Differentiation of cyclophosphamide‐treated hamster secondary palate: Ultrastructural and biochemical observations

Shah, Ravindra M.

doi:10.1002/aja.1001870102

Cited by 9 publications

(18 citation statements)

References 65 publications

(75 reference statements)

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“…Thus, in comparison to normal development, the appearance of lysosomes in the BrdU-treated palatal cells was abnormal. A similar abnormal lysosomal response following BrdU-treatment has been observed in several other tissues (Abbott et al, 1972;Wrathall et al, 1973;Tancer and Brachet, 1973;Endo and Hu 1974;ONeill and Stockdale, 1974;Ho et al, 1977;Garcia et al, 1979;Tone et al, 1983;Bannigan, 1985) and in cleft palate induced by other chemicals Burdett and Shah, 1988;Shah, 1989).…”

Section: Discussionmentioning

confidence: 65%

“…Ferguson (1977) noted mesenchymal cell death in the developing rat palate following 5-f luoro-2-desoxyuridine treatment. In addition, other changes, such as fragmentation and loss of basal lamina, and the epithelial-mesenchymal communications in the developing palate seen following exposure to many teratogens (for review see Burdett and Shah, 1988;Shah, 1989) were absent following BrdU treatment (present study). Clearly, the species, chemical nature of the teratogen, various maternal, placental, and fetal pharmacokinetic aspects, and the metabolic state of the developing palatal tissues at the time of drug administration are critical in determining the differing tissue responses.…”

Section: Discussionmentioning

confidence: 70%

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Pathogenesis of bromodeoxyuridine‐induced cleft palate in hamster

1991

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In the present study, the morphological, histochemical, biochemical, and cellular aspects of the pathogenesis of bromodeoxyuridine (BrdU)-induced cleft palate in hamster fetuses were analyzed. Morphological observations indicated that BrdU interferes with the growth of the vertical shelves and thus induces cleft palate. At an ultrastructural level, BrdU-induced changes were first seen in the mesenchymal cells. Eighteen hours after drug administration, the initial alterations were characterized by swelling of the nuclear membrane and the appearance of lysosomes in the mesenchymal cells of the roof of the oronasal cavity. During the next 6 hr, as the palatal primordia developed, lysosomes were also seen in the overlying epithelial cells. The appearance of lysosomal activity, which was verified by acid phosphatase histochemistry, was temporally abnormal and was interpreted as a sublethal response to BrdU treatment. Later the cellular alterations subsided; 48 hr after BrdU treatment, they were absent in both the epithelial and mesenchymal cells of the vertically developing palatal shelves. Subsequently, unlike controls (in which the palatal shelves undergo reorientation and fusion), the BrdU-treated shelves remained vertical until term. Biochemical determination of DNA synthesis indicated that although there was an inhibition of DNA synthesis at the time of appearance of palatal primordia, a catch-up growth during the ensuing 12 hr may have restored the number of cells available for the formation of a vertical palatal shelf. It was suggested that BrdU affected cytodifferentiation in the palatal tissues during the critical phase of early vertical development to induce a cleft palate.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 70%

Pathogenesis of bromodeoxyuridine‐induced cleft palate in hamster

1991

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“…The lysosomal response observed following hadacidin treatment may thus be interpreted as a protective response. A similar proposition has been also made for the effects of other chemicals on embryonic tissues, including palate (Theodosis and Fraser, 1978;Shah et al, 1984Shah et al, ,1991Shah, 1990).…”

Section: Discussionmentioning

confidence: 61%

“…Briefly, these were stage 1, appearance of the palatal primordia from the roof of the mouth; stage 2, vertical development of the palatal shelf; stage 3, horizontal shelves; and stage 4, fused shelves. The gross and histological appearances of these stages of palatal development in hamster have been documented repeatedly in the literature (Shah and Travill, 1976a;Shah 1979cShah , 1984Shah , 1990. Hence, for the sake of brevity, they are not shown in the present study.…”

Section: Controlmentioning

confidence: 77%

“…This morphological mechanism differs from the development of cleft palate following treatment with several other teratogens where either the reorientation of the shelves was delayed, or fusion between the shelves was prevented, or the shelves ruptured following fusion (Walker and Fraser, 1957;Kitamura, 1966;Angelici, 1968;Dostal and Jelinek, 1972;Shah and Travill, 1976a;Ferguson, 1977;Shah, 1979cShah, , 1990Shah and Wong, 1980;Kiso et al, 1984;Shah et al, 1989a-c).…”

Section: Discussionmentioning

confidence: 95%

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Genesis of hadacidin‐induced cleft palate in hamster: Morphogenesis, electron microscopy, and determination of DNA synthesis, cAMP, and enzyme acid phosphatase

et al. 1991

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A morphological, electron microscopic, and biochemical study was undertaken to analyze the genesis of hadacidin-induced cleft palate in hamster fetuses. Gross and light microscopic observations indicated that hadacidin affected the growth of vertical palatal shelves to induce cleft palate. Electron microscopic observations showed that initial hadacidin-induced changes were seen in the mesenchymal cells. Within 12 hr of drug administration, the perinuclear space was swollen and a lysosomal response injury was evident in the mesenchymal cells. Subsequently, 24 hr after hadacidin treatment, lysosomes appeared in the epithelial cells; changes were also seen in the basal lamina which included separation of the lamina densa from the basal cells, duplication of lamina densa, and complete loss of basal lamina. Between 36 and 42 hr post-treatment, the cellular and basal lamina changes subsided, and the epithelium of vertical shelves underwent stratification. Biochemical determination of enzyme acid phosphatase indicated that the levels of enzyme activity in both the control and treated palatal tissues corresponded to the appearance of lysosomes. Measurement of cAMP levels suggested that the peak activity of cAMP corresponded to that of enzyme acid phosphatase and cell injury. The cAMP activity in hadacidin-injured cells, however, was significantly lower in comparison to that of the dying cells of control palates. Hadacidin treatment also affected DNA synthesis in the developing primordia of the palate. It was suggested that hadacidin injures the precursor cells of the palate prior to the appearance of the primordia, and subsequently affects their proliferative behavior, stunting the vertical growth of the palatal shelves and inducing a cleft palate.

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Cell‐cycle alterations underlie cyclophosphamide‐induced teratogenesis in the chick embryo

Heringová

Jelínek

Dostál

2003

Birth Defects Research

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CP-induced cytotoxicity manifested by dose-dependent disturbance of cell-cycle resulted in an overall depression of proliferation activity clearly associated with the occurrence of malformations and embryonic death. Although a non-significant depression of mitotic activity appeared sufficient to produce malformations on Day 2, remarkably deeper disturbance was needed to interfere with the development of the embryos in more advanced stages. Changes in proliferation rate appear to be a primary and most important event in teratogenesis induced by general toxic agents.

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Differentiation of cyclophosphamide‐treated hamster secondary palate: Ultrastructural and biochemical observations

Cited by 9 publications

References 65 publications

Pathogenesis of bromodeoxyuridine‐induced cleft palate in hamster

Pathogenesis of bromodeoxyuridine‐induced cleft palate in hamster

Genesis of hadacidin‐induced cleft palate in hamster: Morphogenesis, electron microscopy, and determination of DNA synthesis, cAMP, and enzyme acid phosphatase

Cell‐cycle alterations underlie cyclophosphamide‐induced teratogenesis in the chick embryo

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