Dataset Information

Effects of sex, age, and fasting conditions on plasma lipidomic profiles of fasted Sprague-Dawley rats.

ABSTRACT: Circulating lipid molecules reflect biological processes in the body and, thus, are useful tools for preclinical estimation of the efficacy and safety of newly developed drugs. However, background information on profiles of circulating lipid molecules in preclinical animal models is limited. Therefore, we examined the effects of multiple factors such as sex (fasted male vs. female), age (fasted 10 vs. 30 weeks old), and feeding conditions (feeding vs. fasting, 16 vs. 22 hr fasting, 10 AM vs. 4 PM blood collection), on the global profiles of lipid molecules in plasma from Sprague-Dawley rats by using a lipidomic approach. Our assay platform determined 262 lipid molecules (68 phospholipids, 20 sphingolipids, 138 neutral lipids, and 36 polyunsaturated fatty acids and their metabolites) in rat plasma. Multivariate discriminant analysis (orthogonal partial least squares discriminant analysis) and heat maps of statistically significant lipid molecules revealed that the plasma lipid profiles in rats are predominantly influenced by feeding conditions, followed by sex and age. In addition, the fasting duration (16 vs. 22 hr fasting) or the time of blood collection (10 AM vs. 4 PM blood collection) has limited or no contribution on the profiles of lipid molecules in rat plasma. Our results provide useful, fundamental information for exploring and validating biomarkers in future preclinical studies and may help to establish regulatory standards for such studies.

SUBMITTER: Saito K

PROVIDER: S-EPMC4223040 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Effects of sex, age, and fasting conditions on plasma lipidomic profiles of fasted Sprague-Dawley rats.

Saito Kosuke K Ishikawa Masaki M Murayama Mayumi M Urata Masayo M Senoo Yuya Y Toyoshima Katsuko K Kumagai Yuji Y Maekawa Keiko K Saito Yoshiro Y

PloS one 20141106 11

Circulating lipid molecules reflect biological processes in the body and, thus, are useful tools for preclinical estimation of the efficacy and safety of newly developed drugs. However, background information on profiles of circulating lipid molecules in preclinical animal models is limited. Therefore, we examined the effects of multiple factors such as sex (fasted male vs. female), age (fasted 10 vs. 30 weeks old), and feeding conditions (feeding vs. fasting, 16 vs. 22 hr fasting, 10 AM vs. 4 P ...[more]

PMID: 25375860

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Project description:Preclinical efforts to improve medical countermeasures against organophosphate (OP) chemical threat agents have largely focused on adult male models. However, age and sex have been shown to influence the neurotoxicity of repeated low-level OP exposure. Therefore, to determine the influence of sex and age on outcomes associated with acute OP intoxication, postnatal day 28 Sprague-Dawley male and female rats were exposed to the OP diisopropylfluorophosphate (DFP; 3.4 mg/kg, s.c.) or an equal volume of vehicle (∼80 µL saline, s.c.) followed by atropine sulfate (0.1 mg/kg, i.m.) and pralidoxime (2-PAM; 25 mg/kg, i.m.). Seizure activity was assessed during the first 4 h post-exposure using behavioral criteria and electroencephalographic (EEG) recordings. At 1 d post-exposure, acetylcholinesterase (AChE) activity was measured in cortical tissue, and at 1, 7, and 28 d post-exposure, brains were collected for neuropathologic analyses. At 1 month post-DFP, animals were analyzed for motor ability, learning and memory, and hippocampal neurogenesis. Acute DFP intoxication triggered more severe seizure behavior in males than females, which was supported by EEG recordings. DFP caused significant neurodegeneration and persistent microglial activation in numerous brain regions of both sexes, but astrogliosis occurred earlier and was more severe in males compared to females. DFP males and females exhibited pronounced memory deficits relative to sex-matched controls. In contrast, acute DFP intoxication altered hippocampal neurogenesis in males, but not females. These findings demonstrate that acute DFP intoxication triggers seizures in juvenile rats of both sexes, but the seizure severity varies by sex. Some, but not all, chronic neurotoxic outcomes also varied by sex. The spatiotemporal patterns of neurological damage suggest that microglial activation may be a more important factor than astrogliosis or altered neurogenesis in the pathogenesis of cognitive deficits in juvenile rats acutely intoxicated with OPs.

Project description:BackgroundSeveral chronic pain disorders, such as migraine and fibromyalgia, have an increased prevalence in the female population. The underlying mechanisms of this sex-biased prevalence have yet to be thoroughly documented, but could be related to endogenous differences in neuromodulators in pain networks, including the endocannabinoid system. The cellular endocannabinoid system comprises the endogenous lipid signals 2-AG (2-arachidonoylglycerol) and AEA (anandamide); the enzymes that synthesize and degrade them; and the cannabinoid receptors. The relative prevalence of different components of the endocannabinoid system in specific brain regions may alter responses to endogenous and exogenous ligands.MethodsBrain tissue from naïve male and estrous staged female Sprague Dawley rats was harvested from V1M cortex, periaqueductal gray, trigeminal nerve, and trigeminal nucleus caudalis. Tissue was analyzed for relative levels of endocannabinoid enzymes, ligands, and receptors via mass spectrometry, unlabeled quantitative proteomic analysis, and immunohistochemistry.ResultsMass spectrometry revealed significant differences in 2-AG and AEA concentrations between males and females, as well as between female estrous cycle stages. Specifically, 2-AG concentration was lower within female PAG as compared to male PAG (*p = 0.0077); female 2-AG concentration within the PAG did not demonstrate estrous stage dependence. Immunohistochemistry followed by proteomics confirmed the prevalence of 2-AG-endocannabinoid system enzymes in the female PAG.ConclusionsOur results suggest that sex differences exist in the endocannabinoid system in two CNS regions relevant to cortical spreading depression (V1M cortex) and descending modulatory networks in pain/anxiety (PAG). These basal differences in endogenous endocannabinoid mechanisms may facilitate the development of chronic pain conditions and may also underlie sex differences in response to therapeutic intervention.

Dataset Information

Effects of sex, age, and fasting conditions on plasma lipidomic profiles of fasted Sprague-Dawley rats.

Publications

Effects of sex, age, and fasting conditions on plasma lipidomic profiles of fasted Sprague-Dawley rats.

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