Intra‐uterine Growth Restriction Downregulates the Hepatic Toll Like Receptor‐4 Expression and Function

Abstract

Maternal starvation is a significant cause of intrauterine growth restriction (IUGR) in the world and increases the risk of infection in the neonate. We examined the effect of maternal starvation on Toll like receptor (TLR)4 expression in hepatic, splenic and intestinal tissues obtained from the adult IUGR offspring of prenatal calorie restricted rats. The hepatic TLR4 protein concentration was undetectable in the IUGR rats that had restricted milk intake during the suckling period (SM/SP; n ¼ 4; p , 0:05) as compared to the normal growth controls (CM/CP; n ¼ 4), and access to ad lib milk intake during the sucking period partially corrected the hepatic TLR4 expression (SM/CP; n ¼ 4). IUGR had no effect on the splenic (n ¼ 4) or intestinal (n ¼ 4) TLR4 mRNA levels. In the liver, IUGR led to a 20% increase in baseline tumor necrosis factor (TNF)-a mRNA expression ð p , 0:03Þ and a 70% increase in interleukin-1b (IL-1b) mRNA expression ð p , 0:008Þ as compared to the control rats (CM/CP; n ¼ 7). LPS-induced hepatic TNF-a release was significantly higher in SM/SP as compared to CM/CP. We propose that IUGR dysregulates TLR4 expression and function in the offspring, which may help explain the increased risk of Gram-negative sepsis and inflammatory diseases in this population.

Perinatal undernutrition alters intestinal alkaline phosphatase and its main transcription factors KLF4 and Cdx1 in adult offspring fed a high-fat diet

“…An inhibitory effect of IUGR on intestinal IAP activity has been observed in rat neonates, but to date, no data are available on the effects of IUGR on IAP gene expression [40]. A down-regulation of TLR4 mRNA levels in the liver but not in the intestine or spleen of adult IUGR rats has been reported [41]. We found that IUGR induced a strong reduction of Table 7 Relative mRNA levels of various genes in epithelial cells isolated from jejunal mucosa of 240-day-old rats born to control or protein-restricted dams (IUGR) that were fed standard chow (NF) or a high-fat diet (HF) for 10 days before sacrifice TNF-α mRNA expression in enterocytes.…”

Prenatal undernutrition increases the febrile response to lipopolysaccharides in adulthood in male rats

“…Another possibility is that the responses of peripheral, but not central, tissues to LPS are increased in IUGR rats. It has been reported that the regulation of TLR4 is disturbed and the responses of hepatic pro‐inflammatory cytokines to LPS are increased in prenatally undernourished IUGR rats (Equils et al, 2005). In addition, it has been reported that prenatal and postnatal stress attenuates the febrile response by altering the corticosterone response in rodents (Ellis et al, 2005; Mouihate, 2012).…”

“…Most of the abovementioned studies focused on the effects of IUGR or SGA on adaptive immunity, and little data is available about the effects of such conditions on the innate immune system. In 2005, Equils et al suggested that IUGR rats exhibit increased innate immune system activity (Equils et al, 2005). They revealed that hepatic inflammatory cytokine expression was increased under basal and lipopolysaccharide (LPS)‐injected conditions in IUGR rats and that dysregulation of the LPS receptor, toll‐like receptor (TLR) 4, might be involved in these changes.…”

Retinoic Acid Rescues Alveolar Hypoplasia in the Calorie-Restricted Developing Rat Lung

“…Animal models describing the effects of compromised nutrient delivery to a developing fetus include experimental perturbations of maternal placental-fetal blood flow (21,22) and caloric restriction during either prenatal or early postnatal stages (23,24). Few studies have explored the combined effects of caloric restriction during embryonic and early postnatal development on lung morphogenesis.…”