Strain-specific steroidal control of pituitary function

We have previously shown that 7B2 null mice on the 129/SvEvTac (129) genetic background die at 5 weeks of age with hypercorticosteronemia due to a Cushing's-like disease unless they are rescued by adrenalectomy; however, 7B2 nulls on the C57BL/6NTac (B6) background remain healthy, with normal steroid levels. Since background exerts such a profound influence on the phenotype of this mutation, we have evaluated whether these two different mouse strains respond differently to high circulating steroids by chronically treating wild-type 129 and B6 mice with the synthetic steroid dexamethasone (Dex). Dex treatment decreased the dopamine content of the neurointermediate lobes (NIL) of 129 mice, leading to NIL enlargement and increased total D₂R mRNA in the 129, but not the B6, NIL. Despite the decrease in this inhibitory transmitter, Dex-treated 129 mice exhibited reduced circulating α-melanocyte-stimulating hormone (α-MSH) along with reduced POMC-derived peptides compared with controls, possibly due to reduced POMC content in the NIL. In contrast, Dex-treated B6 mice showed lowered cellular ACTH, unchanged α-MSH and β-endorphin, and increased circulating α-MSH, most likely due to increased cleavage of NIL ACTH by increased PC2. Dex-treated 129 mice exhibited hyperinsulinemia and lowered blood glucose, whereas Dex-treated B6 mice showed slightly increased glucose levels despite their considerably increased insulin levels. Taken together, our results suggest that the endocrinological response of 129 mice to chronic Dex treatment is very diffirent from that of B6 mice. These strain-dependent differences in steroid sensitivity must be taken into account when comparing different lines of transgenic or knockout mice.