SRI Supplement to Reproductive Sciences - Volume 25 Number 1 - March 2018 - 273A

Scientific Abstracts

was determined by DESeq2 and Wald's test, with tests of interaction
between PM and gravidity. Functional enrichment analysis was performed
using DAVID to identify changes related to PM and gravidity.
RESULTS: We observed a significant interaction between PM and
gravidity. Between the two cell types, 276 differentially expressed genes
were found to overlap. K-means clustering on these 276 genes resulted
in 4 distinct clusters. Cluster 1 was characterized by inverse expression
in primigravidas (increased) vs. multigravidas (decreased) in both fetal
and maternal macrophages. Pathway analysis revealed that genes in this
cluster were involved in cytokine response and leukocyte activation.
Cluster 2 represented genes that were also inversely expressed, but in the
opposite direction as in Cluster 1 (decreased in primigravidas vs. increased
in multigravidas). The genes in this group were mainly involved in the
regulation of cellular biosynthetic processes.
CONCLUSION: These results suggest that maternal gravidity influences
the distinct fetal HBCs and MIMs responses to PM, which may contribute
to the different susceptibilities to adverse clinical outcome with PM.

S-061

S-062
Developmental Programming (DP) by Baboon Maternal Obesity
and Overnutrition (MO) Produces Offspring (F1) Term Liver Sex
Dependent Decreases in Autophagy Gene Proteins with Greater
Decreases in MO than IUGR F1. Qiurong Wang†, Cun Li*, Peter W
Nathanielsz*. University of Wyoming, Laramie, WY, United States.
INTRODUCTION: Autophagy degrades and recycles damaged
cell components to maintain tissue and organ health. Few studies
address potential involvement of autophagy changes in developmental
programming (DP) by altered maternal nutrition. Decreased autophagy

273A

produces cellular dysfunction that could lead to long term adverse DP
outcomes. Altered autophagy is also involved in aging. We evaluated DP
effects of IUGR and MO on key autophagy gene proteins in F1 fetal liver.
METHODS: Non-pregnant baboons of similar morphometry were
randomly divided into three groups: fed 1) primate chow (C) ad lib; 2)
70% feed eaten by C who deliver IUGR F1; 3) a high energy high fat diet
and extra sucrose drinks for at least a year to induce MO before breeding.
F1 fetuses were removed and euthanized under general anesthesia and
liver frozen at -80°C until submitted to Western analysis.
RESULTS: MO decreased Atg5 protein by 50% in F1 females and 26%
in F1 males. LC3-I and LC3-II protein were down 78 and 77% in MO
females whereas in males LC3-I was down by 43%. Effects were much
less apparent in IUGR F1 in which only Atg5 protein was reduced by
22% in females and no gene protein in males. Thus MO has different and
more marked effects on autophagy genes than IUGR.
*Figure(s) will be available online.
Table 1: Ratio of liver autophagy gene protein in MO males and females
vs. control; Atg5/7: Autophagy Related 5/7, LC3-I/II: Microtubuleassociated protein 1A/1B-light chain 3 isoform I/II. M ± SEM, *p < 0.05
, **p < 0.01 vs. control.
CONCLUSION: The amount of the decrease in autophagy gene product
depends on the nature of the challenge and sex of F1. MO produced more
change than IUGR. Reduced Atg5 protein which is essential for initiation
and elongation of autophagosome, and LC3-I/II which is core component
of autophagosome formation, indicate that the autophagy process is
depressed by DP. Insufficient autophagy in MO fetal liver could indicate
a possible mechanism of MO-induced fetal hepatic dysfunction and long
term adverse F1 health effects. Funded: HD21350

