Nathan Drever

Fetal Programming: Early-life Modulations that Affect Adult Outcomes

Asthma is a common disease, and the number of people diagnosed with it increases every year. Although genetic background and environmental exposures play major roles in the development of asthma, one cannot overlook the developmental origin of adult disease or fetal programming theory. This review examines the social, genetic, and environmental factors that are associated with fetal programming of asthma. We also present recent studies from our laboratory that strengthen these observations. It is our hope that the reader will come away with a current view of fetal programming in asthma.

THE EXPRESSION OF ANTIOXIDANT ENZYMES IN A MOUSE MODEL OF FETAL ALCOHOL SYNDROME

OBJECTIVE Superoxide dismutase, glutathione peroxidase, and catalase prevent cellular damage produced by free radicals. Our objective was to evaluate if prenatal alcohol exposure decreased the expression of antioxidant enzymes in the brain, liver, or placenta of fetal mice. STUDY DESIGN Timed, pregnant C57BL6/J mice were treated on gestational day 8 with intraperitoneal injection of alcohol (0.03 mL/g) or saline (control). Fetuses were harvested on gestational day 18. Fetal brain, liver, and placenta were analyzed for mRNA expression of superoxide dismutase, glutathione peroxidase, and catalase by real-time polymerase chain reaction, with 18S RNA used as reference. RESULTS Superoxide dismutase, glutathione peroxidase, and catalase expression was lower in fetal brains exposed to alcohol with no differences detected in the liver or placenta between the 2 groups. CONCLUSION Maternal alcohol consumption causes a decrease in superoxide dismutase, glutathione peroxidase, and catalase expression in the fetal brain. This may explain the long-term neurologic findings in fetal alcohol syndrome.

Prepregnancy obesity and sFlt1-induced preeclampsia in mice: developmental programming model of metabolic syndrome

OBJECTIVE We sought to establish a model of fetal programming of metabolic syndrome by exposure to soluble fms-like tyrosine kinase-1 (sFlt1)-induced preeclampsia (PE) and preexisting maternal obesity (MO). STUDY DESIGN CD-1 female mice were placed on either standard or high-fat diet for 3 months. On day 8 of pregnancy, mice were injected with either adenovirus-carrying sFlt1 or adenovirus-carrying murine immunoglobulin G2α Fc fragment. Offspring were studied at 6 months of age. RESULTS Exposure to MO with/without PE resulted in significant increase in progenys weight and adiposity. Blood pressure in males was significantly increased due to MO with PE. Metabolic blood analytes were affected in males and females exposed to only PE or MO with/without PE; inflammatory-in females exposed to MO with/without PE and males born to MO with PE; atherosclerotic-in females exposed to MO. CONCLUSION Exposure to maternal prepregnancy obesity and sFlt1-induced preeclampsia alter the offsprings blood pressure, metabolic, inflammatory, and atherosclerotic profiles later in life.

The role of NADPH oxidase in a mouse model of fetal alcohol syndrome

OBJECTIVE Fetal alcohol syndrome (FAS) is the most common cause of nongenetic mental retardation. Oxidative stress is one of the purported mechanisms. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is an enzyme involved in the production of reactive oxygen species. Our objective was to evaluate NOX in the fetal brain of a well-validated mouse model of FAS. STUDY DESIGN Timed, pregnant C57BL/6J mice were injected intraperitoneally with 0.03 mL/g of either 25% ethyl alcohol or saline. Fetal brain, liver, and placenta were harvested on gestational day 18. The unit of analysis was the litter; tissue from 6-8 litters in the alcohol and control group was isolated. Evaluation of messenger ribonucleic acid (mRNA) expression of NOX subunits (DUOX1, DUOX2, NOX1, NOX2, NOX3, NOX4, NOXA1, NOXO1, RAC1, p22phox, and p67phox) was performed using quantitative real-time polymerase chain reaction; alcohol vs placebo groups were compared using a Student t test or a Mann-Whitney test (P < .05). RESULTS Alcohol exposed fetal brains showed significant up-regulation in subunits DUOX2 (1.61 ± 0.28 vs 0.84 ± 0.09; P = .03), NOXA1 (1.75 ± 0.27 vs 1.09 ± 0.06; P = .04), and NOXO1 (1.59 ± 0.10 vs 1.28 ± 0.05; P = .02). Differences in mRNA expression in the placenta were not significant; p67phox was significantly up-regulated in alcohol-exposed livers. CONCLUSION Various NOX subunits are up-regulated in fetal brains exposed to alcohol. This effect was not observed in the fetal liver or placenta. Given the available evidence, the NOX system may be involved in the causation of FAS through the generation of reactive oxygen species and may be a potential target for preventative treatment in FAS.

225: Developmental programming of adult disease: the role of DNA methylation in genes responsible for antioxidant enzymes

gain, fetal weights, placental weights or number of pups between the RV and control groups. Treatment with RV had no significant effect on baseline myometrial contractility nor on contractility after indomethacin or nifedipine treatment. CONCLUSION: Unlike its effect on vascular smooth muscle, resveratrol does not seem to affect myometrial contractility nor potentiate the effect of tocolytics in pregnant mice.