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United States Department of Agriculture

Agricultural Research Service

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2011 Annual Report

1a. Objectives (from AD-416)
1. Establish benchmark transcriptome profiles induced by uterine stress during gestation that are predictive of altered physiological mechanisms in key organs critical to the piglet immune and metabolic stress responses. 2. Identify critical gene(s), gene products, and their mechanism of action in the stress response of piglets associated with morbidity, growth rate, and body composition. 2.A. Identify key secretory proteins that are regulated by stress in the preweaning pig. 2.B. Identify key secretory proteins produced by adipose tissue that are regulated by stress in the preweaning pig. 3. Develop comprehensive in vitro models to analyze the mechanistic role of select, important developmental or metabolic factors in mediating the organism’s response to stresses via functional genomic approaches. 3.A. Determine the physiological mechanisms of key stress-regulatory proteins that regulate nutrient partitioning in the liver and adipose tissue. 3.B. Characterize the role of trophectoderm-derived estrogen as a modulator of “programmed” set points that determines the development potential of the peri-implantation embryo. 4. Define the repertoire of biomarkers that may be predictive of neonatal growth potential by using models of induced metabolic stress.

1b. Approach (from AD-416)
High preweaning mortality or impaired stress-related growth of live-born piglets continue to be major problems that negatively impact commercial swine production. Piglets exhibiting decreased vitality are at greater risk of morbidity or death and a decreased growth rate extending the farrow-to-market time, which results in increased producer costs. Considering embryo development as a continuum, it is plausible that abnormal piglet development and loss through adulthood is a consequence of aberrant embryonic/uterine development. This research will identify physiological mechanisms modulating piglet stress responses to pinpoint targets for interventions to improve “at risk” piglet survival. The research addresses three elemental issues 1) elucidation of the relationship between developmental perturbations and etiology of abnormal postnatal stress responses, 2) paucity of predictive screening tools for “at risk” neonates, and 3) lack of interventions to ameliorate postnatal development of “at risk” piglets. The impact of the uterine milieu on alterations of key physiological mechanisms that modulate stress response in metabolic or immune organs will be evaluated by comparative transcriptomic analysis between induced intrauterine growth retardation (IUGR), i.e. runting, and control concepti. To identify postnatal stress responses that are disrupted and persist ex utero as a consequence of in utero growth retardation or parturition complications and detect compensatory mechanisms, the gene expression of key metabolic and immune tissues from growth retarded piglets, (induced IUGR or spontaneous IUGR) and piglets exhibiting decreased vitality will be assessed by in-depth proteomic or transcriptomic analyses throughout the preweaning period. Functional analyses utilizing in vitro model systems and technologies, such as RNAi, will evaluate the mechanistic role of specific stress-related factors/pathways that are identified in metabolically important tissues. The relevance of putative stress-related factors/pathways will be assessed in vivo, employing distinct models of induced metabolic stress. The knowledge acquired will enable 1) the discovery of new biomarkers indicative of metabolic or immune stress response, 2) the identification physiological mechanisms/factors that can be targeted to develop new improved interventions that decrease mortality and days to market of “at risk” piglets and 3) the establishment of public “systems biology” database for specific gestational and environmental stresses.

3. Progress Report
Progress was made on all objectives to be addressed in FY11. For Objective 1, studies were continued to define physiological changes occurring in vital organs with the onset of intrauterine growth retardation (IUGR) during gestation, which impact neonatal piglet growth. A longitudinal mRNA expression (microarray) study to pinpoint developmental changes in fetal metabolic organs with the onset of IUGR demonstrated that mRNA profiles were distinct and segregated by fetal age but not IUGR. Specific genes involved in placental development or function were also examined to identify changes or compensatory mechanisms concomitant with IUGR. Alterations in the mRNA expression of a blood vessel tone/growth associated protein previously detected between normal weight and IUGR fetuses at gestational day 50 was not apparent with advanced gestation; at the protein level, age but not IUGR differences were found. An examination of the expression of an additional 18 genes indicated that like fetal organs, most expression differences in placental tissue were related to gestational age; only a few correlated with IUGR. Under Objective 3, studies were conducted to elucidate the pro-inflammatory stress response in baby pigs by using their hepatocytes and investigating cytokine action in vitro. Hepatocyte cultures were exposed to reagents that modify oxidative metabolic processes: vitamin E isoforms (a and d), N-acetyl cysteine, hemin and resveratrol. Early events that follow stress induction such as transcription factor phosphorylation and activation of transcription factors were demonstrated for the first time in porcine liver. A unique form of transcription factor kappa B was observed in nuclei and proteomic tools are being employed to identify this molecule. Preliminary results indicate that antioxidants have differential impact on short-term (minutes) transcription factor activity and on long-term (24 hr) protein expression. To address objective 4, studies were conducted to assess the body composition of neonatal pigs during growth from birth to weaning – a critical time period for piglet survival. At weaning, litter pairs of the highest and lowest weight piglets were selected from 30 litters for body composition measurement by dual-energy X-ray absorptiometry (DEXA). Body composition indicated that absolute fat, lean, and bone mineral content were 44%, 34% and 33%, respectively, higher in the largest pigs. However, between groups there was not a difference in the ratio of lean or fat to body weight, suggesting that bigger pigs at weaning are not necessarily leaner pigs. In a separate study, slow growing (SG) and fast growing (FG) littermates that diverged from a common birth weight were scanned by DEXA to measure body composition. Scans showed that SG piglets are leaner with 90.2% lean tissue mass versus 86.6% for the FG piglets. SG piglets also had lower concentrations of body fat (9.8%) than the FG littermates (13.4%). These data suggest that selecting pigs for high pre-weaning growth rate may result in inefficient pigs with an increased propensity for fat gain, thus reducing the efficiency of production.

4. Accomplishments
1. Adipose tissue secretes immunological factors that affect critical energy storage in the neonatal pig. Neonatal mortality in swine is approaching 20%, at a huge cost to farmers. Survival is dependent on adequate energy stores and the primary site of energy storage in the neonatal pig is fat. This research by ARS scientists at Beltsville, Maryland addresses the Global Food Security priority by determining if neonatal pig fat produces the cytokine tumor necrosis a (TNFa) and if this cytokine affects fat storage in the neonatal pig, since this protein is known in humans to reduce fat production. Blood levels of TNFa and TNFa gene expression in fat tissue were shown to rise from birth to weaning and paralleled the accumulation of body fat during the preweaning period, implying that TNFa is secreted by neonatal pig adipose tissue. The metabolic consequence of this TNFa production was to block the ability for insulin to stimulate energy storage in the fat. Thus, TNFa potentially affects neonatal survival by modifying the accumulation of critical energy stores and the development of methods to reduce its production in the fat may improve neonatal survival of pigs.

Review Publications
Mitchell, A.D. 2011. Validation of QMR body composition analysis for infants. Pediatric Research. 69(4):330-335.

Blomberg, L., Schreier, L.L., Li, R.W. 2010. Characteristics of peri-implantation porcine concepti population and maternal milieu influence the transcriptome profile. Journal of Molecular Reproduction and Development. 77:978-989.

Last Modified: 2/23/2016
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