Human foetal palatal corticoid receptors and teratogens for cleft palate

Goldman, Alvin I.; Shapiro, Barry A.; Katsumata, Masuyuki

doi:10.1038/272464a0

Cited by 66 publications

(17 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The incidence of fetal deaths in treated pregnancies does not exceed that predicted for the general population [39]. Importantly, no cases have been reported of cleft palate, placental degeneration or fetal death, which have been observed in a rodent model of in utero exposure to high-dose glucocorticoids [40]. …”

Section: Outcome Of Prenatal Treatmentmentioning

confidence: 99%

Prenatal Diagnosis and Treatment of Congenital Adrenal Hyperplasia

Nimkarn

New

2006

Horm Res Paediatr

View full text Add to dashboard Cite

Congenital adrenal hyperplasia is a group of inherited disorders caused by an enzyme deficiency in steroid biosynthesis. The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency, which in its severe form can cause genital ambiguity in females. Steroid 21-hydroxylase deficiency can be diagnosed in utero through molecular genetic analysis of fetal DNA. Prenatal treatment successfully reduces genital ambiguity, and the subsequent problems of sex misassignment and gender confusion. Data from current studies show that prenatal diagnosis and treatment are safe for the mother and the fetus. The evidence also suggests that it is safe over the long term, but all subjects exposed to dexamethasone treatment during embryonic and fetal life should have their physical, cognitive and emotional developments recorded.

show abstract

Section: Outcome Of Prenatal Treatmentmentioning

confidence: 99%

Prenatal Diagnosis and Treatment of Congenital Adrenal Hyperplasia

Nimkarn

New

2006

Horm Res Paediatr

View full text Add to dashboard Cite

show abstract

“…Dexamethasone is a known teratogen and fetotoxicant (27)(28)(29)(30)(31)(32)(33)(34). We observed that at a maternal dose of 15 mg/kg of dexamethasone, embryos from Ahr Ϫ/Ϫ dams exhibited a 9-fold higher level of mortality than those from Ahr ϩ/ϩ dams (p Ͻ 0.0006, Fig.…”

Section: Resultsmentioning

confidence: 58%

A Maternal Ahr Null Genotype Sensitizes Embryos to Chemical Teratogenesis

Thomae

Glover

Bradfield

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

The aryl hydrocarbon receptor (encoded by the Ahr locus) is a ligand-activated transcription factor that mediates the toxicology and teratology of 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin). In an effort to understand the role of the maternal compartment in dioxin teratology, we designed a breeding strategy that allowed us to compare the teratogenic response in embryos from Ahr ؊/؊ (null) and Ahr ؉/؉ (wild-type) dams. Using this strategy, we demonstrate that embryos from the Ahr ؊/؊ dams are 5-fold more sensitive to dioxin-induced cleft palate and hydronephrosis as compared with embryos from an Ahr ؉/؉ dam. Moreover, this increased teratogenic sensitivity extends beyond dioxin, because embryos from Ahr ؊/؊ dams exhibited a 9-fold increase in their sensitivity to the fetotoxic effects of the glucocorticoid, dexamethasone. In searching for an explanation for this increased sensitivity, we found that more dioxin and dexamethasone reached the embryos from Ahr ؊/؊ dams as compared with embryos from Ahr ؉/؉ dams. We propose that increased deposition of teratogens/fetotoxicants to the embryonic compartment is the result of porto-systemic shunting and/or blocked P4501A induction in Ahr ؊/؊ dams. In addition to demonstrating the importance of maternal AHR in teratogenesis, these data may have implications that reach beyond the mechanism of action of dioxin. In this regard, the Ahr ؊/؊ mouse may provide a system that allows pharmacological agents and toxicants to be more easily studied in a model where first pass clearance is a significant obstacle.Chemical teratogens can perturb normal mammalian development through direct action on the embryo, indirectly through maternal toxicity, or as the result of a combination of both of these mechanisms. The maternal compartment can afford protection by functioning as a metabolic or physical barrier that reduces embryonic exposure to a given agent (1). The maternal compartment also holds the potential to serve as a site of teratogen bioactivation and may serve to increase the concentrations of active metabolites that directly perturb normal embryonic development (2, 3). Understanding the relative contributions of maternal and embryonic physiology for a given teratogen can be difficult, especially when chemical agents induce a variety of teratogenic end points or display remarkable pharmacological potency.One approach to understanding the relative contributions of the maternal and embryonic physiology is to define these two compartments via their respective genotypes. Such an approach is particularly powerful when working with null alleles that have been generated via gene targeting. In such cases, the dominance order is clear, as is the functional relationship between one or two copies of the wild-type allele. Through appropriate genetic crosses one can then generate informative combinations of maternal and embryonic genotypes that can help identify when maternally or embryonically expressed loci play a differential role in the teratogenic response to a specific chemical (4).Based...

show abstract

“…Intrauterine growth retardation and unexplained fetal death have been observed in 2% or less of treated pregnancies, which is not significantly different from the percentage found in the population at large [29]. The risk of overt human fetal defects appears to be low compared with complications observed in a rodent model of in utero exposure to high-dose glucocorticoids, which features frequent cleft palate in addition to fetal growth retardation and/or demise [30]. Pregnant rats treated with the same dexamethasone weight-based dose used in human prenatal treatment for CAH, i.e.…”

Section: Prenatal Treatment: Outcomes and Risksmentioning

confidence: 84%

Prenatal and Early Postnatal Treatment of Congenital Adrenal Hyperplasia

Ghizzoni¹,

Cesari²,

G³

et al. 2007

Congenital Endocrinopathies

View full text Add to dashboard Cite

Congenital adrenal hyperplasia is a group of monogenic autosomal recessive disorders due to an enzyme deficiency in steroid biosynthesis. The most frequent form of congenital adrenal hyperplasia is 21-hydroxylase (21-OH) deficiency, which in its severe form can cause ambiguous genitalia in the female patient. Recent advances in molecular genetic analysis allow for prenatal diagnosis and treatment of at-risk fetuses. The objective of prenatal diagnosis and treatment of 21-OH deficiency is the prevention of prenatal virilization in affected female infants, reducing the risks of sex misassignment and gender confusion, and the need for corrective genital surgery. Prenatal treatment of 21-OH deficiency is effective in reducing genital ambiguity, and short-term outcome studies of children exposed to dexamethasone in utero indicate no significant adverse effects. However, more long-term studies of treated versus untreated pregnancies are warranted to monitor the safety of treatment and enhance our understanding of the effects of prenatal steroid exposure to the human brain. In the first year of life, optimization of medical treatment in salt-wasting patients is achieved by combining the lowest dose of glucocorticoid able to suppress androgen secretion with the normalization of sodium balance by giving appropriate sodium chloride supplementation.

show abstract

Human foetal palatal corticoid receptors and teratogens for cleft palate

Cited by 66 publications

References 23 publications

Prenatal Diagnosis and Treatment of Congenital Adrenal Hyperplasia

Prenatal Diagnosis and Treatment of Congenital Adrenal Hyperplasia

A Maternal Ahr Null Genotype Sensitizes Embryos to Chemical Teratogenesis

Prenatal and Early Postnatal Treatment of Congenital Adrenal Hyperplasia

Contact Info

Product

Resources

About