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Strain differences in estrogen-induced pituitary proliferative response and gene expression patterns between Fischer 344 and Brown Norway rats

Year: 2026

Type: article

Abstract: Estrogen-induced pituitary proliferative lesions exhibit marked strain differences in rats; however, the molecular basis of this resistance remains unclear. This study compared estrogen-responsive Fischer 344 (F344) rats with resistant Brown Norway (BN) rats to identify candidate genes associated with resistance. Male F344 and BN rats received subcutaneous estradiol valerate (EV, 20 mg/kg) either as a single dose/as five injections over 9 weeks, with sampling performed one day after the final treatment; corn oil-treated animals served as controls. Macroscopic examination, pituitary weight measurement, and histopathology were conducted, followed by transcriptome analysis using RNA sequencing, and validation by quantitative polymerase chain reaction and immunohistochemistry. After 9 weeks of estradiol valerate treatment, F344 rats exhibited pronounced pituitary enlargement, accompanied by dark reddish discoloration with diffuse hyperplasia, characterized by hypertrophy of acidophilic cells, vascular congestion, and brown pigment deposition. In contrast, the BN rats showed only a slight increase in pituitary weight and no overt histological alterations. Transcriptome analysis identified 27 genes consistently regulated in BN rats after both single-dose and 9-week EV treatment but not significantly changed in F344 rats. Changes in the selected candidate genes were confirmed by quantitative polymerase chain reaction. Immunohistochemistry demonstrated increased RASA4 immunoreactivity and reduced GNB3 immunoreactivity in BN rats following treatment. These findings indicate that BN rats exhibit pituitary-specific resistance, potentially mediated by the strain-dependent transcriptional modulation of Ras-related pathways.

Source: Journal of Toxicologic Pathology

DOI: 10.1293/tox.2026-0015