Cell Death and Reduced Proliferative Rate

ScottJr., William J.

doi:10.1007/978-1-4615-8933-4_4

Cited by 67 publications

(18 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data, coupled with those demonstrating the striking ability of embryos to compensate for cell loss (Snow and Tam, 1979), eliminated the contradictions pointed out by Scott (1977), suggesting that the apoptotic machinery is an important component of mechanisms that determine whether or not teratogen-induced early cytotoxicity culminates in maldevelopment. Therefore, there is intense interest in understanding how the apoptotic machinery functions in embryos exposed to embryopathic stresses.…”

Section: Introductionmentioning

confidence: 51%

“…This author presented a list of agents inducing the cytotoxic effect in embryonic structures destined to be malformed, comprised of more than 60 chemicals and physical factors, among which were such welldocumented teratogens as thalidomide, antineoplastic drugs, ethyl alcohol, hydroxyurea, X-radiation, hyperthermia, rubella, vitamin A excess and deficiency, and folate deficiency. Scott (1977) wrote that these observations hardly allow hesitation in attributing the malformation to early cytotoxicity. At the same time, he pointed out two items that he suggested cloud the issue: 1) agents that at high doses produce cell death and teratogenesis and at low doses continue to kill cells but do not produce malformations; and 2) many cytotoxic, teratogenic agents produce cell death in tissues that appear normal at birth.…”

Section: Introductionmentioning

confidence: 96%

“…As early as the 1960s and 1970s, considerable evidence was collected demonstrating that many chemical and physical developmental toxicants that induce structural anomalies also induce cell death in embryonic structures that turn out to be malformed in fetuses and newborns (Scott, 1977). This author presented a list of agents inducing the cytotoxic effect in embryonic structures destined to be malformed, comprised of more than 60 chemicals and physical factors, among which were such welldocumented teratogens as thalidomide, antineoplastic drugs, ethyl alcohol, hydroxyurea, X-radiation, hyperthermia, rubella, vitamin A excess and deficiency, and folate deficiency.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Teratogen-induced apoptotic cell death: Does the apoptotic machinery act as a protector of embryos exposed to teratogens?

2005

View full text Add to dashboard Cite

Considerable evidence has been collected demonstrating that many teratogens induce apoptotic cell death in embryonic structures that turn out to be malformed in fetuses and newborns. Apoptosis is a genetically regulated process that is realized by the activation of death and pro-survival signaling cascades, and the interplay between these cascades determines whether the cell exposed to apoptotic stimuli dies or survives. Therefore, there is intense interest in understanding how the apoptotic machinery functions in embryos exposed to teratogens. However, the interpretation of the results obtained remains problematic. The main problem is that excessive embryonic cell death, regardless of its nature, if uncompensated for, ultimately leads to maldevelopment or embryonic death. Therefore, we can easily interpret results when the intensity of teratogen-induced cell death and the severity or incidence of teratogen-induced anomalies directly correlate with each other. However, when teratogen-induced cell death is not followed by the formation of anomalies, a usual explanation is that teratogen-induced apoptotic cell death contributes to the renewal of teratogen-targeted cell populations by promoting the removal of injured cells. It is clear that such an explanation leaves vague the role of the anti-apoptotic signaling mechanism (and, hence, the apoptotic machinery as a whole) with respect to protecting the embryo against teratogenic stress. In this review, we summarize the data from studies addressing the function of the apoptotic machinery in embryos exposed to teratogens, and then we discuss approaches to interpreting the results of these studies. We hypothesize that activation of a proapoptotic signaling in teratogen-targeted cell populations is a necessary condition for an anti-apoptotic signaling that counteracts the process of maldevelopment to be activated. If such a scenario is true, we need to modify our approaches to choosing molecular targets for studies addressing this topic.

show abstract

Section: Introductionmentioning

confidence: 51%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Teratogen-induced apoptotic cell death: Does the apoptotic machinery act as a protector of embryos exposed to teratogens?

