摘要:

AbstractThe epidemiologic approach to determining the etiology of disease involves identification of potential risk factors and then comparison of disease incidence among people with varying levels of exposure to the potential risk factors. This paper defines risk factors which correspond to different levels of genetic and environmental proximity to index cases of birth defects. Genetic proximity is estimated by the coefficient of relationship (R): 0.5 for siblings and dizygotic twins and 1.0 for monozygotic twins. Environmental proximity is measured by a combination of two variables: one variable for those potentially preventable risk factors common to siblings (S) and another for those common only to twins (T). Discordance in identical twins is attributed to a third type of environmental factors (U) that are unshared by twins and include random (stochastic) factors. The association between these risk factors and birth defects is estimated by using a linear model of the correlation of liability for different relatives. The coefficients derived from the model reflect the relative importance of genetic and different types of environmental risk factors as causes for the defects and can be used to identify birth defects most likely to be caused by measurable and possibly preventable risk factors. These defects could then be assigned high priority for future studies and preventive efforts.

ISSN:0040-3709    

DOI:10.1002/tera.1420380402

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractThe teratogenic effects of valproic acid and its 4‐propyl‐4‐pentenoic acid (4‐en) metabolite were investigated in three inbred mouse strains that were known to possess differing sensitivity to heat‐induced neural tube defects. In the heat‐resistant DBA/2J strain, administration of either valproic acid or the metabolite during the critical period of neural tube development failed to produce any abnormal offspring. Similar treatment in the moderately heat‐sensitive LM/Bc strain resulted in up to 19.8% exencephalic fetuses. The highly heat‐sensitive SWV strain was also very susceptible to the induction of neural tube defects by either valproic acid or its 4‐en metabolite. When administered on gestational day 8 plus 12 hours, the parent compound produced 35% exencephalic fetuses, while the metabolite had a response frequency of 32.4%. Thus, the hierarchy of susceptibility for the induction of neural tube defects in these inbred mouse strains was exactly the same whether the teratogen was a physical agent such as hyperthermia or a chemical compound such as valproic acid. If such diverse agents as these should interact to produce malformations, then it is possible that a wide variety of other agents might interact in a similar manner to produce ne

ISSN:0040-3709    

DOI:10.1002/tera.1420380403

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractRetinoic acid‐induced transformation of reticulate scales to feather‐like structures (Dhouailly and Hardy, '78) provides a useful model to study biochemical differentiation in avian skin. In this study, immunofluorescent analysis of reticulate scale‐feathers (RSFs) indicates that they contain β keratin in feather barbs and, thus, are true feathers, biochemically. Epidermal cells that would otherwise produce only α keratin in reticulate scales are induced to reorganize and differentiate into barb ridge cells that accumulate feather β keratins. The mechanism for these dramatic morphological and biosynthetic responses to retinoic acid is

ISSN:0040-3709    

DOI:10.1002/tera.1420380404

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractThis study was undertaken to assess the developmental toxicity and drug distributional and metabolic characteristics of prenatal valproic acid (VPA) exposure in rhesus monkeys. Oral administration of 20–600 mg/kg/ day VPA (approximately 1–15 × human therapeutic dose) to 33 animals on variable gestational days (GD) during organogenesis resulted in dose‐dependent developmental toxicity manifested as increased embryo/fetal mortality, intrauterine growth retardation, and craniofacial and skeletal defects. Biphasic plasma elimination curves were observed for total and free VPA on the first (GD 21) and last (GD 50) days of treatment in the 100‐ and 200‐mg/kg/day dose groups. VPA exhibited dose‐independent elimination kinetics at the plasma concentrations observed in this study. There was no significant change in pharmacokinetic parameters (maternal plasma elimination rate, area under the curve, peak plasma concentration) between the first and last days of treatment at either dose level. Placental transfer studies indicated that embryos were exposed to half the free VPA concentrations present in maternal plasma on GD 37. Comparisons of interspecies sensitivity to VPA‐induced developmental toxicity in the mouse, rat, monkey, an

ISSN:0040-3709    

DOI:10.1002/tera.1420380405

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractA cross‐sectional national survey of 11,048 births in the whole of Greece in April 1984 identified 7 cases of anencephalus and 9 of spina bifida. There was thus an incidence of 1.45 neural tube defects per 1,000 total births. This is the first geographically defined population study from southern Europe. In comparison with hospital‐based data from the 2 countries on its borders, the Greek rates are rather similar to those of Yugoslavia but much lower than reports from Tur

