Distribution and metabolism of triamcinolone acetonide in inbred mice with different cleft palate sensitivities

Zimmerman, Ernest F.; Bowen, Donna

doi:10.1002/tera.1420050308

Cited by 37 publications

(4 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Glucocorticoids can cross the rodent placenta without being metabolized. When administered in pharmacologic doses to pregnant mice, a large fraction of the administered steroid reached embryos unmetabolized and appeared to function as the active teratogenic agent (22).…”

Section: Glucocorticoid-induced Cleft Palatementioning

confidence: 99%

Receptor-dependent mechanisms of glucocorticoid and dioxin-induced cleft palate.

Pratt¹

1985

Environ Health Perspect

View full text Add to dashboard Cite

Glucocorticoids (triamcinolone) and dioxins (TCDD) are highly specific teratogens in the mouse, in that cleft palate is the major malformation observed. Glucocorticoids and TCDD both readily cross the yolk sac and placenta and appear in the developing secondary palate. Structure-activity relationships for glucocorticoid-and TCDD-induced cleft palate suggest a receptor involvement. Receptors for glucocorticoids and TCDD are present in the palate and their levels in various mouse strains are highly correlated with their sensitivity to cleft palate induction. Receptors for glucocorticoids appear to be more prevalent in the palatal mesenchymal cells whereas those for TCDD are probably located in the palatal epithelial cells. Glucocorticoids exert their teratogenic effect on the palate by inhibiting the growth of the palatal mesenchymal cells whereas TCDD alters the terminal cell differentiation of the medial palatal epithelial cells. Glucocorticoid-Induced Cleft PalateGlucocorticoids administered to several species of experimental animals at midgestation inhibit complete formation of the secondary palate (1-4). Development of the mammalian secondary palate is a complex process that depends upon the presence of various hormones and growth factors (5). The palatal shelves first appear as outgrowths from the maxillary process and subsequently grow in a vertical position alongside the tongue. The shelves undergo a rapid reorientation to the horizontal position above the tongue which brings the apposing epithelia into contact at the midline. The medial epithelial cells then undergo a programmed cell death with resorption ofthe basement membrane and cell remnants, and the two shelves fuse into a single tissue, the secondary palate, which separates the oral and nasal cavities (6,7).Different strains of inbred mice exhibit different degrees of susceptibility to glucocorticoid-induced cleft palate (1,8 (5,11,12). Walker and Fraser (6) showed that during normal development, the palatal shelves became horizontal later in the A/J than the C57BL/6J strain and suggested that this difference makes A/J mice more susceptible to cortisone than C57BL/6J mice (13). A recent study utilizing frozen sections (14) showed that, in addition to delaying palatal shelf elevation, cortisone treatment severely reduced the extent of contact between the palatal shelves in A/J mice. Although contact was present in 20% of the cortisone-treated fetuses, the mean area of the shelf contact was only 20% of that in control palates. Therefore, the net shelf contact in cortisone-treated litters was only 4% of the potential contact in control litters. Other studies in which shelf contact was assessed in glucocorticoid-treated fetuses reported contact in 27-30% of the fetuses. However, this limited contact, observed between the shelves in the midpalate region, was considered adequate for complete palatal fusion, and a failure in the fusion mechanism was proposed as an alternative (4,15). Diewert and Pratt (14) also observed shelf contact in the midpalate re...

show abstract

Section: Glucocorticoid-induced Cleft Palatementioning

confidence: 99%

Receptor-dependent mechanisms of glucocorticoid and dioxin-induced cleft palate.

Pratt¹

1985

Environ Health Perspect

View full text Add to dashboard Cite

show abstract

“…The rat EDs0 for cleft palate induction by TAC appears to be similar to doses required to produce this level of effect in A/J mice [9] but is lower than that for C3H mice [9,10], although no EDs0 calculations were reported in the mouse studies. The rat EDs0 for TA is higher than that for hamsters [6].…”

Section: Discussionmentioning

confidence: 80%

Comparative teratogenicity of triamcinolone acetonide, triamcinolone, and cortisol in the rat

Rowland

Hendrickx

1983

Teratog. Carcinog. Mutagen.

View full text Add to dashboard Cite

Pregnant rats were injected im with 0.5 mg/kg triamcinolone acetonide (TAC) on day 12, 13, or 14 of gestation and the fetuses were examined for cleft palate on day 20. All three TAC-treated groups showed an increased proportion of fetuses with cleft palate compared to an untreated control group. Only the group treated on day 13 showed a significant increase in the proportion of litters affected. This indicates that day 13 of gestation is the most sensitive day for cleft palate induction by TAC in the rat. Pregnant rats were then treated on day 13 of gestation with either TAC, triamcinolone (TA), or cortisol. TAC was 59 times as potent as TA in inducing cleft palate, with ED50 values of 1.1 mg/kg and 65 mg/kg respectively. Cortisol induced a significant increase in cleft palates at 500 mg/kg, but the efficacy of this compound was too low to calculate an ED50 and relative teratogenic potency value. Other developmental abnormalities including umbilical hernias, resorption, and fetal death resulted from TAC treatment. Fetal growth retardation was produced by all three compounds. The rank order of teratogenic potency was determined to be TAC greater than TA greater than cortisol.

show abstract

“…They furthermore showed that the resistant CBA strain metabolized the drug faster than A/Jax and C3H mice [15], As a consequence of the increased maternal metabolism of the drug, the level of the unmetabolized drug was less in CBA embryos compared to A/Jax and C,H embryos and they con cluded that this was the reason for the low incidence of corticosteroidinduced cleft palates in the CBA strain. However, it was not possible to explain the greater resistance of C3H as compared to A/Jax to an increased metabolism of the drug.…”

Section: Discussionmentioning

confidence: 97%

“…It was suggested that genetic differences in the metabolism and/or tissue binding were responsible for the observed differences and that the higher percentage of the injected dose found in the A/Jax fetuses would allow a higher concentration of the teratogen at the receptor site. Several studies using labelled corticosteroids have been performed to further test this hypothesis [9,10,12,14,15].…”

Section: Introductionmentioning

confidence: 99%

<sup>3</sup>H-Corticosterone Incorporation in CBA and Transferred A/Jax Embryos in CBA Mothers

Marsk¹,

Ranning²,

Larsson³

1974

Neonatology

View full text Add to dashboard Cite

The ³H-corticosterone incorporation in mouse embryos of resistant and sensitive mouse strains was studied using blastocyst transfer technique. There was no greater incorporation of the labelled corticosteroid in the sensitive A/Jax embryos transferred as blastocysts compared to native CBA embryos in the CBA mothers. These results do not support the hypothesis that a difference in concentration of teratogen at the receptor site should be the reason for a strain difference in cortisone-induced cleft palate in the A/Jax and CBA strains. Studies with various labelled corticosteroids given at various stages of embryonic development and measured by different methods are discussed in order to find an explanation for the strain difference in drug-induced malformations.

show abstract

Distribution and metabolism of triamcinolone acetonide in inbred mice with different cleft palate sensitivities

Cited by 37 publications

References 13 publications

Receptor-dependent mechanisms of glucocorticoid and dioxin-induced cleft palate.

Receptor-dependent mechanisms of glucocorticoid and dioxin-induced cleft palate.

Comparative teratogenicity of triamcinolone acetonide, triamcinolone, and cortisol in the rat

<sup>3</sup>H-Corticosterone Incorporation in CBA and Transferred A/Jax Embryos in CBA Mothers

Contact Info

Product

Resources

About