A two-hit hypothesis has been proposed to describe the pathophysiology of lipoid congenital adrenal hyperplasia. In previous studies using conventional steroidogenic acute regulatory protein (Star) gene knockout (KO) mice, adrenocortical lipid accumulation was already prominent at birth. Thus, the two-hit hypothesis was verified in the gonads of Star KO mice but not in the adrenal cortices. We generated time-dependent conditional Star KO mice induced by tamoxifen (TAM) injections and analyzed the adrenal cortices of the mice histologically and endocrinologically before, 24 hours after, and 8 weeks after TAM. We performed RNA sequencing analyses of the adrenal glands before and 8 weeks after TAM and histologically analyzed autologous adrenal cortices of TAM-induced Star KO mice with transplantation of wild-type adrenal gland. Lipid accumulation was scattered 24 hours after TAM and was prominent 8 weeks after TAM. Steroidogenic capacity decreased sequentially after TAM. Gene expression related to steroid biosynthesis significantly decreased 8 weeks after TAM compared with that before TAM. TAM-induced Star KO mice with adrenal transplantation showed normal ACTH levels and mild lipid accumulation. These results showed that the steroidogenic capacity decreased without histological change (the first hit) and declined with histological change (the second hit). Thus, we visualized the two-hit hypothesis in the adrenal cortex. The key feature of the secondary decline of steroidogenic capacity might be the decreased gene expression related to steroid biosynthesis after lipid accumulation exacerbated by ACTH hypersecretion.
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