A Practical Approach, Second Edition=Ronald D. Ho.pdf

30 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONresultant cellular perturbations. (See discussion below on enzyme inhibition and how these mechanisticstudies were incorporated into a biologically based dose-response model.) These mechanisticstudies thus reveal the need for researchers to shift their investigations from one biological level— DNA and molecular level changes — to assessments at the cellular level. They might thusidentify critical rate-limiting processes that could more effectively explain the overall complexprocesses of nucleotide pool alterations and subsequent DNA synthesis perturbations.2. RadiationThe effects of radiation on fetal development, including the developmental effects of radiationinducedcell loss, have been well documented. 58,66–71 The effect of radiation on chromatid formationand cell cycling likely underlies radiation-induced cell cycle perturbations. 5 However, the variedeffects of radiation on DNA fidelity make it difficult to attribute radiation-induced teratogenicitysolely to effects on cycling cells. Among the DNA effects showing dose-response relationshipsfollowing radiation exposure are chromosome instability, single strand breaks, double strand breaks,DNA-protein cross-links, apoptosis, p53 activity, and mitotic inhibition. 72–75 The most sensitiveperiod for radiation-induced malformations is following day eight of organogenesis in the rat(corresponding to weeks 8 to 25 in the human fetus), during the period of maximal proliferationof neuronal precursors. Exposure (e.g., 100 Rd in the rat) prior to organogenesis can cause eitherfetal death or have no effect. Exposure during organogenesis results in decreased weight andthickness of cortical layers, formation of ectopic structures, and microcephaly. CNS effects arenoted if exposure takes place late in gestation, reflecting the extended period of sensitivity ofnervous system development (see reviews by Brent, 76 Beckman and Brent, 77 and Kimler 67 ).3. Antitubulin AgentsPerturbations in the mitotic spindle may result in cytoskeletal disruption, aneuploidy, micronuclei,alterations in cell division rate, cell cycle arrest, and/or cell death. The coincidence of these typesof toxicological manifestations is indicative of antimitotic agents that affect tubulin. 78 Classicantitubulin agents, such as benzimidazoles, carbamates, and colchicine, have been demonstrated toelicit aneuploidy 79–86 and developmental toxicity both in vivo (reviewed in Delatour and Parish, 87Ellis et al., 88 and Van Dyke 89 ) and in vitro. 78,90 These studies used dose-response relationships andstructure-activity information to strengthen the support for mitotic perturbations as the mechanismof action by which these agents cause developmental toxicity. Other methodological approachesused in these studies were comparisons across species that revealed significant cross-speciesdifferences in tubulin binding affinities that were related to their differing potency as toxicants indifferent species.4. MethylmercuryNumerous mechanisms have been proposed by which methylmercury (MeHg) may disrupt normalcell function, and these mechanisms are postulated to result in neurodevelopmental toxicity. Most,if not all, are associated with the exceptional affinity of MeHg for the thiol group, with theassociation constant of the Hg-SH pair being orders of magnitude greater than MeHg’s interactionwith any other ligand. 91 MeHg may interfere with the proper functioning of cells by disrupting thethiol bond–mediated structure and the function of key proteins or other molecules. While this ideais mechanistically a very simple concept, the numerous affected pathways may include (1) disruptionof protein synthesis, 92–94 (2) disruption of cellular energy production, 95–97 (3) disruption ofintracellular calcium levels, 98,99 particularly in the mitochondria, (4) disruption of microtubuleassembly and cellular division and transport, 100–104 and (5) induction of oxidative stress, either© 2006 by Taylor & Francis Group, LLC