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JournalISSN: 0270-3211

Teratogenesis Carcinogenesis and Mutagenesis 

About: Teratogenesis Carcinogenesis and Mutagenesis is an academic journal. The journal publishes majorly in the area(s): Genotoxicity & Micronucleus test. It has an ISSN identifier of 0270-3211. Over the lifetime, 821 publications have been published receiving 16954 citations.


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Journal ArticleDOI
TL;DR: Hyperthermia appears to be capable of causing congenital defects in all species and may act alone or synergistically with other agents.
Abstract: Although hyperthermia is teratogenic in birds, all the common laboratory animals, farm animals, and primates and satisfies defined criteria as a teratogen, its study as a human teratogen has been neglected. Homeothermic animals, including humans, can experience body temperature elevations induced by febrile infections, heavy exercise and hot environments which exceed the thresholds (1.5-2.5 degrees C elevation) which are known to cause a syndrome of embryonic resorptions, abortions, and malformations in experimental animals. Hyperthermia is particularly damaging to the central nervous system, and if a threshold exposure occurs at the appropriate stages of embryonic development, exencephaly, anencephaly, encephalocoele, micrencephaly, microphthalmia, neurogenic talipes, and arthrogryposis can be produced in a high proportion of exposed embryos, the incidence and type of defect depending on the species and strain within species, the stage of development, and the severity of hyperthermic exposure. Other defects which can be induced experimentally include exomphalos, hypoplasia of toes and teeth, renal agenesis, vertebral anomalies, maxillary hypoplasia, facial clefting, cataract, coloboma, and heart and vascular defects. Proliferating cells are particularly sensitive to temperature elevations, resulting in arrest of mitotic activity and immediate death of cells in mitosis with threshold elevations (1.5-2.5 degrees C) and delayed death of cells probably in S phase with higher elevations (3.5 degrees C). In general, lower temperature elevations (2.5 degrees C) require longer durations of elevation to cause defects than a simple spike at a higher elevation (4.5 degrees C). The death of cells is largely confined to the brain and in the day 21 guinea pig embryo to the alar regions of the brain. Cell death probably accounts for most of the defects in the central nervous system, but microvascular disturbances leading to leakage, oedema and haemorrhage, placental necrosis, and infarction are other known effects of hyperthermia; and these are probably involved in the pathogenesis of many defects of the heart, limbs, kidneys, and body wall. Recent experiments have demonstrated protection of rat embryos in culture against a known teratogenic exposure by a brief nonteratogenic exposure given at least 15 min earlier. This protection is associated with the synthesis of heat-shock proteins, and temporary arrest of the cell proliferative cycle. Hyperthermia appears to be capable of causing congenital defects in all species and may act alone or synergistically with other agents.(ABSTRACT TRUNCATED AT 400 WORDS)

249 citations

Journal ArticleDOI
J. L. Stuckhardt1, S. M. Poppe1
TL;DR: The procedure used in this lab is a complete and systematic necropsy of the fresh fetus requiring minimum equipment and time and yields an intact skeleton which can subsequently be processed for skeletal examination.
Abstract: A method for examining the viscera of rat and rabbit fetuses is described. Techniques used in detecting visceral alterations in rats and rabbits for routine teratogenicity screens have varied over the years. The method used should be quick and simple but at the same time must be accurate, reliable, and comprehensive. The procedure used in this lab is a complete and systematic necropsy of the fresh fetus requiring minimum equipment and time. The examination can be done immediately following cesarean section and yields an intact skeleton which can subsequently be processed for skeletal examination. The fresh specimen and the natural coloration of in situ organs makes color photography of visceral alterations clear and concise. Any lesion can be appropriately fixed for histopathic examination. This technique begins with the examination of the organs in the abdominal cavity and proceeds to the thorax. Of special interest is the procedure used to inspect the internal anatomy of the fresh fetal heart. A description of the internal examination of both rat and rabbit heads and eyes is also included.

