摘要:

AbstractAn oral dose of 1.8 g/kg ethanol given once per week throughout gestation to gravid pig‐tailed macaques(Macaca nemestrina)has been established previously as teratogenic. This study was designed to use this nonhuman primate model to mimic a common problematic human circumstance in which women intermittently abuse alcohol into early pregnancy, realize that they are in fact pregnant, and then want to know the chance that the conceptus is harmed. In order to evaluate this situation, gravid macaques were assigned to one of four dosing cohorts. Animals were given the 1.8 gm/kg dose of ethanol once per week for the first 3, 6, or 24 weeks (full gestation) of pregnancy. Control animals received an isocaloric, isovolemic sucrose solution once per week for 24 weeks. The pregnancies were carefully monitored and the infants were comprehensively evaluated for the first 24 months of life. This paper describes the pregnancies while subsequent papers will describe the infants.Peak plasma ethanol levels ranged from 175 to 250 mg/dl. Weekly maternal exposure to this intoxicating dose of ethanol, starting early in pregnancy, did not influence risk of pregnancy failure during the first 30 days of gestation but appeared to be associated with an increased risk of abortion occurring between gestational days 30 and 160. Of the pregnancies that were successfully carried to full term, the potentially teratogenic dose of ethanol did not alter pregnancy outcome in any clinically significant wa

ISSN:0040-3709    

DOI:10.1002/tera.1420450102

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

年代:1992

数据来源: WILEY

摘要:

AbstractThe embryotoxicity of phenol and twelve para‐substituted congeners on mid‐gestation rat embryos was evaluated in vitro. Through application of correlative procedures and stepwise regression, equations describing the relationship between physical‐chemical properties and various measures of activity were developed. Embryotoxicity was quantified by the log of the reciprocal of the potency estimates for reduction in selected growth parameters and induction of four morphological defects. In general, co‐cultured hepatocytes ameliorated embryotoxicity; only phenol‐induced embryotoxicity was enhanced by the presence of hepatocytes. In the absence of hepatocytes, measures of growth retardation were positively correlated with molar refractivity of the phenols. With hepatocytes, lipophilicity became important for describing the potential to induce growth deficits. The structural defects had varying correlation patterns in both culture systems. Potencies of these congeners in vitro were also compared to maternal and developmental potencies observed in vivo (Kavlock, Teratology,41:43–59, '90). Two of the congeners were very toxic in both systems. For the remaining congeners, one maternal toxicity measure was found to be positively correlated with embryotoxicity for growth and development in vitro without hepatocytes. With hepatocytes, a broad spectrum of correlations, both positive and negative, were observed between in vivo developmental toxicity endpoints and in vitro embryotoxicity. Data from preliminary dosimetry studies suggest that phenol congeners may accumulate in embryos exposed in vitro more readily than with in vivo exposure. Potency calculations based on dosimetry information may demonstrate better correlations between data and allow additional relationships between chemical structure and activity to b

ISSN:0040-3709    

DOI:10.1002/tera.1420450103

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

年代:1992

数据来源: WILEY

摘要:

AbstractCleft palate (CP) can be induced in embryonic mice by a wide range of compounds, including glucocorticoids and 2,3,7,8‐tetrachlorodibenzop‐dioxin (TCDD). Hydrocortisone (HC), a glucocorticoid, retards embryonic growth producing small palatal shelves, while TCDD exposure blocks the fusion of normally sized shelves. TCDD induction of CP involves altered differentiation of the medial epithelial cells. Recent studies indicate that growth factors such as EGF, TGF‐α, TGF‐β1, and TGF‐β2 are involved in palatogenesis, regulating proliferation, differentiation, and extracellular matrix production. A synergism has been observed between HC and TCDD in which doses too low to induce CP alone are able to produce>90% incidence when coadministered. In the present study a standard teratology protocol was performed in C57BL/6N mice to examine the synergism at doses lower than those previously published. Data from this study indicate synergistic interactions at doses as low as 3 μg TCDD/kg + 1 mg HC/kg. This extreme sensitivity suggests the involvement of a receptor‐mediated mechanism possibly resulting in altered regulation of gene expression. Mechanisms of interaction were further studied by comparing growth of the shelves, fate of the medial epithelium, and expression of growth factor mRNAs and peptides. Pregnant mice were dosed on GDs 10–13 with HC (100 mg/kg sc) or with HC (25 mg/kg sc) + TCDD (3 μg/kg orally), doses producing 30% and 99% CP, respectively. The interaction between HC and TCDD results in a small HC‐like palate, rather than the morphology typical of TCDD‐induced clefting. Both compounds inhibited programmed cell death of the medial epithelium, which instead differentiated into an oral‐like epithelium. The alterations in growth factor expression after HC or HC + TCDD were similar. Expression of EGF, TGF‐β1, TGF‐β2, and EGF receptor increased in specific palatal regions. Increased levels of mRNA were observed only for TGF‐β1. The effects of TCDD alone on growth factor expression differ from those seen with HC or HC + TCDD. These divergent effects on growth factor expression may contribute to the differences in shelf size and thus to the different mechanisms of HC and TCDD clefting. Thus the synergism between HC and TCDD may involve similar and potentially additive effects on regulators of proliferation and differentiation in the palate, but additional contri