ISSN:0040-3709    

DOI:10.1002/tera.1420380406

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractSm 857 SE is an antiallergic drug chemically described as 11‐Oxo‐11H‐pyrido(2,1‐b)quinazoline‐2‐carboxylic acid that has activity against allergic bronchoconstriction in animal models. The purpose of this study was to investigate the teratogenic potential in pregnant rats and rabbits when administered during the critical period of organogenesis. The drug was suspended in aqueous 0.25% carboxymethylcellulose (CMC) solution. Daily doses of 20, 90, or 400 mg/kg were given orally by gavage to rats on days 7 through 17 of gestation and to rabbits on days 6 through 18. Two additional studies were done in rats dosed with 400 mg/kg, and with 90, 200, or 400 mg/kg, respectively. Doses of 20, 90, and 200 mg/kg had no meaningful effects on maternal animals of either species or on their offspring. A dose of 400 mg/kg was maternally toxic in rats as shown by the effects on body weight and food consumption. Among pregnant rabbits, two deaths and three miscarriages occurred at this dose. In rats, 400 mg/kg caused embryonic death, retarded fetal development, and two specific malformations, namely microphthalmia and vertebral‐costal defects. A mild teratogenic action of 400 mg/kg also occurred in the first additional study but not in the second one. There was, however, one anophthalmia in a rat fetus of the 90 mg/kg group. In rabbits, no embryotoxic or teratogenic effects were observed. These species differences were explained by the concentration and protein binding in maternal serum as well as by the relatively high concentration of14C‐Sm 857 SE i

ISSN:0040-3709    

DOI:10.1002/tera.1420380407

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractThe capability of rodent embryos to recover in growth and development subsequent to exposure to an insult was investigated employing whole embryo culture. Early somite stage mouse embryos were exposed to 32mM D,L,‐beta‐hydroxybutyrate (D,L,‐βOHB) for 24 hr (Period I), and were then transferred and maintained in control medium for an additional 36 hr maximum (Period II). Growth of this recovery group (Group B) was monitored at various time points of Period II and the results were compared with an unexposed control group (Group A) and another continuously‐exposed reference group (Group C). At the end of Period I, 100% of D,L,‐βOHB‐exposed embryos exhibited neural tube closure defects and were growth retarded. At 36 hr of Period II, cranial and caudal neural tube defects of Group B embryos were reduced to 3–7% and 0%, respectively. These embryos also demonstrated an excess in growth velocity during recovery so that at the end of Period II, total protein content was comparable to control values. In contrast, Group C embryos remained growth retarded and showed a significant increase in cranial and caudal neural tube defects (20 and 75%, respectively). Thus, neurulating mouse embryos were capable of catch‐up growth following an embryotoxic exposure to D,L,‐βOHB. The progression of development of total protein values and morphological features such as elimination of neural tube defects was intimately related to the amount of time allowed for recovery. Moreover, an elevation of growth rate over normality, which is characteristic of catch‐u

ISSN:0040-3709    

DOI:10.1002/tera.1420380408

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractRat embryos explanted at head fold stage were stored under various levels of hypothermia prior to culture. The storage media were Hanks' Balanced Salt Solution (BSS), 50% rat serum with 50% Dulbecco's Modification of Eagle's Medium (standard medium), or 100% rat serum. The media were gassed with 5% O2/5% CO2/90% N2or 20% O2/5% CO2/75% N2. Subsequent development of embryos after storage at temperatures between 10°C and 30°C for 5 hr in Hanks' BSS, or for 5–10 hr in standard medium or serum, was similar to that of controls. Some embryos developed well even after storage for 48 hr in standard medium. Development was poorer after storage at 0°C or 5°C, and after storage at all temperatures in ungassed Hanks' or standard medium (pH>8.0). Differences in oxygen level had little effect. For routine explantation at room temperature in (ungassed) phosphate‐buffered saline solutions such as Hanks', it is recommended that the delay before transferring the embryos to the culture incubator not exceed

ISSN:0040-3709    

DOI:10.1002/tera.1420380409

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

ISSN:0040-3709    

DOI:10.1002/tera.1420380410

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

ISSN:0040-3709    

DOI:10.1002/tera.1420380411

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY