Inhibition of Programmed Cell Death in Mouse Embryonic Palate in Vitro by Cortisol and Phenytoin: Receptor Involvement and Requirement of Protein Synthesis

Goldman, Alvin I.; Baker, Mary K.; Piddington, Ronald; Herold, Richard

doi:10.3181/00379727-174-41731

Cited by 38 publications

(13 citation statements)

References 13 publications

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“…Phospholipase A2 catalyzes the release of arachidonic acid from its position on the number 2 carbon of phospholipids; an increase in PLIP therefore sharply decreases the availability of arachidonic acid. This sequence has been verified by experiments that demonstrate that specific blockade of the cytosolic glucocorticoid receptor or provision of exogenous arachidonic acid will act to prevent the malformation (28)(29)(30). In this system, arachidonic acid availability for prostaglandin synthesis appears to be of major importance, since indomethacin will reverse the protective effects of exogenous arachidonic acid (28,29).…”

Section: Discussionmentioning

confidence: 86%

Hyperglycemia-induced teratogenesis is mediated by a functional deficiency of arachidonic acid.

Goldman¹,

Baker²,

Piddington³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

173

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Congenital malformations now represent the largest single cause of mortality in the infant of the diabetic mother. The mechanism by which diabetes exerts its teratogenic effects is not known. This study evaluated whether arachidonic acid might be involved, a possibility raised by the role of arachidonic acid in palatal elevation and fusion, processes analogous to neural tube folding and fusion. This hypothesis was tested in two animal models of diabetic embryopathy, the in vivo pregnant diabetic rat and the in vitro hyperglycemic mouse embryo culture. The subcutaneous injection of arachidonic acid (200-400 mg/kg per day) into pregnant diabetic rats during the period of organ differentiation (days 6-12) did not alter the maternal glucose concentration, the maternal weight gain, or the weight of the embryos. However, the incidence of neural tube fusion defects was reduced from 11% to 3.8% (P < 0.005), the frequency of deft palate was reduced from 11% to 4% (P < 0.005), and the incidence of micrognathia was reduced from 7% to 0.8% (P < 0.001). The addition of arachidonic acid to B10.A mouse embryos in culture also resulted in a reversal of hyperglycemiainduced teratogenesis. The teratogenic effect of D-glucose (8 mg/ml) in the medium resulted in normal neural tube fusion in only 32% of the embryos (P < 0.006 when compared to controls). Arachidonic acid supplementation (1 or 10 jug/ml) produced a rate of neural tube fusion (67%) that was not significantly different from that observed in controls. The evidence presented indicates that arachidonic acid supplementation exerts a significant protective effect against the teratogenic action of hyperglycemia in both in vivo (rat) and in vitro (mouse) animal models. These data therefore suggest that the mechanism mediating the teratogenic effect of an increased glucose concentration involves a functional deficiency of arachidonic acid at a critical stage of organogenesis.Although major advances have been made over the past 20 years in the prognosis of the newborn infant of the diabetic mother, no appreciable improvements have been noted in the rates of malformations seen in these infants (1, 2). Malformations have now become the leading cause of death in infants of diabetic mothers (3). Although the lesion most specific for human maternal diabetes is the caudal regression syndrome (4), spina bifida, hydrocephalus, anencephaly, and other central nervous system defects also occur at a high rate (5). This had led to studies of diabetic embryopathy focused on animal models of failure of neural tube folding and fusion. These defects can be produced by exposing either rat or mouse embryos to high concentrations of glucose in vitro, thus demonstrating that increased glucose levels alone are sufficient to produce malformations (6, 7). However, the mechanism linking hyperglycemia with malformations remains unknown. In this paper, we present evidence that exogenous arachidonic acid exerts a highly significant protective effect against the teratogenic action of hyperglycemia i...

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Section: Discussionmentioning

confidence: 86%

Hyperglycemia-induced teratogenesis is mediated by a functional deficiency of arachidonic acid.

Goldman¹,

Baker²,

Piddington³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

173

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show abstract

“…Phospholipase A2 catalyzes the release of arachidonic acid from its position on the number 2 carbon of phospholipids; and an increase in PLIP therefore sharply decreases the availability of arachidonic acid. This sequence has been verified by experiments that demonstrate that either specific blockade of the cytosolic glucocorticoid receptor or provision of exogenous arachidonic acid will act to prevent the malformation (12,13,33). In this system, arachidonic acid availability for prostaglandin synthesis appears to be of major importance, since indomethacin will reverse the protective effects of exogenous arachidonic acid (12,13).…”

Section: Discussionmentioning

confidence: 91%

The arachidonic acid cascade is involved in the masculinizing action of testosterone on embryonic external genitalia in mice.

