Homeostasis, the dynamic state of physiological balance, is fundamentally changed in mammals exposed to either microgravity (spaceflight) or hypergravity (centrifugation). In pregnant and lactating mammals, failure to maintain homeostasis exerts pronounced effects on both mothers and their offspring. Our previous data, derived from pregnant rats exposed to either micro- or hypergravity, support: 1) decreased mammary metabolic activity with increased gravitational force; 2) changes in maternal and neonatal energy balance; 3) altered maternal care; and 4) neonatal mortality. The specific aims are:
1. To measure metabolic and hormonal changes in metabolism during hypergravity that may explain how gravitational forces alter whole body physiology during preganncy and lactation.
2. To measure behavioral changes that are coupled with physiological changes when animals are exposed to hypergravity and have the additional stress of pregnancy and lactation.
Further studies were designed to determine if: 1) the lactation defect was caused by changes in energy balance; 2) the lactation defect could be corrected by injections of prolactin or bromocryptine; or 3) global gene expression profiles would elucidate an alternate mechanism to explain the lactation defect that occurs in hypergravity. Studies supported by this grant demonstrated that Perturbations in PRL concentration were accompanied by a decrease in PRL receptor (PRLR) mRNA abundance. Further experiments were conducted to evaluate whether glucocorticoid supplementation could increase the PRLR in animals exposed to HG. Preliminary investigations utilizing across tissue gene enrichment analysis identified derangement in a unique set of genes pivotal to lipid synthesis in HG rats, particularly, in the lactating mammary gland. Therefore, investigations were extended to map-out other alterations in transcriptional crosstalk across key metabolic tissues induced by exposure to HG during the transition from pregnancy to lactation.
Mammary metabolism as measured by glucose oxidation to carbon dioxide and incorporation into lipid was significantly decreased in response to hypergravity during pregnancy and lactation. There was also a very significant response to hypergravity with all animals exhibiting a marked decrease in mammary metabolism (p < .0001). Along with other metabolic and behavioral changes, fetal weight is decreased and survival of the neonates decreases to 50% within the first 48 hours after birth for animals exposed to 2-G. This indicates that hypergravity causes a mammary metabolic defect during both pregnancy and lactation. Changes in mammary metabolism were due to hypergravity and in general were independent of food intake. Serum Prolactin levels tends to be very variable among animals and have not shown a consistent relationship to the changes in metabolism. Neither Prolactin nor bromocryptine injection affected mammary metabolism. That is, glucose oxidation to carbon dioxide was reduced about 30% and glucose incorporation into lipid was reduced 70% compared to stationary controls, which was no different than the hypergravity controls.
Behavioral analyses indicated that the behavior was not altered to the extent previously thought, indicating that a lack of mothering ability is not likely causing the observed neonatal mortality. However, the amount of time nursing may be increased, which may be related to reduced milk production.
Expression of number of metabolic genes such as ATP citratate lyase and acetyl co A carboxylase as well as the Prl receptor were altered due to hypergravity indicating that changes in gene expression during hypergravity acccompany the observed metabolic changes. The established novel data set encompassing gene expression signatures and in-vitro incorporation of labeled glucose into lipids across key metabolic tissues is to be utilized to develop a testable and mechanism-based model of the biological system. Alterations in transcriptional crosstalk across key metabolic tissues that were induced by exposure to HG during the transition from pregnancy to lactation were identified. Gene expression data sets ("Transcription profiling of rat response to changes in developmental stage - 3 types of tissue, 3 gravity conditions, 2 developmental conditions") are available at NASA's GeneLab repository (accession number GLDS-63).
Casey T, Patel O, Dykema K, Dover H, Furge K, Plaut K. "Molecular signatures reveal circadian clocks may orchestrate the homeorhetic response to lactation." PLoS One. 2009 Oct 9;4(10):e7395. doi: 10.1371/journal.pone.0007395
Casey T, Patel OV, Plaut K. "Transcriptomes reveal alterations in gravity impact circadian clocks and activate mechanotransduction pathways with adaptation through epigenetic change." Physiol Genomics. 2015 Apr;47(4):113-28. http://dx.doi.org/10.1152/physiolgenomics.00117.2014.
Casey T, Zakrzewska EI, Maple RL, Lintault L, Wade CE, Baer LA, Ronca AE, Plaut K. (2012). "Hypergravity disruption of homeorhetic adaptations to lactation in rat dams include changes in circadian clocks." Biology Open, 1:570-581. doi:10.1242/bio.2012687
Lintault LM, Zakrzewska EI, Maple RL, Baer LA, Casey TM, Ronca AE, Wade CE, Plaut K. "In a hypergravity environment neonatal survival is adversely affected by alterations in dam tissue metabolism rather than reduced food intake." J Appl Physiol. 2007 Jun;102(6):2186-93.
Patel OV, Casey T, Dover H, Plaut K. "Homeorhetic adaptation to lactation: comparative transcriptome analysis of mammary, liver, and adipose tissue during the transition from pregnancy to lactation in rats." Funct Integr Genomics. 2011 Mar;11(1):193-202. doi: 10.1007/s10142-010-0193-0. Epub 2010 Sep 18.
Patel OV, Maple R, Bear L, Ronca A, Wade C, Plaut K. "Tissue-specific variation in expression of prolactin receptor gene subtypes in hypergravity-exposed rats." Journal of Gravitational Physiology 2007;14: 129-30.
Patel OV, Zakrzewska E, Maple RL, Baer LA, Ronca AE, Wade CE, Plaut K. "Lipogenesis impaired in periparturient rats exposed to altered gravity is independent of prolactin and glucocorticoid secretion." Eur J Appl Physiol. 2008 Nov;104(5):847-58. doi:10.1007/s00421-008-0840-5. (NOTE: originally reported as "American journal of physiology. Regulatory, integrative and comparative physiology, Submitted October 2007.")
Plaut K, Maple R, Vyas C, Munaim S, Darling A, Casey T, Alberts, JR. The effects of spaceflight on mammary metabolism in pregnant rats. Proc Soc Exp Biol Med. 222: 85–89, 1999.
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