Glucocorticoid receptor regulation in the rat embryo: A potential site fordevelopmental toxicity?

Glucocorticoids play a key role in controlling numerous cellular processes during embryogenesis and fetal development. Excess glucocorticoids during d evelopment have been linked to dysmorphogenesis and/or intrauterine growth impairment in rodents. The actions of glucocorticoids are mediated by inter action with their receptors. Negative feedback regulation of glucocorticoid receptor (GR) is important for limiting cellular sensitivity to the hormon es. Hence, acute exposure of the adult rat to the synthetic glucocorticoid dexamethasone (DEX) reduced both GR mRNA and protein in a variety of tissue s that include hippocampus and liver, in a dose- and time-dependent fashion . Reduction in GR mRNA and protein were observable when DEX was given repea tedly at doses as low as 0.05 mg/kg. In the control whole rat embryo, GR mR NA was low but measurable at as early as gestational day (GD) 10, but under went rapid ontogenetic increase in the ensuring days. In contrast to the ad ult, neither GR mRNA nor protein in the whole rat embryo was affected by ac ute or repeated DEX administration to pregnant rats on GD10-13, even at dos es 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 t hat GR autoregulation does not occur during organogenesis in the rat. Accor dingly, hormonal elevations from stress or chemical insults can be transduc ed unrestrictedly, ultimately leading to aberrant cell function and develop ment. The unique mode of GR regulation seen in the embryonic cells may prov ide a potential common mechanism for developmental perturbation and toxicit y for a variety of insults.