ABSTRACT
Exposure to intrauterine growth restriction (IUGR) is an important risk factor for impaired learning and memory, particularly in males. Although the basis of IUGR-associated learning and memory dysfunction is unknown, potential molecular participants may be insulin-like growth factor 1 (Igf1) and its receptor, IGF1r. We hypothesized that transcript levels and protein abundance of Igf1 and IGF1r in the hippocampus, a brain region critical for learning and memory, would be lower in IUGR male rats than in age-matched male controls at birth (postnatal day 0, P0), at weaning (P21) and adulthood (P120). We also hypothesized that changes in messenger Ribonucleic acid (mRNA) transcript levels and protein abundance would be associated with specific histone marks in IUGR male rats. Lastly, we hypothesized that IUGR male rats would perform poorer on tests of hippocampal function at P120. IUGR was induced by bilateral ligation of the uterine arteries in pregnant dams at embryonic day 19 (term is 21 days). Hippocampal Igf1 mRNA transcript levels and protein abundance were unchanged in IUGR male rats at P0, P21 or P120. At P0 and P120, IGF1r expression was increased in IUGR male rats. At P21, IGF1r expression was decreased in IUGR male rats. Increased IGF1r expression was associated with more histone 3 lysine 4 dimethylation (H3K4Me2) in the promoter region. In addition, IUGR male rats performed poorer on intermediate-term spatial working memory testing at P120. We speculate that altered IGF1r expression in the hippocampus of IUGR male rats may play a role in learning and memory dysfunction later in life.
ABSTRACT
OBJECTIVE: To examine the contribution of variants in fetal and maternal cholesterol metabolism genes in preterm delivery (PTD). STUDY DESIGN: A total of 40 single-nucleotide polymorphisms (SNPs) in 16 genes related to cholesterol metabolism were examined for 414 preterm infants (gestational ages 22 to 36 weeks; comprising 305 singletons and 109 twins) and at least 1 parent. Fetal effects were assessed using the transmission disequilibrium test (TDT) for each SNP, followed by a log linear model-based approach to utilize families with missing parental genotypes for those SNPs showing significance under TDT. Genetic variant effects were examined for a role in PTD, gestational age and birth weight. Maternal effects were estimated using a log linear model-based approach. RESULT: Among singleton gestations, suggestive association (P<0.01 without adjusting for multiple comparisons) was found between birth weight and fetal DHCR7 gene/SNP combinations (rs1630498, P=0.002 and rs2002064, P=0.003). Among all gestations, suggestive associations were found between PTD and fetal HMGCR (rs2303152, P=0.002) and APOA1 (rs 5070, P=0.004). The result for HMGCR was further supported by the log linear model-based test in the single births (P=0.007) and in all births (P=0.006). New associations (APOE and ABCA1) were observed when birth weight was normalized for gestational age suggesting independent effects of variants on birth weight separate from effects on PTD. Testing for maternally mediated genetic effects has identified suggestive association between ABCA1 (rs4149313, P=0.004) and decreased gestational age. CONCLUSION: Variants in maternal and fetal genes for cholesterol metabolism were associated with PTD and decreased birth weight or gestational age in this study. Genetic markers may serve as one mechanism to identify high-risk mothers and fetuses for targeted nutritional treatment and/or prevention of low birth weight or PTD.
