Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000) / Chapter Skim
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4 Mechanisms of Developmental Toxicity
4 Mechanisms of Developmental Toxicity
Pages 58-87
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From page 58... ...
HISTORY OF DEVELOPMENTAL TOXICOLOGY: GROWTH OF A NEW FIELD Teratology, the study of abnormal development, has a long history, much of which is shared with developmental biology. Progress in experimentally determining the causes of abnormal development began in earnest in the nineteenth century and continued through the first half of the twentieth century.
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From page 59... ...
Knowledge about normal developmental processes was applied to understand abnormal development, the pathogenesis resulting in malformations. In the course of such investigations, various chemical and physical insults were used to perturb development to elucidate the underlying normal processes.
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From page 60... ...
, emphasizing the fact that abnormal development can manifest itself as subtle functional deficits and not just structural changes. Another heavy metal, mercury, also was identified as a human developmental toxicant after an epidemic of cerebral palsy with microcephaly in Minamata, Japan, was associated with the ingestion of fish contaminated with methyl mercury (Harada and Noda 1988~.
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From page 61... ...
2. "The final manifestations of abnormal development are death, malformation, growth retardation, and functional disorder." This principle highlights the now well-known fact that structural malformations are not the only possible outcome after the conceptus is exposed to a developmental toxicant.
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From page 62... ...
The final point to be made is that development from fertilization to birth is a progressive process so that any adverse outcome (i.e., death, growth retardation, malformation, or functional deficits) after exposure to developmental toxicants will be dictated, in part, by the set of developmental processes active at the time of exposure.
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From page 63... ...
Recent advances in research on signaling pathways and genetic regulatory circuits in development might have identified especially critical processes, ones that, if studied for their alteration by developmental toxicants, might provide exciting new clues for mechanistic investigations (see discussion in Chapters 6 and 7~. For now, such insights are available in only a few cases, such as toxicant interactions with components of the nuclear hormone-receptor family of signal receptors and gene regulators.
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From page 64... ...
and thus manifest impacts at the organ level. Yet other toxicants might cause cell death in the conceptus at a variety of times and locations and have multiple impacts.
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From page 65... ...
. Agents that interact with one or more of these receptors and are known to produce abnormal development include retinoic acid and synthetic retinoids, glucocorti
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From page 66... ...
Despite the few examples of toxicant interactions with membrane receptors, the mechanism might be important in understanding how certain chemicals disrupt development. Most normal developmental processes involve cell-cell signaling and are mediated by trans-membrane receptors, including inductions, cellmatrix interactions, cell proliferation, cell movement, and autocrine and paracrine effects.
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From page 67... ...
67 ca C)
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68 A ·_4 o ca C)
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From page 69... ...
site. Metals like mercury and cadmium are examples of developmental toxicants that cause oxidative stress and bind strongly to sulfhydryl groups and interfere with function (see reviews by Clarkson 1993; Stohs and Bagchi 1995; Quig 1998~.
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From page 70... ...
The events that take place within the embryo after toxicant-induced zinc deficiency are equivalent to those occurring during dietary deficiency, but the salient point for developmental toxicology and risk assessment is the recognition that maternal factors might contribute substantially to embryonic response. Other Mechanistic Considerations There are other mechanisms that might be found to affect development.
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From page 71... ...
The classes of function include altered · signal transduction. gene expression, patterns of apoptosis (programmed cell death)
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From page 72... ...
First, SHH is synthesized as a precursor that must be cleaved and covalently linked with cholesterol to be active (Roelink et al.1995; Porter et al.1996~. Second, SHH is necessary and sufficient for patterning the ventral neural tube (Tanabe and Jessell 1996~.
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From page 73... ...
is an anticonvulsant used to treat epilepsy. It produces abnormal development in fetuses whose mothers take the drug during pregnancy.
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From page 74... ...
1989~. It has been observed that DPH treatment in rodents decreases the expression of the mRNAs for a number of important growth factors, including TGF0, NT3 and WNT1 (Musselman et al.
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From page 75... ...
Retinoic Acid Vitamin A (retinol) and the structurally related retinoids have a special place in developmental toxicology, both currently and historically.
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From page 76... ...
binding proteins. A number of enzymes are capable of converting retinal to retinoic acid, including CYP monooxygenases, alcohol dehydrogenases, and aldehyde dehydrogenases.
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From page 77... ...
, rather than a transient high dose. The receptors for retinoids are of the nuclear hormone ligand-dependent transcription-factor superfamily (Nuclear Receptors Committee 1999~.
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From page 78... ...
1995~. It is intriguing that in both cases the receptor is not required for normal development of the affected tissues but does mediate the teratogenic action, a result indicating that the receptor, when activated by exogenously added RA, is affecting gene expression at abnormal times and places, as compared with that done by endogenous retinoids.
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From page 79... ...
The misexpressed HOX gene then activates and represses many other genes in abnormal places and thereby initiates abnormal development. Pathogenetic changes observed in retinoid
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From page 80... ...
For example, disruption of membranes, changes in phosphorylation, and increases in reactive oxygen species might play roles in retinoid teratogenicity. The significance of the retinoids in developmental toxicology might extend further, because a range of chemicals likely mediate their developmental toxicities by interfering with endogenous retinoid signaling.
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From page 81... ...
In organ culture, developing mouse and human embryo palates respond similarly to TCDD. Exposure to the chemical causes excessive epithelial cell proliferation, via several steps, which interferes with fusion of the opposing palatal shelves.
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From page 82... ...
is approximately 1,500 times lower in human embryo palates than in mouse palates under identical exposure conditions. Valproic Acid Valproic acid (VPA)
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From page 83... ...
1994~. Likewise, excessive teratogen-induced cell death is directly linked to abnormal development by the finding that 2-chloro-2'deoxyadenosine-induced eye defects are associated with excessive teratogen-induced cell death (Wubah et al.
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From page 84... ...
The ability of cells to perceive a stimulus or perturbation and then transduce these events into appropriate intracellular responses is commonly referred to as signal transduction. Although little is known about the interaction between developmental toxicants and signaling pathways in mammalian embryos, a recent report showed that heat shock can rapidly activate the stressactivated protein kinase pathways mediated by c-dun terminal kinase (JNK)
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From page 85... ...
(1996~. able to describe alterations of the human brain stem related to autism and to create an animal model of the initial insult using exposure to valproic acid (Rodier et al.
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From page 86... ...
SUMMARY Early researchers of the causes of abnormal development used many of the same methods and animal models as developmental biologists studying normal development. Knowledge about normal developmental processes was essential to understand the developmental pathogenesis induced by chemical and physical agents, and, reciprocally, such agents at that time were used to disrupt normal development in order to understand the processes.
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From page 87... ...
and cell biology (e.g., the cell cycle and checkpoint pathways) have identified critical processes, which, if investigated for their alteration by developmental toxicants, can provide exciting new advances in mechanistic investigations.
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