Spontaneous and induced alterations in the cardiac membranous ventricular septum of fetal, weanling, and adult rats

Solomon, Howard M.; Wier, Patrick J.; Fish, C. J.; Hart, T.K.; Johnson, Connie; Posobiec, Lorraine M.; Gowan, C. C.; Maleeff, Beverly E.; Kerns, William

doi:10.1002/(sici)1096-9926(199703)55:3<185::aid-tera3>3.0.co;2-1

Cited by 47 publications

(11 citation statements)

References 18 publications

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“…It is also teratogenic in a number of laboratory test species in which anomalies of the heart, craniofacial region, limbs and viscera have all been reported in a dose-and time-dependent manner (Rifkind, 1974;Buttar et al, 1978;Brown et al, 1979;Khera, 1985;Wells et al, 1989;Miller and Scott, 1992;Solomon et al, 1997;Fleeman et al, 2004). TMD is N-demethylated by several CYPs to yield DMO (Tanaka et al, 2003), which is both the pharmacologically active 7.…”

Section: Discussionmentioning

confidence: 99%

“…The human trimethadione syndrome includes intrauterine growth retardation (IUGR), developmental delay, axioskeletal abnormalities and cardiac defects (Zackai et al,1975). Rat embryos exposed to TMD present with a similar constellation of anomalies (Buttar et al, 1978) with several independent researchers reporting a 90-100% incidence of intraventricular septation defects (VSD) in offspring (Solomon et al,1997). The similarity of the trimethadione syndrome noted in rats and humans, together with the high incidences of VSD, suggested that TMD might be a useful tool to studychemical-induced CHD.…”

Section: Introductionmentioning

confidence: 86%

“…6). The mean incidence of VSD in control was 14 AE 25% and entirely attributable to one litter with a 44% incidence of VSD (normal background rates are 2-3%; Fleeman et al, 2004;Solomon et al, 1997). No DMO was detected in the serum of this dam, ruling out the possibility that these spurious findings were the result of dosing error and therefore there was no rationale for excluding this dam from study.…”

Section: The Effect Of Dmo On Malformationsmentioning

confidence: 94%

“…of TMD on gestation day (GD) 9 and 10 induced a 90-100% incidence of VSD in exposed offspring (Solomon et al, 1997;Veuthey, 1990). However, more recent studies reported dose-limiting maternal toxicity above 300 mg/kg b.i.d.…”

Section: Introductionmentioning

confidence: 99%

“…We believe the heightened maternal sensitivity to TMD was the result of the re-derivation of the Sprague-Dawley rat by Charles River in 1998 to yield the Crl:CD(SD)IGS BR foundation colony (White and Lee, 1998). Reduced maternal tolerance resulted in lower embryonic exposures, which may explain the disparity of the incidences of VSD between by Fleeman et al (2004) and by Solomon et al (1997) and Veuthey, 1990. A further, possibly related, contributing factor may have been genetic drift in the Ndemethylation activities of the pre-and post-rederived SpragueDawley rat.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Maternal rat serum concentrations of dimethadione do not explain intra-litter differences in the incidence of dimethadione-induced birth defects, including novel findings in foetal lung

et al. 2014

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 86%

Section: The Effect Of Dmo On Malformationsmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Maternal rat serum concentrations of dimethadione do not explain intra-litter differences in the incidence of dimethadione-induced birth defects, including novel findings in foetal lung

et al. 2014

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Developmental toxicity and toxicokinetics of two endothelin receptor antagonists in rats and rabbits

et al. 1999

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Embryo‐fetal development studies with toxicokinetic evaluations were conducted in rats and rabbits after oral or intravenous administration of two endothelin receptor antagonists. In the rat studies, females were administered SB‐217242 (0.01–300 mg/kg/day) orally or SB‐209670 (0.01–50 mg/kg/day) intravenously from days 6–17 postcoitus (pc). External and visceral fetal examinations were performed at necropsy on day 21 pc. Maternal body weight and food consumption were decreased only at 300 mg/kg/day SB‐217242. Embryolethality was seen at 300 mg/kg/day SB‐217242. Decreased fetal body weight occurred at 300 mg/kg/day SB‐217242 and 50 mg/kg/day SB‐209670. Dose‐dependent increases in the mean percentage of fetuses per litter with malformations were seen at ≥50 mg/kg/day SB‐217242 and ≥10 mg/kg/day SB‐209670. Craniofacial, great vessel, heart, and thyroid were the predominant malformations. In the rabbit studies, females were administered SB‐217242 (0.01–50 mg/kg/day) orally or SB‐209670 (0.01–25 mg/kg/day) intravenously from days 6–20 pc. There was no drug‐related effect on maternal body weight or food consumption. Embryolethality was observed at 50 mg/kg/day of SB‐217242. Dose‐related increases in the mean percentage of fetuses per litter with malformations were seen at ≥10 mg/kg/day SB‐217242 and ≥10 mg/kg/day SB‐209670. The malformations were similar to those observed in the rat studies, except that craniofacial development was not altered by SB‐209670. The malformations observed are consistent with the pattern of endothelin‐1 gene expression described in mouse embryonic pharyngeal arches and heart, and with the craniofacial and cardiovascular malformations observed in endothelin‐1‐deficient mice. Given the known role for endothelins in development, and concordant malformations in rats and rabbits observed in this study, teratogenicity is likely to be a class effect of endothelin receptor antagonists. Teratology 59:51–59, 1999. © 1999 Wiley‐Liss, Inc.

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Benzofuranyl ureas with potent cardiovascular teratogenicity in rats

et al. 2000

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Spontaneous and induced alterations in the cardiac membranous ventricular septum of fetal, weanling, and adult rats

Cited by 47 publications

References 18 publications

Maternal rat serum concentrations of dimethadione do not explain intra-litter differences in the incidence of dimethadione-induced birth defects, including novel findings in foetal lung

Maternal rat serum concentrations of dimethadione do not explain intra-litter differences in the incidence of dimethadione-induced birth defects, including novel findings in foetal lung

Developmental toxicity and toxicokinetics of two endothelin receptor antagonists in rats and rabbits

Benzofuranyl ureas with potent cardiovascular teratogenicity in rats

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