2005

View full text Add to dashboard Cite

show abstract

“…However, if oxidants cause embryonic defects by inducing cell death, then there must be some mechanism to explain how only some cells are killed while others are spared, despite equivalent exposure of all embryonic cells to the source of the oxidative stress. It has been noted that if embryonic cell death induced by teratogens (including oxidative stress) were severe, then the whole embryo would die, while comparatively mild teratogen exposure would kill only some cells [44]. In attempting to explain the localized nature of teratogen-induced malformations, it has been proposed that cells within the vicinity (temporally and spatially) of cells which die as part of a normal developmental program could be particularly vulnerable to teratogen-induced cell death [45].…”

Section: Discussionmentioning

confidence: 99%

Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects

et al. 2003

View full text Add to dashboard Cite

Aims/hypothesis. Maternal diabetes increases oxidative stress in embryos. Maternal diabetes also inhibits expression of embryonic genes, most notably, Pax-3, which is required for neural tube closure. Here we tested the hypothesis that oxidative stress inhibits expression of Pax-3, thereby providing a molecular basis for neural tube defects induced by diabetic pregnancy. Methods. Maternal diabetes-induced oxidative stress was blocked with α-tocopherol (vitamin E), and oxidative stress was induced with the complex III electron transport inhibitor, antimycin A, using pregnant diabetic or non-diabetic mice, primary cultures of neurulating mouse embryo tissues, or differentiating P19 embryonal carcinoma cells. Pax-3 expression was assayed by quantitative RT-PCR, and neural tube defects were scored by visual inspection. Oxidation-induced DNA fragmentation in P19 cells was assayed by electrophoretic analysis.Results. Maternal diabetes inhibited Pax-3 expression and increased neural tube defects, and α-tocopherol blocked these effects. In addition, induction of oxidative stress with antimycin A inhibited Pax-3 expression and increased neural tube defects. In cultured embryo tissues, high glucose-inhibited Pax-3 expression, and this effect was blocked by α-tocopherol and GSHethyl ester, and Pax-3 expression was inhibited by culture with antimycin A. In differentiating P19 cells, antimycin A inhibited Pax-3 induction but did not induce DNA strand breaks. Conclusion/interpretation. Oxidative stress inhibits expression of Pax-3, a gene that is essential for neural tube closure. Impaired expression of essential developmental control genes could be the central mechanism by which neural tube defects occur during diabetic pregnancy, as well as other sources of oxidative stress. [Diabetologia (2003) 46:538-545]

show abstract

“…Furthermore, there was no electron microscopic evidence of alterations in the protein synthetic machinery of the epithelial and mesenchymal cells of developing palatal primordia. Scott (1977) and Adhami (1979) suggested that if 6MP or its metabolites rapidly inhibited DNA synthesis the first morphologically demonstrable lesion could be expected within a few hours after drug administration. In the delayed cytologic response following 6MP administration, however, Tidd et al (1972) and Horakova and associates (1974) suggested that the cells must go through the DNA synthesis phase at least once.…”

Section: Discussionmentioning

confidence: 98%

Gross and cellular analysis of 6‐mercaptopurine‐induced cleft palate in hamster

Burdett

Shah

1988

Am. J. Anat.

View full text Add to dashboard Cite

The present study analyzes the morphological, histochemical, and ultrastructural aspects of the pathogenesis of 6-mercaptopurine (6MP)-induced cleft palate in hamster fetuses. Gross and light microscopic observations indicated that 6MP stunts the growth of vertical palatal shelves and thus induces cleft palate. Ultrastructural analysis showed that, in contrast to controls, 6MP-induced alterations were first seen in the mesenchymal cells 24 hr after drug administration. The initial alterations were characterized by swelling of the nuclear membrane. During the next 12 hr, lysosomes were seen first in the mesenchymal cells and then in the cells of the medial edge epithelium (MEE) of the developing palatal primordia. The appearance of lysosomes was temporally abnormal and was interpreted as a sublethal response to 6MP treatment. Subsequently, the nuclear alterations and the lysosomes diminished; and 48 hr after 6MP administration, they were absent from the palatal tissues. Ninety hours after 6MP administration, unlike the controls (in which the palatal shelves were already fused), changes were seen at the epithelial-mesenchymal interface in the developing cleft palatal shelves. These changes were characterized by breakdown of the basal lamina and epithelial-mesenchymal contacts. Eventually, at term, the MEE of the vertical shelf stratified. It was suggested that 6MP affected cytodifferentiation in the palatal tissues during the critical phase of early vertical shelf development and thereby induced cleft palate.

show abstract

Cell Death and Reduced Proliferative Rate

Cited by 67 publications

References 53 publications

Teratogen-induced apoptotic cell death: Does the apoptotic machinery act as a protector of embryos exposed to teratogens?

Teratogen-induced apoptotic cell death: Does the apoptotic machinery act as a protector of embryos exposed to teratogens?

Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects

Gross and cellular analysis of 6‐mercaptopurine‐induced cleft palate in hamster

Contact Info

Product

Resources

About