MechanismComparative studies on effects of all-trans-retinoic acid and all-trans-retinoyl-β-d-glucuronide on the development of foetal mouse thymus in an organ culture system

Add time:08/21/2019    Source:sciencedirect.com

The thymus is a target organ of retinoid teratogens. Retinoids with a generally reduced teratogenic potency should therefore also exert reduced adverse effects on thymus development. The effects of all-trans-retinoic acid (a-tRA) and all-trans-retinoyl-β-glucuronide (a-tRAG) on the in vitro development of thymic lobes of 15-day-old mouse foetuses were compared in an organ culture system. Both compounds were added to the medium at concentrations ranging from 10−7 to 10−5 m. The culture period was 6 days. The investigations showed a concentration-dependent effect of both substances on the proliferation of the lymphatic cells. At 10−5m the number of thymocytes was significantly reduced to values of about 70% of the controls by either of the retinoids (P ⩽ 0.05). Results of flow cytometry showed significant differences concerning the differentiation markers CD4 and CD8 after the culture period. The presence of 10−6m a-tRA induced a significant increase in the percentages of CD4+CD8− cells and a significant decrease of CD4+CD8+ cells. At 10−5m a-tRA an additional significant increase in the percentages of CD4−CD8− cells was found. In contrast, after treatment with a-tRAG, percentages of these populations were in the same range as the controls. Light and electron microscopic investigations revealed a depletion of lymphatic cells and an increase of intracytoplasmic vacuoles in the thymic epithelial cells at 10−6 and 10−5m of either retinoid. HPLC analyses revealed a remarkable degree of retinoid isomerization and (in the case of a-tRAG) of hydrolysis. Compared with the culture medium, retinoids were accumulated in the thymic lobes. Possibly a-tRAG acts by way of limited hydrolysis to retinoic acid.

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