Teratogenicity of 3,3‐dimethyl‐1‐phenyltriazene in the rat: Gross malformations including micrognathism

Frank, Arthur J.; Thompson, Daniel J.; Kazacos, Evelyn A.

doi:10.1002/tera.1420390107

Cited by 11 publications

(4 citation statements)

References 19 publications

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“…Early studies of the vascular disruption mechanism involved uterine vascular clamping, which produced abdominal wall, limb, renal, and other defects (Brent and Franklin, 1960). Also, experimental studies of animal models have shown that various hemorrhage‐inducing agents can produce these defects, such as thalidomide (Delahunt and Lassen, 1964; Wilson and Gavan, 1967), triazene (Frank et al, 1989; Louryan et al, 1995; Glineur et al, 1999), cocaine (Webster and Brown‐Woodman, 1990), and salicylates (Warkany and Takacs, 1959; Kimmel et al, 1971; Khera, 1976). In humans, associations have been reported for a variety of vasoactive agents, including thalidomide (Brent and Holmes, 1988), misoprostol (Orioli and Castilla, 2000; Vargas et al, 2000), cigarette smoking (Goldbaum et al, 1990; Haddow et al, 1993; Czeizel et al, 1994; Kallen, 1997a, 1997b; Skelly et al, 2002) cocaine (Hoyme et al, 1990; Addis et al, 2001), aspirin (Kozer et al, 2002), and ibuprofen (Werler et al, 2004).…”

Section: Vascular Disruptionmentioning

confidence: 99%

Teratogen update: Pseudoephedrine

Werler

2006

Birth Defects Research

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Pseudoephedrine is contained in decongestants such as the Sudafed line of products. It is an alpha-adrenergic receptor agonist, which causes blood vessel constriction, including the therapeutic effect of reducing airflow resistance in the nasal cavity. Pseudoephedrine is one of the most commonly used medications in pregnancy, with an estimated 25% of women exposed. It has been demonstrated that alpha-adrenergic receptor agonists slow uterine blood flow, but their effects have not been studied in relation to most reproductive outcomes in animals or humans. Two analyses of health maintenance organization pharmacy data identified 9 malformed infants among 902 first-trimester pseudoephedrine exposures, suggesting no association with birth defects overall; however, studies of such data sets often lack sufficient power to identify risks for specific birth defects. The related compounds, epinephrine, ephedrine, and phenylephrine, have been associated with hemorrhages and cardiovascular and limb malformations in animal models. Risk of ventricular septal defects was associated with decongestant use in pregnant women in 1 recent study. The vasoconstrictive effects of these drugs raise the hypothesis that their use in early pregnancy might increase the risk of vascular disruption defects. Case-control studies, which often do have power to identify risks related to specific birth defects, have explored this hypothesis. Decongestant use in the first trimester has been associated with small increases in risks of 3 defects thought to arise, at least in some instances, from vascular disruption-gastroschisis, small intestinal atresia, and hemifacial microsomia. These findings are somewhat consistent in terms of magnitude of effect and suggest that risks are even greater among women also exposed to the vasoconstrictive effects of cigarette smoking. There are, however, limitations to these studies, including the possibilities of inaccurate recall of exposures and confounding by indication. In addition, the majority of decongestant use is in oral form and the question of whether intranasal formulations carry risk has not been adequately addressed. Birth Defects Research (Part A) 76:445-452, 2006.

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Section: Vascular Disruptionmentioning

confidence: 99%

Teratogen update: Pseudoephedrine

Werler

2006

Birth Defects Research

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“…Micrognathism, a permanent structural alteration, is a teratogenic effect. In rat embryos, DMPT-induced micrognathism is produced at a very high incidence (18) and is minimally affected by phase specificity (Frank, unpublished data (6,7). Odontomas are uncommon lesions in laboratory animals (17).…”

Section: Experimental Animalsmentioning

confidence: 99%

“…From gestation day 11 through gestation day 15, teratogenic targets of DMPT include the central nervous system, limbs, and craniofacial region. The mandible is most commonly affected by DMPT, and this remarkable organotropism makes DMPT an excellent experimental model of micrognathism (18). Classical alkylating teratogens exhibit marked phase specificity, and administration of these agents on gestation days [12][13][14][15] should induce a high percentage of urogenital malformations (29).…”

Section: Introductionmentioning

confidence: 99%

Renal Transplacental Carcinogenicity of 3,3-Dimethyl-1-Phenyltriazene in Rats: Relationship of Renal Mesenchymal Tumor to Congenital Mesoblastic Nephroma and Intralobar Nephrogenic Rests

et al. 1992

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Exposure of rat embryos to 3,3-dimethyl-1-phenyltriazene (DMPT) results in numerous malformations, but the urogenital system is not affected. In contrast, exposure of rat fetuses to DMPT has been reported to result in renal neoplasms, which were not further classified. To better understand this discrepancy in organotropism of the teratogenic and transplacental carcinogenic processes, the present study was undertaken to characterize the neoplasms induced in rat fetuses exposed to DMPT in utero. Renal neoplasms and persistent mesenchyme were observed in 19.2 and 11.5%, respectively, of the offspring of rats treated with 1 mg DMPT/ kg body weight intraperitoneally on gestation days 16, 18, and 20. The majority of these renal lesions were observed in females. The renal neoplasms were mixtures of various types of mesenchymal tissue derivatives including smooth muscle and fibrous connective tissue. These neoplasms would be classified as renal mesenchymal tumors in rats. Brain neoplasms (numerous types), compound odontomas, and micrognathism were observed predominantly in male offspring from the same group. This treatment also resulted in decreased body weights, increased incidence of sudden loss of body weight, tremors and ataxia, and hypoplastic testes. Exposure to single intraperitoneal doses of DMPT on gestation day 20 did not produce a classic dose-response pattern: Minimal effects were observed with 10 mg DMPT/kg (occasional renal mesenchymal tumors and brain neoplasms), marked effects were observed with 30 mg DMPT/kg (lower incidence rate of most of the alterations observed with 1 mg/kg on gestation days 16, 18, and 20), and no effects were observed with 60 mg DMPT/kg. DMPT administered intraperitoneally at 1 mg/kg body weight on gestation days 16, 18, and 20 is an animal model of transplacental chemically induced renal neoplasms, which provide lesions with similarities to both intralobar nephrogenic rests and congenital mesoblastic nephroma of humans. Why the kidney is a carcinogenic target and not a teratogenic target remains unknown.

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“…Frank et al .,[23] described the effects of 30 mg/kg of 3.3 dimethyl-1-phenyl triazene administered on day 12 of gestation in the rat. At external examination, they found 82% of cases with micrognathia and 100% of embryos with CP.…”

Section: Formation Of Orofacial Cleftingmentioning

confidence: 99%