Mutagens as Teratogens: A Correlative Approach

Schreiner, Ceinwen A.; Holden, Henry E.

doi:10.1007/978-3-642-81919-3_9

Cited by 15 publications

(6 citation statements)

References 194 publications

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“…Two large subclasses of teratogenic chemicals are those damaging DNA and those altering membrane function. Schreiner and Holden (20) have observed that most chemicals damaging DNA and therefore causing mutations are teratogenic to animals at some, generally maternally toxic, dose. Agents affecting cell membrane function are usually teratogenic at somewhat less maternally toxic doses.…”

Section: Putative Teratogensmentioning

confidence: 99%

Chemical and toxicological characterization of residential oil burner emissions: II. Mutagenic, tumorigenic, and potential teratogenic activity.

Braun

Busby

Liber

et al. 1987

Environ Health Perspect

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Extracts of effluents from a modern residential oil burner have been evaluated in several toxicological assay systems. Bacterial mutagens were detected in extracts from both the particulate and vapor phase emissions. Effluents from continuous operation were an order of magnitude less mutagenic than those from cyclic (5 min on, 10 min off) operations. No difference in the yield of bacterial mutagens per gram of fuel burned was found between cyclic operation under low and moderate sooting conditions. On the basis of elution behavior from alumina it appeared that the bacterial mutagens collected from high sooting effluents were more polar than those from low sooting effluent. An extract that was mutagenic in bacteria did not induce a significant increase in mutation frequency to human lymphoblasts. No evidence of tumorigenicity was observed in a limited number of newborn mice after IP injection of effluent extract when compared to historical control data. Putative nonmutagenic teratogens were detected in effluent using an attachment inhibition assay. The level of these agents was reduced in effluents from continuous oil burner operation.

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Section: Putative Teratogensmentioning

confidence: 99%

Chemical and toxicological characterization of residential oil burner emissions: II. Mutagenic, tumorigenic, and potential teratogenic activity.

Braun

Busby

Liber

et al. 1987

Environ Health Perspect

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“…We have investigated the effects of maternal administration of CPA 60 h after copulation on the cell number, chromosomal aberrations, mitotic index, histone synthesis, and DNA synthesis, and in vitro postimplantation development of blastocysts with a view to gaining insight into the molecular mechanisms of perturbation of pre-and peri-implantational development of mouse embryos, and to assess the possible value of these methods in examining the embryotoxic potential of drugs and chemicals. In general, studies on the effects of drugs and chemicals on the chromosomes of developing embryos in the uterus are extremely rare [18], and more specifically, as far as we have been able to ascertain, the effects of CPA on chromosome structure and histone synthesis and DNA synthesis in the cleavage stages of the preimplantation embryo have not been previously reported.…”

Section: Introductionmentioning

confidence: 95%

Maternal administration of cyclophosphamide induces chromosomal aberrations and inhibits cell number, histone synthesis, and DNA synthesis in preimplantation mouse embryos

Kola

Folb

Parker

1986

Teratog Carcinog Mutagen

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The effects of cyclophosphamide (CPA), administered to pregnant inbred CBA/Ca mice 60 h after copulation, on cell number, mitotic index, chromosome structure, histone synthesis, and DNA synthesis of 84-h blastocysts, and the subsequent development of these blastocysts cultured for a further 120 h in vitro are described. Cyclophosphamide 4, 20, and 40 mg/kg significantly increased the number of chromosomally aberrant cells, chromosomal aberrations, and chromosome breaks in the blastocysts. Chromosomal rearrangements were significantly increased in the CPA 20 and 40-mg/kg treated groups, and in the 40-mg/kg group the number of cells with ring chromosomes was significantly increased. Histone synthesis and DNA synthesis were significantly inhibited in the CPA 20 and 40-mg/kg treated groups. Blastocyst cell number in each of the treated groups was less than the controls. On subsequent culture in vitro, significantly fewer embryos in the CPA 20 and 40-mg/kg groups hatched, attached, developed trophoblast outgrowths, and expanded their inner cell masses. However, the differentiation of inner cell mass into ectoderm and endoderm was impaired by all three doses of the drug. These results demonstrate that CPA administered to pregnant mice 60 h after copulation has a clastogenic effect and interferes with synthesis of DNA and histones in the preimplantation embryo, and that the drug inhibits the subsequent development and differentiation of these embryos. Cytogenetic analysis of preimplantation embryos might be a useful adjunct to the existing methods in the evaluation of the embryotoxicity of drugs and chemicals.

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“…Some as yet undetermined proportion of the chemicals in commerce is capable of disrupting reproduction or development at some relevant exposure level. Structure-activity relationships or other interesting alternatives (Schreiner, 1983) are not adequate to accurately identify agents capable of affecting reproduction and/or development, but prioritized (Johnson, 1987b) standard tests in laboratory animals have proven remarkably predictive of human effects. These tests are complex and must be fully controlled during execution and the relevant data interpreted with full awareness of potential variables and confounders.…”

Section: Classes Of Adverse Effectsmentioning

confidence: 99%

Perspectives On Reproductive and Developmental Toxicity

1986

Toxicol Ind Health

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Human reproduction and development is a cycle of interdependent events. Virtually all of its phases have been shown to be the primary target of one or more non-mutagenic exogenous agents. Such agents interfere with certain of the countless epigenetic or ontogenic events essential for normal completion of the cycle. Mutagens disrupt this cycle at some points, but the overwhelming majority of reproductive and developmental toxins are not mutagenic. As in all aspects of toxicology, the reproductive and developmental effects of chemicals are determined by the intrinsic nature of the chemical, the quantity of the chemical exposure, the duration of exposure and the stage of the cycle at which it occurs. Signs of reproductive toxicity range from reduced fertility to spontaneous abortion. Adverse effects on the conceptus are categorized as functional deficits, developmental retardation, structural abnormality and death. One or more of these is anticipated to occur as a result of excess exposure to most chemicals. Although the degree of hazard and risk potential can be calculated in each instance, chemicals differ markedly in their ability to interfere with reproduction (Amann, 1982) and/or development (Johnson, 1984). Standardized methods for reproductive and developmental toxicity safety evaluation are available for detecting adverse effects upon any aspect of reproduction and development. Data currently available establish that these state-of-the-art tests conducted in laboratory animals are often highly predictive of the type of adverse effect a particular chemical will have in humans, as well as the exposure level at which it will occur. By adding a modest safety factor to the no-observed-effect-level of well-executed animal studies, safe human exposure levels can be established. Responsibility for determining the intrinsic hazard potential and the risk estimate of exposure rests with manufacturers and major users of occupational and other environmental chemicals. As public awareness of reproductive and developmental hazards has increased in recent years, it has come to be understood that some chemicals have a predilection for causing reproductive impairment and/or disrupting development in the absence of other toxicity. Such substances must be identified to establish safe exposure levels and to determine the types of effects to be expected, should excessive human exposure occur. The setting of safe exposure levels is necessary both from the standpoints of ensuring public safety and avoiding product liability.

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Mutagens as Teratogens: A Correlative Approach

Cited by 15 publications

References 194 publications

Chemical and toxicological characterization of residential oil burner emissions: II. Mutagenic, tumorigenic, and potential teratogenic activity.

Chemical and toxicological characterization of residential oil burner emissions: II. Mutagenic, tumorigenic, and potential teratogenic activity.

Maternal administration of cyclophosphamide induces chromosomal aberrations and inhibits cell number, histone synthesis, and DNA synthesis in preimplantation mouse embryos

Perspectives On Reproductive and Developmental Toxicity

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