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Maternally-Mediated Effects on Development*
Citation:
Hood, R. D. AND J. M. ROGERS. Maternally-Mediated Effects on Development*. 3rd, Chapter 4, R.D. Hood (ed.), Developmental and Reproductive Toxicology: A Practical Approach. Informa Healthcare, London, Uk, 1:60-74, (2011).
Impact/Purpose:
In standard laboratory dose-response assays for developmental toxicity of chemicals, test animals (rodents, rabbits) are dosed during pregnancy and fetuses are removed and examined prior to birth. Guidelines for such studies require some evidence of maternal toxicity at the highest dosage used, as a formoflimittest. Often,developmental(i..e.,fetal)effectsareobservedonlyatdosagesalsocausing toxicity to the mother. Such maternal toxicity may be coincidental but may also be causal to the developmental effects observed. In the latter case, such developmental toxicity would not likely be observedinhumansexposedto muchlowerdosages.Thus,interpretation ofdevelopmentaltoxicity occurring only at dosages toxic to the mother is difficult, and determining the relationship between maternal and developmental toxicities requires further experimentation. Further, any chemical at high enough dosage is likely to cause a stress response in the maternal animal, and much work has been done to elucidate the adverse developmental effects of maternal stress. This chapter covers the literature of the past several decades related to the effects of maternal toxicity and maternal stress in developmental toxicity bioassays,and considerations for interpreting such effects for human risk assessments
Description:
In standard Segment II mammalian bioassays for developmental toxicity, it is the pregnant animal that is exposed to the test article, so in this sense, all in utero developmental toxicity is mediated by the mother. This will include absorption, distribution, metabolism and excretion of administered chemicals, but may also include pharmacodynamic effects on the mother. In this chapter, we define maternally-mediated effects on development as those adverse consequences to the developing conceptus that occur secondarily as a result of an untoward effect on the pregnant mother. They differ from direct effects on the conceptus primarily in their immediate source, rather than the end result. Since likely mechanisms for maternally-mediated effects are more limited in number than are direct-acting mechanisms, the range of consequences to the offspring may also be more limited. Nevertheless, as pointed out by Daston, I because there are multiple mechanisms by which maternally-mediated effects may occur, it is unlikely that they would result in a consistent, limited spectrum of effects on the offspring.