192 citations

Journal ArticleDOI
TL;DR: In conclusion, available evidence supports the hypothesis that DNA is the primary target in terms of the teratogenic, mutagenic, and antineoplastic effects of CP, and preliminary information obtained from embryos exposed to CP metabolites suggests that, although DNA cross-linking might play a role in CP teratogenesis, metabolite-induced DNA strand breakage and/or induction of mutations might also play arole.
Abstract: Cyclophosphamide (CP) is one of the best studied teratogens; it produces primarily central nervous system and skeletal anomalies in rats, mice, rabbits, monkeys, and humans. Furthermore, CP is one of the most extensively studied antineoplastic agents. Recent work using in vitro rodent embryo culture has demonstrated that CP must be bioactivated to be teratogenic. This finding extends earlier work showing that CP must be activated to achieve its antineoplastic and mutagenic effects. Activation of CP to its teratogenic, mutagenic, and antineoplastic form is mediated by microsomal cytochrome P-450 monooxygenases, which convert CP to 4-hydroxycyclophosphamide (4OHCP). In the absence of detoxification, 4OHCP spontaneously breaks down to phosphoramide mustard (PM) and acrolein (AC). PM is the CP metabolite believed to be responsible for the antineoplastic and mutagenic effects of CP, whereas AC is thought to cause the side effects associated with CP chemotherapy. Recent work has shown that the teratogenic effects of CP are mediated by both PM and AC. Although it is far from proven, available evidence supports the hypothesis that DNA is the primary target in terms of the teratogenic, mutagenic, and antineoplastic effects of CP. Although the nature of the DNA lesions produced by CP, which are responsible for its teratogenic, mutagenic, and antineoplastic effects, is not completely understood, cross-linking of DNA seems to play a critical role in the antineoplastic properties of CP. Preliminary information obtained from embryos exposed to CP metabolites suggests that, although DNA cross-linking might play a role in CP teratogenesis, metabolite-induced DNA strand breakage and/or induction of mutations might also play a role. Although insights into the molecular mechanisms underlying CP teratogenesis are just beginning to accumulate, the availability of in vitro embryo culture combined with the modern armamentarium of molecular biology will allow teratologists to probe further the molecular aspects of teratogenesis.

177 citations

Journal ArticleDOI
TL;DR: In vitro effects appear to be comparable to the in vivo observations and suggest a direct teratogenic action of valproic acid on the developing rodent embryo, which is similar to that seen in the CD-1 mouse.
Abstract: The in vivo teratogenic potential of valproic acid was evaluated in the CD-1 mouse. Dose selection was based on the estimated lethality curve and several doses were evaluated. Treatment during early organogenesis (Days 8–10) produced a dose related increase in congenital abnormalities which was accompanied by a decrease in fetal weight, Rib and vertebral abnormalities together with exencephaly were the most common defects. Greater embryo mortality was apparent following teatment during late organogenesis (Days 11–13), but the surviving fetuses were less sensitive to the dysmorphogenic effects and cleft palate was now the most common defect, Early neurula stage mouse (Day 9) and rat (Day 10) embryos were cultured in the presence of valproic acid (0.6–1.8 mM) for 48 hr. There was significant reduction in growth which was accompanied by a variety of dysmorphogenic effects. Irregular segmentation of somites together with incomplete and irregular fusion of brain folds were most evident. These were observed at concentrations of valproic acid where no adverse effects on the yolk sac circulatory system were apparent. These in vitro effects appear to be comparable to the in vivo observations and suggest a direct teratogenic action of valproic acid on the developing rodent embryo.

164 citations

Journal ArticleDOI
TL;DR: A simple test for determining the teratogenic potential of compounds is described using embryonic limb bud cells in culture, which shows how compounds which interfere with growth or differentiation reduce the amount of proteoglycan and as a consequence, reduce alcian blue staining.
Abstract: A simple test for determining the teratogenic potential of compounds is described using embryonic limb bud cells in culture. These mesenchyme cells multiply and differentiate into chondrocytes during a 6-day culture period. The extent of chondrogenesis is assessed by staining for the cartilage specific proteoglycan with alcian blue. The amount of stain is then measured spectrophotometrically. Compounds which interfere with growth or differentiation reduce the amount of proteoglycan and as a consequence, reduce alcian blue staining. Compounds can be added directly to the media or be activated using several different metabolizing systems. The dose of a compound needed to reduce alcian blue staining by 50% is designated the teratogenic potential (TP50) of that compound. TP50's of proven teratogens compare favorably with in vivo teratogenic doses of the teratogens.

136 citations

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Performance
Metrics
No. of papers from the Journal in previous years
YearPapers
20051
200341
200249
200141
200033
199937