Perinatal chemical exposures may lead to increased risk of childhood cancers, as well as those later in life. Studies with animal models are utilized to detect such risks through bioassays, and to increase understanding of underlying cellular and molecular mechanisms. Assays of two pharmaceutical drugs have given provocative results. The anti-AIDS drug AZT, in the U.S. currently prescribed as the standard of care for HIV-positive pregnant women, has been tested for transplacental carcinogenicity in CD-1 Swiss mice. It caused a significant, 2- to 5- fold increase in liver and lung tumors in male offspring, lung and reproductive system tumors in female offspring, and TPA-promotable skin tumors in offspring of both sexes. The incidence of spontaneous lymphomas in these mice was reduced by the AZT treatment. These effects were associated with incorporation of AZT into fetal DNA and also telomere shortening, and with oxidative damage of fetal DNA. Given to pregnant patas monkeys at a dose similar to that used in humans, AZT incorporation into fetal DNA was again detected, and preliminary results indicate an increase in oxidative DNA damage. Although the benefits of AZT in preventing perinatal HIV transmission far outweigh any potential cancer risk, our results urge follow-up of exposed children so that any adverse effects can be detected early. Tamoxifen is another drug widely prescribed for women and will inevitably be given to pregnant women. Due to its similarity to diethylstilbestrol, an established human transplacental carcinogen, possible fetal effects of tamoxifen are of concern. We have found that administration of tamoxifen to pregnant mice resulted in a high incidence of long-term effects selective for the female reproductive system, as for diethylstilbestrol. These included hyperplasia of the oviduct, uterine squamous metaplasia, polyps, leiomyomas, a leiomyosarcoma, and several ovarian tumors. Treatment of pregnant women with tamoxifen should be avoided whenever possible, and any exposed offspring followed carefully. Special sensitivity of fetal genes to mutations leading to cancer has long been an hypothesis, but experiments testing this idea are limited. Lung tumors caused by transplacental exposure of mice to N- ethylnitrosourea on certain days of gestation are more rapidly growing and malignant than other mouse lung tumors. Searching for a molecular reason for this unique quality, we found that these tumors contained K- ras mutations in codon 12, with the same changes seen in human lung adenocarcinomas, whereas the more benign tumors had only codon 61 changes. These results confirm gestation stage-specific sensitivity of fetal genes to mutation, and have larger implications for the etiological pathway leading to human lung adenocarcinomas. AIDS Title: Transplacental carcinogenic effects of AZT.
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