously aborted (SAb) fetuses are ChA, and roughly 70% suffer from DA. Only about 20% of abortuses are without any pathologic finding.

From data of ChA and DA distribution in newborns and those in abortuses, together with knowledge about abortion rates in various gestation phases, the prenatal pop- ulation structure may be estimated. From this reconstruc- tion, it followed that in the pregnancy establishment phase (4th to 6th week) about 7% ChA and 10% to 15% DA con- ceptuses remain in the population of surviving fetuses. Pre- natal selection decreases the frequency of anomalies grad- ually to values found at term. The disappearance of

particular types of anomaly is nonrandom, changing the malformation spectrum continually. However, risk of pre- natal elimination of the anomaly is not invariably propor- tional to the degree ofphenotype damage of fetus. The par- adox mentioned evokes the idea that some specific selection mechanism is operating. Warkany assumes that under- standing and exploitation of such a mechanism in the fu- ture would replace the use of therapeutic abortions.

In the last several years, valuable knowledge concern- ing some etiologic connection has been assembled as a re- sult of the studies of SAb. For example, significant associa- tion of the risk oftrisomies and triploidies in aborted fetuses with gonadal x-ray doses above 10 mGy has been found. In aborted fetuses of females using salicylates, a significant ex- cess of polyploidies and trisomies was established. Similar connections between penicillin use and X-monosomic abortions also have been found. Further interesting etio- logic connections were proved for alcohol drinking of male and female progenitors and severe developmental malfor- mations of aborted fetuses.

High prevalence of pathology in SAb increases the sta- tistical power of etiologic studies considerably. Therefore, the chance of valid evaluation of particular exposure/effect relation increases significantly.

Study of this hidden portion of the prenatal population makes it possible to cover a considerably greater fraction of the whole reproduction output, supplementing the knowl- edge that currently derives mostly from the study of neo- natal populations.

Developmental Immunotoxicology Miroslav Dostal Institute of Experimental Medicine, Czechoslovak Acad- emy of Sciences, Prague, Czechoslovakia

In a manner similar to structural congenital defects induced by exposure of the maternal organism to embryotoxic drugs or chemicals during the period oforganogenesis, functional defects can be induced by exposures in the fetal and/or peri- natal period. An important field of functional teratology is developmental immunotoxicology (Roberts and Chap- man, 1981).

The immune system is, compared to other systems, ex- tremely sensitive to toxicants, as both its development and functions are carried out by cooperation of continuously proliferating and differentiating cell subpopulations. There is evidence that some toxicants can selectively target the im- mune system at doses below those that produce manifesta- tions of toxic damage to other tissues. Also, it has been found that the developing immune system is more sensitive to toxicants and, moreover, that with some chemicals it is possible to affect only the developing, and not the adult, im- mune system.

At present, results of numerous studies of prenatal and perinatal effects of xenobiotics on the postnatal functional development of the immune system are available. These studies were performed with laboratory rodents by means of functional assays used in experimental and diagnostic immunology. Functional immune parameters have been found to be altered by prenatal exposure to heavy metals (cadmium, lead, methylmercury), pesticides, polychlori- nated hydrocarbons, carcinogens, cytostatics (busulfan, cy- clophosphamide), hormones, immunomodulators, vita-