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

Abstract

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...

The aryl hydrocarbon receptor and glucocorticoid receptor interact to activate human metallothionein 2A

“…Many groups have reported the possibility of an interaction between AHR and GR. In early studies, it was noted that glucocorticoids and TCDD work independently in the yolk sac and placenta, and affect palate formation via activation of each receptor in different cell types in the developing palate (Pratt, 1985). AHR regulates the expression pattern of several growth factors, such as TGFβ, in the embryonic palate (Puga et al, 2005).…”

“…Excess glucocorticoids also induce cleft palate. A synergistic effect was observed in embryonic cleft palate induced by cotreatment with 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) and hydrocortisol, AHR and GR agonists, respectively (Pratt, 1985; Abbott, 1995; Abbott et al, 1999). Using a reporter gene assay with a GRE-driven reporter construct, Dvořák1 et al show that TCDD enhanced GR transactivation induced by dexamethasone (Dex), a synthetic GR agonist, in HepG2 cells (Dvořák et al, 2008).…”

Systems Biology and Birth Defects Prevention: Blockade of the Glucocorticoid Receptor Prevents Arsenic-Induced Birth Defects

“…Several possible mechanisms can cause the disruption of the GR signaling pathway, such as excessive amounts of GCs leading to intrauterine growth retardation and low birth weight (Drake et al 2007). In the fetus, unmetabolized GCs appear to function as the active teratogenic agent (Goldman et al 1978; Pratt 1985). GCs can also influence glycolysis via a GR-mediated mechanism (Loiseau et al 1985).…”

“…GCs can also influence glycolysis via a GR-mediated mechanism (Loiseau et al 1985). Evidence suggests that GC teratogenicity is a result of direct action on the embryo, which triggers a characteristic pattern of dysmorphogenesis via the biochemical and GC-mediated anti-inflammatory pathway (Kay et al 1990; Pratt 1985). …”

Genetic and Molecular Aspects of 2,3,7,8-Tetra-Chlorodibenzo-P-Dioxin Action

“…Thus, the hr locus (152) merits additional study, because it may encode a protein(s) that controls susceptibility to TCDD-induced neopla sia. Likewise, TCDD's immunologic and teratogenic effects are restricted to certain cell types (153,154) . This tissue-specificity implies the existence of additional controls, either positive or negative, that modulate the response of the receptor-enhancer system to TCDD.…”