Introduction: IUGR severely affects the development of organs and functions during prenatal life. This has remarkable consequences later in life as an increased incidence of non-communicable diseases. Immunological abnormalities in malnourished individuals are largely described, notably an increased susceptibility to early severe infections. IUGR is also associated with a higher risk of atopy, asthma or allergies. Yet, the association of IUGR exposition and later autoimmune disorders is poorly reported. Our work aims at studying the molecular modifications associated with IUGR exposition and predictive of a risk of later autoimmune disorders in a rat model.
Methods: Sprague-Dawley rat dams were exposed to normal chow (control, CTRL) or to a low protein diet (LPD, isocaloric 9% casein) during whole pregnancy to induce IUGR. At 180 days of life specimen were sacrificed and thymus were collected and analysed. We assessed basic morphologic thymic parameters (thymus on body weight ratio and thymic cellularity, namely the total number of mixed cells after mashing reported on thymus weight). To assess the thymic primitive functions, we sought for modifications in protein expression of selected markers of thymic function as Lymphotoxin-beta receptor (Ltßr) for the control of entrance and migration of thymocytes progenitors, AutoImmune Regulator (AIRe) for the acquisition of central tolerance, Forkhead box protein 3 (FoxP3) for the presence of regulatory T-cells. We also assessed the protein expression of Sirtuin-1 (Sirt-1) and Forkhead box protein O1 (FOXO-1) as markers of senescence.
Results: IUGR-exposed offspring was differently affected along a gender-manner. In male, the thymus weight / body weight ratio was significantly decreased in LPD group (0.56 vs. 0.4; p = 0.04) and in females, this ratio was significantly increased in LPD group (0.8 vs. 0.65; p = 0.03). In males, the thymic cellularity was significantly decreased in LPD group (71.5 vs. 144.7; p=0.02). The intra-thymic protein expression of the following markers was significantly decreased in males of the LPD group when compared to CTRL group: LtßR (0.22 vs. 0.47; p=0.01), AIRe (0.25 vs. 0.77; p=0.02) and FoxP3 (0.46 vs. 1.15; p=0.01). The intra-thymic protein expression of LtßR and AIRe was not significantly modified by IUGR condition in females (respectively: 0.69 vs. 0.63; p=0.20 and 0.63 vs. 0.81; p=0.39). The expression of FoxP3 was significantly decreased in females of LPD group when compared to CTRL (0.49 vs. 0.75; p=0.04).
Conclusion: Our murine model of IUGR brings evidence of significant changes in protein expression of selected markers of thymic function implicated in the prevention of autoimmunity. Our findings suggest early-programmed modifications of the primitive function of the thymus, associated with marks of intra-thymic immunosenescence. Whether these findings are associated with a significantly increased risk of autoimmune disorders later in life remains to be demonstrated. Interestingly, IUGR-exposed female offspring demonstrated better-conserved thymic development and function. These gender-mannered differences in the impact of IUGR deserve further experimental investigations.