Mechanisms Underlying Children’s Susceptibility to Environmental Toxicants

Could prenatal DES- exposure be responsible for more birth defects than actually reported ?


Identification, characterization, and control of environmental chemicals that adversely impact normal reproduction and development continue to be key public health goals. Approximately 250,000 U.S. children are born each year with birth defects diagnosed at or shortly after birth. Birth defects are the leading cause of infant mortality in the United States. Congenital anomalies, sudden infant death syndrome, and premature birth combined account for more than 50% of all infant mortality, yet the cause of most birth defects is unknown. Approximately 3-10% have been attributed to exogenous and environmental agents. Those environmental agents known to cause birth defects include lead; polychlorinated biphenyls; ethanol; organic mercury; and drugs such as thalidomide, diethylstilbestrol, valproic acid, and 13-cis-retinoic acid. Most of these agents have been identified as developmental toxicants after tragic human exposures occurred.

Dose-Response Considerations for Mechanisms of Susceptibility

The developing nervous system also provides an excellent illustration of the role of dose-response relationships in susceptibility. For example, classic studies with radiation exposures in the rat have shown steep dose-response relationships for brain malformations where a doubling of dose (50-100 rads) on day 9 of rodent gestation can cause a greater than 4-fold increase in rat brain malformations (9-41% incidence). At 200 rads, a 78% incidence of brain malformations was observed. On day 10, one day later in gestation, exposure to 50 rads does not produce brain malformations. Exposure to 100 rads produces only a 3% incidence, but exposure to 200 rads produces a 19% incidence. If exposure occurs earlier, on day 8, neither exposure to 50 nor 100 rads produces brain malformations. These observations convey the significance of evaluating both the dose and the timing of exposure to determine the stage and process of development that will be impacted. The relevancy of these observations is known for radiation exposure in humans, where irradiation of the human fetus at doses of 100 rads early in pregnancy can cause brain malformations such as microcephaly and mental retardation.

Cross-species comparison studies assessing methyl mercury exposure have been able to show consistent effects on neuronal cell number, differentiation, and morphologic organization at similar doses. In both examples, radiation and methyl mercury exposure altered cell number and cell division; these impacts have been postulated as modes of action for the observed adverse effects in neuronal development. The potential implications of such observations are evident when evaluated in context with research showing that altered cell proliferation and focal neuropathologic effects have been linked with specific neurobehavioral deficits (e.g., autism).


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