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Teratogen Update Vol. 12: Fall, 1995

We in society is now both more aware and concerned about the presence of mutagens in the environment. Mutagens are ubiquitous; some are naturally present in plants, many are produced by combustion of organic materials (including cooking), and others are products of industry. Given daily exposures to mutagens it is natural to ask which agents are responsible for birth defects and what reproductive risks may arise from specific exposures. As we will see, the effects we can document in humans are not those commonly anticipated by the public.

The actions of classical teratogens can be recognized from the patterns of birth defects they produce. They interact with cellular receptors that define developmental fields. Mutagens, on the other hand, produce less predictable patterns of anomalies, even under experimental conditions, because they are indiscriminate in the types of cells they damage. However, experiments with ionizing radiation, the simplest mutagen to study, indicate that the developing brain is particularly ill prepared to deal with mutagenic insults and is consistently affected. Hence, microcephaly is the only consistent finding in non-lethal mutagen exposures during pregnancy, but is clearly not an effect exclusive to mutagen exposures. As with any developmental toxin, increasing the dosage of experimental mutagen exposure during pregnancy also leads to miscarriage.

Mutagens can also affect germ cells and there is general concern about environmental exposures leading to birth defects through mutations in egg or sperm cells. Experimental studies, however, show that significant exposures to mutagens are not likely to be detected by increased rates of birth defects. Germ cells are more likely to be killed by DNA damage than to be mutated. This loss of cells will lead to infertility. Mutations in germ cells could introduce new genetic conditions into families, but only those conditions that are dominant and whose phenotypes are viable will be seen.

Experimental data indicate that most dominant mutations induced in germ cells at high levels of exposure are lethal. Conceptions carrying dominant lethal genes are likely to abort early or even fail to implant. Thus the perceived effect is, again, infertility. Recessive mutations induced by mutagens will not be detected until they become homozygous in future generations and many changes in sequence in non-coding regions of the genome will simply remain silent. Each of these effects has been well documented in animal studies (see References for classic investigations by Russell and Russell).

High dose exposures to mutagens in humans have occurred as the result of nuclear explosions and catastrophes, and continue to occur through cancer radiation and chemotherapy. As predicted by the data discussed above, follow up has not documented increased rates of birth defects, except when exposures occur during pregnancy and can directly affect embryonic tissues. Microcephaly is the only consistent finding in these cases. Oncologists routinely recommend pregnancy termination if radiation and/or chemotherapy are to be instituted in gravid women. Infertility is now well documented in some cancer survivors, where treatment frequently leads to decreased sperm counts in men and to premature menopause in women.

Providers of perinatal care rarely encounter pregnancies complicated by high dose exposures to ionizing radiation or chemical mutagens such as may occur with cancer treatment. On the other hand, they are routinely asked questions about effects of diagnostic Xrays and exposures to known carcinogens such as tobacco smoke.

Diagnostic radiation usually involves exposures that result in absorbed doses of radiation measured in millirads, or thousandths of Rads. A Rad is a unit of absorbed radiation that is now being replaced by another unit called a 'Gray' (Gy). One Gy is equal to 100 Rads. Experimental data and epidemiology place the threshold for birth defects at levels of exposure during pregnancy greater than 100 Rads (1 Gy). The threshold for microcephaly is lower, somewhere between 10 and 100 Rads (0.1 to 1 Gy). Diagnostic exposures, even multiple studies, rarely result in doses that exceed 1 Rad (0.01 Gy). On the other hand, fetal exposures as low as 1 Rad (0.01 Gy) have been shown to significantly increase risks for leukemia in childhood. Hence the recommendations to limit exposures during pregnancy.

Most chemical mutagens, especially the carcinogens in tobacco smoke, require metabolism to activate them into compounds that can damage DNA. The enzyme systems that catalyze these reactions simultaneously catalyze reactions responsible for clearance and detoxification. At any given level of exposure, therefore, toxicity is a net effect reflecting the relative balance between metabolic activation and detoxification reactions. As levels of exposure change so may the balance of metabolism. Animal studies document interactions between genetically determined metabolic pathways that may be either protective or teratogenic depending on the level of maternal toxin exposures.

Human studies, in contrast, indicate that, with the exception of the placenta, pathways for metabolic activation are relatively inactive in embryonic and fetal tissues throughout gestation. Human placenta contains enzymes capable of both metabolic activation and detoxification that have high affinity for chemical carcinogens, including many in tobacco smoke. Metabolism of foreign chemicals to compounds that covalently bind to placental DNA has been demonstrated in human pregnancies. Overall, the effect of this placental metabolism is probably protective, but risks remain. Higher doses of chemical carcinogens may produce transplacental DNA damage with adverse effects.

Like ionizing radiation, the role of tobacco smoke as a potential transplacental carcinogen has also been studied in humans. Isolated reports associate childhood cancers such as brain tumors with maternal tobacco smoking, but no consistent pattern of increased risk for childhood cancers has emerged since the increase in maternal smoking following World War II. The story, however, may be far from complete. As 'baby boomers' approach 50, they are only beginning to enter the age range where cancer risks begin to rise dramatically. Cancers result from accumulated mutations within tissues. Potentially oncogenic mutations may as yet lie undetected in clones of cells that are slowly evolving toward malignancies in men and women exposed in utero to tobacco smoke carcinogens.

Direct studies of mutations occurring in utero in any species are very limited because methods for finding rare mutations among large numbers of normal cells are just now being developed. Human cord blood samples have been assayed for somatic mutations at three different detectible loci. Each investigation has documented that mutations do occur during gestation at frequencies in the range of 1 to 2 mutations detected in 106 to 107 cells. In the case of hypoxanthine phosphoribosyltransferase (hprt) -deficient mutants detected as lymphoblasts resistant to 6-thioguanine, large deletions have been shown to dominate the spectrum of mutation seen in cord blood. These appear to have resulted from misdirected recombination, a normal process during development that produces clones of lymphocytes with different T cell receptors. However, additional, potentially environmentally produced, mutations have also been detected. Their source remains unclear with the only hint as yet reported being correlation between higher frequencies of mutants in cord blood and medical indigency.

Translating the results of a few human studies to the many questions that remain about reproductive effects of mutagen exposures is difficult. In summary, experimental evidence from animal models, analyses of ionizing radiation exposures, and the epidemiology of tobacco smoking indicate that current levels of exposures to mutagens are not likely to be contributing significantly to risks for birth defects. However, should mutagen levels increase, developmental effects could be significant. Birth defects are the least sensitive indicator of reproductive toxicity due to mutagens.

See References: Mutagens

The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Genetics Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131

Table Of Contents: Teratogen Update
Introduction
Medications
Substances of Abuse
Maternal Infections
Maternal Disorders
Mutagens
Etiology of Congenital Malformations in Humans: (Table 1)
Known Human Teratogens: (Table 2)
References
Facts About Neural Tube Defects and Folic Acid

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