Glucocorticoid receptor regulation in the rat embryo: a potential site for developmental toxicity?
Glucocorticoids play a key role in controlling numerous cellular processes during embryogenesis and fetal development. Excess glucocorticoids during development have been linked to dysmorphogenesis and/or intrauterine growth impairment in rodents. The actions of glucocorticoids are mediated by interaction with their receptors. Negative feedback regulation of glucocorticoid receptor (GR) is important for limiting cellular sensitivity to the hormones. Hence, acute exposure of the adult rat to the synthetic glucocorticoid dexamethasone (DEX) reduced both GR mRNA and protein in a variety of tissues that include hippocampus and liver, in a dose- and time-dependent fashion. Reduction in GR mRNA and protein were observable when DEX was given repeatedly at doses as low as 0. 05 mg/kg. In the control whole rat embryo, GR mRNA was low but measurable at as early as gestational day (GD) 10, but underwent rapid ontogenetic increase in the ensuring days. In contrast to the adult, neither GR mRNA nor protein in the whole rat embryo was affected by acute or repeated DEX administration to pregnant rats on GD10-13, even at doses as high as 0.8 mg/kg. Similar results were obtained in embryonic palate and liver, tissues known to be glucocorticoid targets. These data suggest that GR autoregulation does not occur during organogenesis in the rat. Accordingly, hormonal elevations from stress or chemical insults can be transduced unrestrictedly, ultimately leading to aberrant cell function and development. The unique mode of GR regulation seen in the embryonic cells may provide a potential common mechanism for developmental perturbation and toxicity for a variety of insults.
Ghosh
B
B
National Research Council, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Wood
C R
CR
Held
G A
GA
Abbott
B D
BD
Lau
C
C
D000704:Analysis of Variance; D000818:Animals; D003907:Dexamethasone / Q000633:toxicity*; D015536:Down-Regulation / Q000187:drug effects; D004622:Embryo, Mammalian / Q000187:drug effects*; D005260:Female; D005938:Glucocorticoids / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D012313:RNA / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D012313:RNA; D003907:Dexamethasone