ISSN:0040-3709    

DOI:10.1002/tera.1420450104

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

年代:1992

数据来源: WILEY

摘要:

AbstractAlthough isotretinoin (ITR) has been suggested to cause malformations via cytopathic effects on embryonic cells, the molecular mechanisms of ITR cytotoxicity in teratogenesis are not clear. Since ITR undergoes metabolism by prostaglandin synthase to a potentially cytotoxic peroxyl free radical, the possible role of prostaglandin synthase metabolism as a modulator of ITR teratogenicity was evaluated. Craniofacial and limb abnormalities were noted in fetuses on day 18.5 of gestation following administration of ITR to pregnant CD‐1 mice in a three dose regime of 100 mg/kg at 4 hr intervals on day 10.5 of gestation (plug day = day 0.5 of gestation). Mice were also treated with acetylsalicylic acid (ASA), an irreversible inhibitor of the cyclooxygenase component of prostaglandin synthase, at doses of 20 and 60 mg/kg body weight 2 hr prior to each ITR dose. ASA pretreatment of mice receiving ITR treatment showed a dose‐dependent decrease in the overall incidence of malformations, number of defects per fetus, and the incidence of specific craniofacial and limb defects. Equivalent doses of ASA given to control mice did not cause malformations or alter the incidence of resorptions. These results demonstrate that ASA is able to ameliorate the teratogenic effects of ITR observed in fetal mice near term and indicate that prostaglandin metabolism could play a mechanistic role in ITR teratogenic

ISSN:0040-3709    

DOI:10.1002/tera.1420450105

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

年代:1992

数据来源: WILEY

摘要:

AbstractThe embryotoxic and teratogenic potential of all‐transretinoic acid was assessed following exposure prior to and during early organogenesis in the cynomolgus monkey(Macaca fascicularis). Sixteen pregnant females were orally administered all‐transretinoic acid (Tretinoin, Hoffmann‐La Roche) once daily from GD 10–20 and twice daily from GD 21–24 at three different dosages, 5 (n=9), 10 (n=6) and 20 mg/kg (n=1). Adverse clinical signs resembling hypervitaminosis A were observed in one animal at 5 mg/kg, in three animals at 10 mg/kg, and in the animal treated with 20 mg/kg all‐transretinoic acid. Maternal weight loss was observed in the 10‐ and 20‐mg/kg groups. A dose‐dependent increase in embryolethality was observed, with 22% (2/9), 50% (3/6), and 100% (1/1) occurring at 5, 10, and 20 mg/kg, respectively. The majority of embryonic deaths occurred between GD 16 and 20; the incidence of these early losses was higher than in historical and concurrent controls. No malformations, but a single growth‐retarded fetus, was observed in the 5‐mg/kg group. Craniofacial malformations, consisting of external ear defects, mandibular hypoplasia, cleft palate, and temporal bone abnormalities, were seen in three viable fetuses in the 10‐mg/kg group. Skeletal variations were common to the majority (70%, 7/10) of viable fetuses in both dose groups and were increased relative to historical controls (32%, 25/77). Unlike previous studies with 13‐cis‐retinoic acid during the pre‐ and early organogenic stages of development (Hummler et al., Teratology 42:263‐272, 1990), no thymic hypo‐ or aplasia or heart anomalies were observed, which may be attributable to the slightly longer 13‐cisretinoic acid treatment period, i.e., GD 10–27. However, external ear and temporal bone defects were common to both all‐transand 13‐cisretinoic acid. The similarity observed in the malformation syndrome induced by both all‐transand 13‐cisretinoic acid in the cynomolgus monkey and 13‐cisretinoic acid embryopathy in humans supports this macaque species as a model for further developmental

ISSN:0040-3709    

DOI:10.1002/tera.1420450106

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

年代:1992

数据来源: WILEY

摘要:

AbstractEight‐week‐old virgin untreated female mice were induced to ovulate using equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG), and were then caged with males overnight. Females with a vaginal plug on the following morning were killed 24 hours later and 2‐cell embryos were flushed from the oviduct. These embryos were transferred to the oviduct of 8‐week‐old control females, to females of the same age treated with 5 μg diethylstilbestrol (DES) sc in olive oil for the first 5 days after birth, or to females treated with 1 μg estradiol‐17β for 2 days before and 2 days after transfer (estrogen dominated/ED/females). Two days after transfer, a significantly lower number of embryos were recovered from oviducts of DES females compared to control females and a still lower number from ED females. The recovered embryos were cultured in vitro for 4 days testing trophoblast outgrowth (“implantation stage”). The incidence of embryos reaching this stage after development in DES‐exposed oviducts was only half of that for embryos passing control oviducts or ED oviducts. It is concluded that the adult oviductal environment in neonatally DES‐treated females significantly decreases early embryo developmental potential. The oviductal factor(s) harmful to the embryo may be related to a persistent and possibly increased level of circulating estroge

ISSN:0040-3709    

DOI:10.1002/tera.1420450107

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

年代:1992

数据来源: WILEY

摘要:

