Abstract
Our previous study showed that prenatal caffeine exposure (PCE) could induce intrauterine growth retardation (IUGR) and glucocorticoid elevation in the fetus. Researchers suggested that IUGR is a risk factor for T helper cell (Th)1/Th2 deviation. However, whether PCE can induce these immune disorders and the underlying mechanisms of that induction remain unknown. This study aimed to observe the effects of PCE on the Th1/Th2 balance in offspring and further explore the developmental origin mechanisms from the perspective of glucocorticoid overexposure-induced thymocyte apoptosis. An IUGR model was established by caffeine administration from gestational day (GD) 9 to GD 18, and the offspring were immunized on postnatal day (PND) 42. The results show that maternal glucocorticoid overexposure increased fetal thymocyte apoptosis by activating both the Fas-mediated and the Bim-regulated apoptotic pathways. After birth, accelerated thymocyte apoptosis and Th1 suppression were also found in the PCE offspring at PND 14 and PND 49. Moreover, the PCE offspring showed immune disorders after immunization, manifesting as increased IgG1/IgG2a ratio and IL-4 production in the serum. In conclusion, PCE could induce fetal overexposure to maternal glucocorticoids and increase thymocyte apoptosis, which could persist into postnatal life and be implicated in Th1 inhibition and further immune disorders.
Highlights
Inflammatory and immune disorders, especially allergic diseases, have become a growing health problem worldwide[9,10,11]
This study provides evidence for elucidating the toxicity of prenatal caffeine exposure (PCE) on fetal thymocyte development and for exploring the developmental origin of immune disorder susceptibility of intrauterine growth retardation (IUGR) offspring caused by PCE
The results showed that the absolute number of double positive thymocytes (DP) and CD4SP thymocytes were significantly decreased in the PCE offspring on postnatal day (PND) 14 and on PND 49 (P < 0.05, Fig. 3D,F,J, and L)
Summary
Inflammatory and immune disorders, especially allergic diseases, have become a growing health problem worldwide[9,10,11]. Recent research has revealed that prenatal exposure to adverse factors might interrupt the Th1 increase and result in a long-lasting Th2-biased immune phenotype after birth. We speculated that PCE can induce thymocyte apoptosis and attenuate thymopoiesis via GCs. The aim of this study was to investigate the effects of PCE on the Th1/Th2 balance and the immune responses in offspring from the perspective of restricted fetal thymopoiesis, and further, to explore the underlying mechanisms by determining the gene expression of GC-mediated apoptosis pathways in the fetal thymus.
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