S-063
Chronically Elevated Norepinephrine Concentrations Impair Glucose
Uptake in Sheep Fetuses. Melissa Davis†, Leticia Camacho†, Miranda
Anderson, Nathan Steffens, Amy Kelly†, Sean Limesand*. University of
Arizona, Tucson, AZ, United States.
INTRODUCTION: Placental insufficiency is the primary cause of
intrauterine growth restriction (IUGR) and leads to fetal hypoglycemia
and hypoxemia, which chronically elevates norepinephrine (NE) in late
gestation. We have shown that chronic elevations in NE have profound
effects on fetal growth, islet function, and insulin secretion. Our objective
was to evaluate glucose metabolism in fetal sheep with chronically high
NE, independent of other IUGR-related insufficiencies.
METHODS: Following surgical placement of catheters (124±1 days
of gestation), normally-grown fetuses were randomly assigned to either
normal saline infusion (SAL, n=6) or NE infusion (NE-E, n=6). NE
concentration was increased after the first day from 1μg/min/kg to 2μg/
min/kg for days 1-5. In NE-E, fetal euglycemia was maintained with
maternal insulin infusion. On day 5 of treatment, weight-specific fluxes
for glucose and radiolabeled glucose were determined at two steady state
periods, euinsulinemic-euglycemic clamp (EEC) and hyperinsulinemiceuglycemic clamp (HEC). Pancreatic hormones were clamped with
somatostatin (1.5 µg/min/kg) and glucagon (10 ng/min/kg). Umbilical
blood flow was calculated by 3H2O diffusion. Data were analyzed with
an ANOVA using MIXED procedures.
RESULTS: Compared to SAL fetuses, NE concentrations in NE-E fetuses
were higher (420±110ng/L vs. 5700±640ng/L; P<0.01). During the EEC,
glucose entry rate (umbilical uptake + exogenous infusion) was lower
(P<0.01) in NE-E (17±3μmol/min/kg) than SAL (32±3μmol/min/kg)
fetuses. Glucose utilization rate was lower (P<0.05) in NE-E (20±3μmol/
min/kg) than SAL (31±3μmol/min/kg) fetuses. During the HEC, glucose
entry rate was lower (P<0.05) in NE-E (33±3μmol/min/kg) than SAL
(46±3μmol/min/kg) fetuses. Glucose oxidation increased between
periods but was not different between groups. Glucose production was
undistinguished in either group. Plasma glucose and insulin concentrations
were not different between groups within a steady state period, but insulin
concentrations increased 10 fold in the HEC. Fetal sex, age and weight
were not different between groups.
CONCLUSION: These findings indicate that chronic exposure to high
plasma NE concentrations lowers glucose uptake in fetal tissues without

Saturday Posters

Divergent Cellular and Molecular Mechanisms Mediate Cardiac
Aging and Developmental Programming of Cardiac Dysfunction.
Youguo Niu†, Nozomi Itani†, Andrew D Kane†, Beth J Allison, Emily J
Camm, Ciara M Lusby, Jane L Tarry-Adkins, Thomas J Ashmore, Andrew
J Murray, Susan E Ozanne, Dino A Giussani*. University of Cambridge,
Cambridge, United Kingdom.
INTRODUCTION: Age-associated cardiovascular functional decline
and developmental programming of cardiovascular disease share
several features, raising the possibility of common mechanistic origins.
However, few studies have tested this systematically. Here, we combine
cardiac functional studies with measurements of mitochondrial oxygen
consumption, cardiac telomere length, cardiac oxidative stress and
molecular markers of cell senescence to establish if developmental
programming of cardiac dysfunction can be dissociated from biological
aging using an established rodent model of developmental hypoxia.
METHODS: Wistar rats were randomly divided into normoxic (N) or
hypoxic (H: 14% O2) pregnancy from days 6-20 of gestation. At birth,
litters were culled to 8 pups and weaned at 21 days. At 4 and 15 months,
cardiac function (Langendorff) and O2 consumption (respirometry) were
determined. Cardiac 4-hydroxynonenal (4-HNE) concentration and p53
gene expression were measured (ELISA and RT-PCR, respectively).
To control for sex and litter, 1 male per litter per outcome was studied.
RESULTS: Hearts from aged (15 month) relative to young adult (4 month)
offspring of normoxic pregnancy showed diastolic dysfunction (increased
LVEDP and Tau), impaired mitochondrial oxygen consumption (Fig.1
A-D), cardiac telomere shortening, increased cardiac lipid peroxidation
(4-HNE) and promotion of myocardial senescence pathways (p53; Fig.
2 A-D). Offspring of hypoxic pregnancy showed significant diastolic
dysfunction and reduced mitochondrial oxygen consumption already at 4
months. However, this was dissociated at this age from increased cardiac
oxidative stress, telomere shortening and cell senescence.
CONCLUSION: Programmed cardiac dysfunction by developmental
hypoxia is not a form of accelerated cardiovascular aging. It is mediated
by different mechanisms, highlighting the need for differential intervention
strategies.
Support: The British Heart Foundation
*Figure(s) will be available online.

Reproductive Sciences Vol. 25, Supplement 1, March 2018

Table of Contents for the Digital Edition of SRI Supplement to Reproductive Sciences - Volume 25 Number 1 - March 2018