Cancer and Developmental Exposure to Endocrine Disruptors. (Research)
Birnbaum, Linda S., Fenton, Suzanne E., Environmental Health Perspectives
Developing organisms have increased susceptibility to cancer if they are exposed to environmental toxicants during rapid growth and differentiation. Human studies have demonstrated clear increases in cancer after prenatal exposure to ionizing radiation, and there is suggestive evidence that brain tumors and leukemia are associated with parental exposures to chemicals. Animal experiments have demonstrated increased tumor formation induced by prenatal or neonatal exposure to a variety of chemicals, including direct-acting carcinogens and drugs. Recently, natural estrogens have been classified as known human carcinogens. Prenatal exposure to natural and synthetic estrogens is associated with increases in breast and vaginal tumors in humans as well as uterine tumors in animals. Synthetic halogenated chemicals increase liver tumors after early life-stage exposure. Recently, a prototypical endocrine-disrupting compound, 2,3,7,8-tetrachlorodibenzo-p-dioxin, has been shown to be a developmental toxicant of the mammary gland in rodents. Dioxin alters multiple endocrine systems, and its effects on the developing breast involve delayed proliferation and differentiation of the mammary gland, as well as an elongation of the window of sensitivity to potential carcinogens. Implications of these new findings suggest that causes of endocrine-related cancers or susceptibility to cancer may be a result of developmental exposures rather than exposures existing at or near the time of tumor detection. Key words: animal models, atrazine, carcinogenesis, childhood cancers, development, dioxin, endocrine disruptors.
The developing child (fetus to prepuberty) is particularly susceptible to environmental insult, because development is a highly integrated process in which high rates of proliferation and extensive differentiation are coordinated with each other and with programmed cell death. Rapid growth rates allow for mutagenic and epigenetic alterations as cells proliferate. Likewise, differentiation represents a highly controlled process in which patterns of gene expression undergo massive changes.
Thus, both cell division and differentiation offer multiple opportunities for the initiation of lesions as well as the promotion of the growth of altered cells; these are hallmarks of the complex process known as cancer. In addition, physiologic protective barriers such as the placenta and the blood-brain barrier are not complete in utero. Further, the metabolizing and elimination capabilities of the developing organism are not fully developed until after birth (Miller 1983), leaving the fetus and newborn particularly susceptible to adverse effects of environmental compounds.
Developmental Carcinogens in Humans
Early childhood exposures to infectious agents are key determinants for both hepatocellular carcinoma (Hsieh et al. 1992) and acute lymphoblastic leukemia (ALL; Greaves 1997). However, exposure to environmental compounds in utero--a proliferative period in human development--has long been thought to be critically involved in the causation of cancers in children and young adults. Although a wide range of potentially harmful agents may be involved, there is unequivocal evidence for two environmental agents: ionizing radiation and the estrogen agonist diethylstilbestrol (DES) (Anderson et al. 2000). The clear evidence for the role of ionizing radiation comes from studies involving diagnostic assessment of pregnant women. Doll and Wakeford (1997) have concluded that low doses of X ray to the fetus, especially during the last trimester, cause an increased risk of leukemia and all other types of cancer during childhood. In addition, therapeutic X ray of infants is also associated with thyroid and breast cancer later in life (Boice and Miller 1999). The clear association between fetal exposure to DES and vaginal adenocarcinoma in those young women (Herbst et al. 1971) led to the suggestion that developmental exposure to other hormonally active substances could also be associated with delayed cancer. …