Maternal Restricted- and over-Feeding during Gestation Alters Offspring Gene Expression of Inflammatory Markers in the Liver at d 135 of Gestation and at Birth

The fetal liver facilitates hematopoiesis and development of both liver-resident and peripheral tissue macrophages, priming postnatal innate immunity. We hypothesized that in the fetal liver, the expression of genes mediating inflammation would be disrupted by exposure to poor maternal nutrition during gestation. To test this hypothesis, pregnant Western White-faced ewes were fed 100%, 60% or 140% of NRC requirements for TDN beginning at d 30.2 ± 0.2 of gestation, with offspring referred to as CON, RES and OVER, respectively. Ewes (n = 3 to 5 per diet per time point) were euthanized at d 135 of gestation for fetal tissue collection or underwent parturition and lambs were euthanized within 24 h of birth. RNA was isolated from the liver of 6 offspring per diet at each time point. The expression of 84 genes mediating inflammation was profiled using real-time RT-PCR arrays. Data were analyzed using PROC MIXED in SAS for main effects and interaction of maternal diet and gender. At d 135 of gestation, maternal diet decreased expression of lymphotoxin-β 1.5-fold in OVER compared with CON (P ≤ 0.03). Chemokine (C-C motif) ligand (CCL)16 expression increased 1.9-fold in RES compared with CON (P ≤ 0.02). At d 135 in males, tumor necrosis factor (TNF) superfamily (SF)14 expression increased 2.9-fold, whereas expression of chemokine (C-C motif) receptor (CCR)6, CCR4, CCL3, interleukin (IL)2 receptor-γ and TNFSF receptor 11B decreased 5.0-, 4.0-, 1.9-, 1.2- and 1.2-fold, respectively (P ≤ 0.05), compared with females. At birth, TNF-α increased 4.5-fold in RES compared with CON (P ≤ 0.05), whereas bone morphogenetic protein 2, chemokine (CXC motif) ligand (CXCL)12 and CXCL10 were reduced by 3.0-, 2.6- and 1.8-fold, respectively, in OVER compared with CON (P ≤ 0.04). A main effect of gender was also observed at birth such that in males, CCL1 expression increased 6.8-fold, but CXCL9, CXCL10, TNFSF10, IL15 and IL5 expression decreased 3.0-, 2.1-, 2.0-, 1.6-, and 1.6-fold, respectively (P ≤ 0.02), compared with females. Additionally, 10 genes at d 135 and 5 genes at birth exhibited an interaction of maternal diet by gender (P ≤ 0.05). In conclusion, expression of genes related to inflammation in the fetal liver is differentially affected by maternal restriction and over-feeding during gestation, with the effects of maternal diet differing at d 135 of gestation and after parturition. This may be a mechanism by which poor maternal nutrition causes unfavorable postnatal growth, metabolism and survival in lambs.