Adrenal hypertrophy in rats caused by 90-day force-feeding concomitant with the non-toxic effects of Antrodia cinnamomea

Abstract

Background: Antrodia cinnamomea (A. cinnamomea), a medicinal fungus native to Taiwan, has been used for decades by folk medicine practitioners to treat liver damage, cancer, and inflammation-related afflictions in Taiwan. The observation of adrenal hypertrophy in rats over a 90-day feeding wild A. cinnamomea test has been reported, however no investigation or conclusive evidence is further provided yet. Purpose: This study aimed to explore the cause of adrenal hypertrophy in rats fed A. cinnamomea (in a 90-day study) followed by Harvey's strategy, considering potential effects on the routinely evaluated stress-sensitive organ systems (adrenal and thymus), without directly assessing the HPA axis function. Study Design: A 90-day study using Sprague-Dawley (SD) rats was conducted in accordance with the ''Regulations on Food Management and Labelling of A. cinnamomea'' by Taiwan FDA, which adhere to the OECD guidelines for the testing of chemicals (Test No 408) specification. Methods: The rats were oral gavaged with raw dish-cultured A. cinnamomea (RDAC) at a dosage of 250 mg kg-1/day for 13 weeks. The evaluation methods included clinical examinations, body weights, food consumption, haematology, coagulation, clinical biochemistry, gross visual observations and macroscopic examinations, organ weights, and histopathology. Results: No adverse effects from RDAC were found, establishing a no-observed-adverse-effect level of 250 mg kg-1/day in rats over a 3-month period. Adrenocortical hypertrophy was observed, but the increase in adrenal-gland-to-brain-weight ratio was not statistically significant (p > 0.05). Changes in biological stress markers, including organ and total body weights, changes in leukocyte counts, as well as reduced food consumption behaviour, serve as evidence to suggest that the hypertrophy was likely not due to adrenocortical steroidogenic inhibition by RDAC. Female rats exhibited a stronger stress response. RDAC suppressed the cell infiltration of Harderian glands. Conclusion: The adrenocortical hypertrophy in SD rats was likely a non-pharmacological stress response due to the unpleasant bitter taste of RDAC, potentially exacerbated by the force-feeding procedure. This study is the first evidence to elucidate the mechanism of adrenal gland hypertrophy in rats fed A. cinnamomea without directly assessing the HPA axis function. This underscores the safety of A. cinnamomea and advocates for further pharmacological research.

Keywords

• Antrodia cinnamomea
• Adrenal hypertrophy
• Sub-chronic toxicity
• Stress