AbstractThis study provides a baseline of mainly quantitative morphologic information in relation to the ectodermal microvilli in ten areas in the control and experimental prenatal rat with special reference to the period of neural tube closure. Embryos from six litters were used and ten areas were examined mainly with the scanning electron microscope. Statistical analysis showed no significant difference between litters nor between the ten areas examined. In the 376 hr (day 15.6) fetus only the ectodermal cells of the nostril region demonstrated a rich population of microvilli, a fact possibly associated with late maturation of that region. Some evidence is provided to show that there is an increase in the population of microvilli in the 276 hr (day 11.5) embryo following experimentally induced zinc deficiency and introduction of nicotine in the culture medium. The possible mechanisms underlying the increase in ectodermal microvilli are i) an attempt by ectodermal cells to absorb nutrients, ii) a reflection of cells under stress, iii) failure of early embryonic ectodermal cells to shed microvilli normally associated with developmental changes, and iv) a generalized developmental delay rather than some cellular response to a trace element nutritional deficiency and a teratogen.

ISSN:0040-3709    

DOI:10.1002/tera.1420450108

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

年代:1992

数据来源: WILEY

摘要:

AbstractThe viability of early mouse embryos is acutely sensitive to (R)‐deoxycoformycin (pentostatin), a tight‐binding inhibitor of adenosine deaminase (ADA). Previous studies have shown that a single 5‐mg/kg dose on day 7 (plug = day 0) of gestation fully inhibits uteroplacental ADA activity within 0.5 h; causes massive cell death in the neural plate and primary mesenchyme by 6 h, major craniofacial anomalies by day 10, and resorption by day 12 [Knudsen] et al., '89; Airhart et al., '91). The present study has examined further the developmental toxicity and early effects of this inhibitor on ADA metabolism. (R)‐Deoxycoformycin was administered to pregnant CD‐1 (ICR) mice as a single intraperitoneal dose of 0.5‐10 mg/kg total body weight on days 6–11 of gestation. The major adverse effect, early resorption, was dose dependent and specific to day 7–8 exposure. Treatment with 5 mg/kg on day 7 resulted in 85% resorptions, 15% malformations, and a 24% reduction in mean fetal weight, whereas the same dose of (S)‐deoxycoformycin had no effect. Levels of adenosine and 2 ′‐deoxyadenosine, which are the endogenous substrates of ADA, were monitored in the embryo/decidual unit (E/D) by reversed‐phase high‐performance liquid chromatography (RP‐HPLC). In response to the inhibitor, both nucleosides increased transiently in the antimesometrial compartment (antimesometrial decidua + embryo). Peak levels (Cmax) of adenosine and 2 ′‐deoxyadenosine were dose dependent over the range tested (0.05‐10 mg/kg). Exposure to 5 mg/kg on day 7 raised adenosine levels within 0.5 h to 42‐fold over the basal level of 0.06 nmol/mg protein. There was an even stronger effect on 2 ′‐doexyadenosine levels, which were elevated 674‐fold over the detection limit of 0.0005 nmol/mg protein. Direct exposure to the inhibitor in serum‐free E/D culture produced similar results: 50 μM (R)‐deoxycoformycin within 1 h raised adenosine levels 26‐fold and 2 ′‐deoxyadenosine levels 410‐fold. In vivo studies also showed a general correlation between embryolethality and the length of adenine nucleoside pool expansion, apparent for exposure on day 7, 8, or 9 but not on day 6, suggesting that the embryo becomes sensitive to adenosine

ISSN:0040-3709    

DOI:10.1002/tera.1420450109

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

年代:1992

数据来源: WILEY

摘要:

AbstractProgressive changes in the dorsolateral angles (DA) and ventral angle (VA) during elevation and convergence of the caudal neural folds were morphometrically analyzed in normal and dysraphic abnormal embryos of the mouse mutant vacuolated lens (vl), and correlations with the configuratio of microfilaments in the apices of neuroepithelial cells were made by means of ultrastructural cytochemistry. In 22‐28 somite stage abnormal (vl/vl) embryos, the DA and VA are larger than those in their normal counterparts at each comparable level of the caudal neural folds, suggesting that defective convergence involves both the DA and VA in this mutant. In 30–35 somite stage abnormal embryos, the VA is likewise larger than that in normal embryos in which the neural folds have converged and closed; however, the DAs are much smaller, indicating that a medial collapse of the dorsal ends of the neural folds may occur secondary to the closure failure. At the DA, the ultrastructural configuration of microfilaments is similar in abnormal and normal embryos in terms of their circumferential arrangement around the perimeters of the neuroepithelial cell apices. In abnormal embryos, however, the bundles of microfilaments are more delicate and less prominent than in normal embryos; thus it is possible that a quantitative and/or functional deficiency in these elements may be involved in the failure of the abnormal neuroepithelium to bend properly during convergence of the neural fo

ISSN:0040-3709    

DOI:10.1002/tera.1420450110

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

年代:1992

数据来源: WILEY

ISSN:0040-3709    

DOI:10.1002/tera.1420450111

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

年代:1992

数据来源: WILEY