Gupta¹,

Goldman²

1986

Proc. Natl. Acad. Sci. U.S.A.

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We have evaluated whether the arachidonic acid cascade may be involved in the folding and fusion of the penis and scrotum in masculine differentiation, a possibility raised by recent observations of the involvement of the arachidonic acid cascade in the analogous embryonic processes of elevation and fusion of the palatal shelves and of folding and fusion of the neural tube. To test this hypothesis, during embryonic masculine differentiation in mice of the B1O.A strain, we administered certain agents that produce blockade of masculinization. We report that arachidonic acid can reverse the inhibition of masculine development in male embryos produced by estradiol-17/8 or by cyproterone acetate, an androgen receptor-site blocker, and that such reversal can be prevented by an inhibitor of cyclooxygenase, such as indomethacin. We have also found that agents that block the arachidonic acid cascade at the level of phospholipase A2 (cortisone, phenytoin) or at the level of cyclooxygenase (indomethacin, aspirin) also block masculine differentiation and that such antimasculinization is reversed by arachidonic acid. The masculinization of male embryos is inhibited by indomethacin and aspirin, and the masculinization of female embryos produced by exogenous testosterone is prevented by indomethacin. These findings provide evidence that the mechanism by which testosterone organizes the genitalia involves a role of the arachidonic acid cascade leading to prostaglandins at a critical period of development and that interference with testosterone synthesis or action leads to a teratogenic deficiency of arachidonic acid during this time in the genital anlagen.Mammalian embryos of either genetic sex have initially an indifferent genital tubercle, which develops into a penis and scrotum, if there is a functioning embryonic testis or if there is not, by administration of testosterone to the mother; otherwise, the inborn female program is expressed (1). Agents that interfere with the synthesis (e.g., estradiol-17/3), circulation, or action of testosterone (e.g., cyproterone acetate) block masculine differentiation of the genitalia of genetically male embryos, as manifested by the production of hypospadias-i.e., a displacement of the urethral orifice down the shaft of the penis from the tip with a shortening of the anogenital distance (2-10). The means by which testosterone organizes masculine differentiation of the genitalia in the embryo depends on classical androgen hormonal receptor mechanisms (5, 9, 11). However, the precise steps involved in this organizing action of testosterone in the embryo are not known.A clue to the possible nature of these steps has been given by evidence (12,13) suggesting that the arachidonic acid cascade leading to prostaglandins may be involved in the elevation and fusion of the embryonic shelves in differentiation of the palate. This suggestion is based on the findings that (i) arachidonic acid reverses both the incidence of cleft palate induced in mice and rats by glucocorticoids in vivo and th...

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“…Additionally, apoptosis plays a pivotal role in embryogenesis and in development (Hinchliffe, 1981;Goldman et al, 1983;Nishikawa et al, 1989). Recent studies suggest that an elevation of cellular calcium is a central event in the activation of a calcium-magnesium-dependent endonuclease which cleaves DNA at regular internucleosomal sites resulting in 180 base pair integer oligonucleosomal fragments (Cohen & Duke, 1984;McConkey et al, 1989a-c andOrrenius et al, 1988Orrenius et al, , 1989.…”

Section: How Do Cells Die?mentioning

confidence: 99%

Drug-target interactions: only the first step in the commitment to a programmed cell death?

Dive

Hickman²

1991

Br J Cancer

366

162

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Inhibition of Programmed Cell Death in Mouse Embryonic Palate in Vitro by Cortisol and Phenytoin: Receptor Involvement and Requirement of Protein Synthesis

Cited by 38 publications

References 13 publications

Hyperglycemia-induced teratogenesis is mediated by a functional deficiency of arachidonic acid.

Hyperglycemia-induced teratogenesis is mediated by a functional deficiency of arachidonic acid.

The arachidonic acid cascade is involved in the masculinizing action of testosterone on embryonic external genitalia in mice.

Drug-target interactions: only the first step in the commitment to a programmed cell death?

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