Critical Windows of Exposure for Children's Health: Cancer in Human Epidemiological Studies and Neoplasms in Experimental Animal Models

Abstract

In humans, cancer may be caused by genetics and environmental exposures; however, in the majority of instances the identification of the critical time window of exposure is problematic. The evidence for exposures occurring during the preconceptional period that have an association with childhood or adulthood cancers is equivocal. Agents definitely related to cancer in children, and adulthood if exposure occurs in utero, include: maternal exposure to ionizing radiation during pregnancy and childhood leukemia and certain other cancers, and maternal use of diethylstilbestrol during pregnancy and clear-cell adenocarcinoma of the vagina of their daughters. The list of environmental exposures that occur during the perinatal/postnatal period with potential to increase the risk of cancer is lengthening, but evidence available to date is inconsistent and inconclusive. In animal models, preconceptional carcinogenesis has been demonstrated for a variety of types of radiation and chemicals, with demonstrated sensitivity for all stages from fetal gonocytes to postmeiotic germ cells. Transplacental and neonatal carcinogenesis show marked ontogenetic stage specificity in some cases. Mechanistic factors include the number of cells at risk, the rate of cell division, the development of differentiated characteristics including the ability to activate and detoxify carcinogens, the presence of stem cells, and possibly others. Usefulness for human risk estimation would be strengthened by the study of these factors in more than one species, and by a focus on specific human risk issues.

Reduced tumorigenesis in p53 knockout mice exposed in utero to low‐dose vitamin E

“…26,27 Similarly, neonatal twin studies suggest that some pediatric leukemias may be initiated in utero, 28 and ALL has been associated with chromosomal abnormalities, including high hyperdiploidy, that may reflect early initiating events in utero ( 29 and references therein). The in utero efficacy of exogenous transplacental carcinogens 30 and the human epidemiological results are consistent with our evidence indicating that some cancers of endogenous origin also are initiated in utero.…”

“…31 GD 13 falls within the critical embryonic period of organogenesis, during which p53 knockout mice are susceptible to developmental abnormalities caused by DNA-damaging agents or altered maternal folate status. 11,13,32 GD 19 falls within the later, fetal period when the conceptus is most susceptible to common transplacental carcinogens that chemically induce postnatal tumorigenesis in the offspring (reviewed in 30 ). The potential carcinogenic relevance of in utero oxidative stress is suggested by the embryopathic importance of oxidative DNA damage and the contravening embryoprotective role for embryonic DNA repair, which are evidenced by the enhanced susceptibility of p53 and ATM knockout mice to ROS-initiating, DNA-damaging teratogens.…”

Treatment of Pregnant Women with a Betamimetic and Verapamil Increases the Micronuclei Frequency in Umbilical Cord Blood Lymphocytes

“…One of the reasons is that the placenta does not completely protect the fetus from the outside influences (Vähäkangas and Myllynen 2006;Myren et al 2007). Factors that may increase fetal susceptibility include higher rates of cell proliferation, the greater number of target cells at risk, lower immunologic competence, and decreased capacity to activate and detoxify carcinogens as well as to repair DNA (Anderson et al 2000;Perera et al 2004;Whyatt et al 2004). A great number of authors showed that the frequency of damages in genetic material of neonates and children, such as MN and chromosome aberrations, increased with the concentration of environmental agents (Bocskay et al 2005;Milošević-Djordjević et al 2005, 2007bNeri et al 2006).…”

Childhood cancer and agricultural pesticide use: an ecologic study in California.

“…In contrast, block groups with the highest use of genotoxic pesticides had significantly lower rates of glioma. In animal studies, chemical exposures have been shown to increase and decrease both the incidence and size of tumors (45,46). We incorporated a large number of multiple comparisons into these analyses by testing many pesticide categories and cancer sites, which increased the likelihood of observing at least one statistically significant finding by chance.…”