Effects of Intrauterine Growth Restriction During Late Pregnancy on the Development of the Ovine Fetal Thymus and the T-Lymphocyte Subpopulation.

PROBLEM:The retarded development of fetal thymus in intrauterine growth restriction (IUGR) from maternal undernutrition during late pregnancy destroys the tridimensional structure and modifies the development of fetal T lymphocytes. The mechanisms, however, remain unclear. The objective of this study was to investigate the effect of IUGR during late pregnancy on the development of the ovine fetal thymus and the T-lymphocyte subpopulation. METHOD OF STUDY:Eighteen time-mated ewes with singleton fetuses were allocated to three groups at day 90 of pregnancy: restricted group 1 (RG1, 0.18 MJ ME/BW(0.75) /day, n = 6), restricted group 2 (RG2, 0.33 MJ ME/BW(0.75) /day, n = 6) and a control group (CG, ad libitum, 0.67 MJ ME/BW(0.75) /day, n = 6). Fetuses were recovered at slaughter on day 140. RESULTS:Fetuses in RG1 exhibited decreased (P < 0.05) thymic weight, cortical thickness, cortical:medullary, DNA content, total antioxidant capacity, and superoxide dismutase; intermediate changes were found in RG2 fetuses, including decreased thymic weight, cortical thickness, and DNA content (P < 0.05). The reductions (P < 0.05) of CD4(+) CD8(+) T cells, relative mRNA expression of keratin 8, recombination activating gene 1 (RAG1), and B-cell lymphoma 2 (Bcl-2) were found in both restricted groups. In addition, there was reduced mRNA expression (P < 0.05) of T-cell receptor, apoptosis antigen 1 ligand, and RAG2 in the RG1 group. In contrast, increases in glutathione peroxidase, malondialdehyde, caspase-3, Cytochrome c, and CD4(+) T cells were observed (P < 0.05), and higher mRNA expressions (P < 0.05) of protein 53, Bcl-2 associated X protein (Bax), and apoptosis antigen 1 (Fas) were found in RG1 fetuses; and thymuses of RG2 fetuses had increased caspase-3, and expression of Fas and Bax (P < 0.05), relative to control fetuses. CONCLUSION:These results indicate that reduced cell proliferation, oxidative stress, and increased cell apoptosis were the potential mechanisms for impaired development and microenvironment of IUGR fetal thymus, and for modifying the maturation of CD4(+) CD8(+) thymocytes underlying their reduced numbers .

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