Skip to main content

Advertisement

SpringerLink
Log in

Influence of pregnancy and non-fasting conditions on the plasma metabolome in a rat prenatal toxicity study

  • Reproductive Toxicology
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

The current parameters for determining maternal toxicity (e.g. clinical signs, food consumption, body weight development) lack specificity and may underestimate the extent of effects of test compounds on the dams. Previous reports have highlighted the use of plasma metabolomics for an improved and mechanism-based identification of maternal toxicity. To establish metabolite profiles of healthy pregnancies and evaluate the influence of food consumption as a confounding factor, metabolite profiling of rat plasma was performed by gas- and liquid-chromatography-tandem mass spectrometry techniques. Metabolite changes in response to pregnancy, food consumption prior to blood sampling (non-fasting) as well as the interaction of both conditions were studied. In dams, both conditions, non-fasting and pregnancy, had a marked influence on the plasma metabolome and resulted in distinct individual patterns of changed metabolites. Non-fasting was characterized by increased plasma concentrations of amino acids and diet related compounds and lower levels of ketone bodies. The metabolic profile of pregnant rats was characterized by lower amino acids and glucose levels and higher concentrations of plasma fatty acids, triglycerides and hormones, capturing the normal biochemical changes undergone during pregnancy. The establishment of metabolic profiles of pregnant non-fasted rats serves as a baseline to create metabolic fingerprints for prenatal and maternal toxicity studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Availability of data and material

All data generated or analysed during this study are included in this published article and its supplementary information files.

References

  • Abumrad NN, Williams P, Frexes-Steed M, Geer R, Flakoll P, Cersosimo E, Hourani H (1989) Inter-organ metabolism of amino acids in vivo. Diabetes Metab Rev 5(3):213–226

    Article  CAS  PubMed  Google Scholar 

  • Adibi SA, Mercer DW (1973) Protein digestion in human intestine as reflected in luminal, mucosal, and plasma amino acid concentrations after meals. J Clin Investig 52(7):1586–1594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aikawa T, Matsutaka H, Yamamoto H, Okuda T, Ishikawa E, Kawano T, Matsumura E (1973) Gluconeogenesis and amino acid metabolism: II. Inter-organal relations and roles of glutamine and alanine in the amino acid metabolism of fasted rats. The Journal of Biochemistry 74(5):1003–1017

    CAS  PubMed  Google Scholar 

  • Altobelli G, Bogdarina IG, Stupka E, Clark AJ, Langley-Evans S (2013) Genome-wide methylation and gene expression changes in newborn rats following maternal protein restriction and reversal by folic acid. PLoS ONE 8(12):e82989

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Alton G, Hasilik M, Niehues R, Panneerselvam K, Etchison JR, Fana F, Freeze HH (1998) Direct utilization of mannose for mammalian glycoprotein biosynthesis. Glycobiology 8(3):285–295

    Article  CAS  PubMed  Google Scholar 

  • Alvarez J, Montelongo A, Iglesias A, Lasuncion M, Herrera E (1996) Longitudinal study on lipoprotein profile, high density lipoprotein subclass, and postheparin lipases during gestation in women. J Lipid Res 37(2):299–308

    Article  CAS  PubMed  Google Scholar 

  • Argilés JM, Herrera Castillón E (1981) Lipids and lipoproteins in maternal and fetus plama in the rat. Biol Neonate 39(1–2):37–44

  • Assel B, Rossi K, Kalhan S (1993) Glucose metabolism during fasting through human pregnancy: comparison of tracer method with respiratory calorimetry. Am J Physiol-Endocrinol Metab 265(3):E351–E356

    Article  CAS  Google Scholar 

  • Bahado-Singh R, Poon LC, Yilmaz A, Syngelaki A, Turkoglu O, Kumar P, Li J (2017) Integrated proteomic and metabolomic prediction of term preeclampsia. Sci Rep 7(1):1–10

    Article  CAS  Google Scholar 

  • Barry S, Clarke G, Scully P, Dinan T (2009) Kynurenine pathway in psychosis: evidence of increased tryptophan degradation. J Psychopharmacol 23(3):287–294

    Article  CAS  PubMed  Google Scholar 

  • Bazer FW (2012) Endocrinology of pregnancy (Vol. 9). Springer Science & Business Media

    Google Scholar 

  • Behr C, Kamp H, Fabian E, Krennrich G, Mellert W, Peter E, Van Ravenzwaay B (2017) Gut microbiome-related metabolic changes in plasma of antibiotic-treated rats. Arch Toxicol 91(10):3439–3454

    Article  CAS  PubMed  Google Scholar 

  • Berger S, Bleich M, Schmid W, Cole TJ, Peters J, Watanabe H, Schütz G (1998) Mineralocorticoid receptor knockout mice: pathophysiology of Na+ metabolism. Proc Natl Acad Sci 95(16):9424–9429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boulter PR, Hoffman RS, Arky RA (1973) Pattern of sodium excretion accompanying starvation. Metabolism 22(5):675–683

    Article  CAS  PubMed  Google Scholar 

  • Boulter PR, Spark RF, Arky RA (1974) Dissociation of the renin–aldosterone system and refractoriness to the sodium-retaining action of mineralocorticoid during starvation in man. J Clin Endocrinol Metab 38(2):248–254

    Article  CAS  PubMed  Google Scholar 

  • Cersosimo E, Williams P, Radosevich P, Hoxworth B, Lacy W, Abumrad N (1986) Role of glutamine in adaptations in nitrogen metabolism during fasting. Am J Physiol-Endocrinol Metab 250(6):E622–E628

    Article  CAS  Google Scholar 

  • Cersosimo E, Williams PE, O’Donovan D, Lacy DB, Abumrad NN (1987) Role of acidosis in regulating hepatic nitrogen metabolism during fasting in conscious dog. Am J Physiol-Endocrinol Metab 252(3):E313–E319

    Article  CAS  Google Scholar 

  • Cetin I, Ronzoni S, Marconi AM, Perugino G, Corbetta C, Battaglia FC, Pardi G (1996) Maternal concentrations and fetal-maternal concentration differences of plasma amino acids in normal and intrauterine growth-restricted pregnancies. Am J Obstet Gynecol 174(5):1575–1583

    Article  CAS  PubMed  Google Scholar 

  • Chaves J, Herrera E (1978) Invitro glycerol metabolism in adipose tissue from fasted pregnant rats. Biochem Biophys Res Commun 85(4):1299–1306

    Article  CAS  PubMed  Google Scholar 

  • Clinton CM, Bain JR, Muehlbauer MJ, Li Y, Li L, O’Neal SK, Ferguson KK (2020) Non-targeted urinary metabolomics in pregnancy and associations with fetal growth restriction. Sci Rep 10(1):5307. https://doi.org/10.1038/s41598-020-62131-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Commission Regulation (EU) (2016) 2016/266 of 7 December 2015 amending, for the purpose of its adaptation to technical progress, Regulation (EC) No 440/2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH). Commission Regulation (EU) 2016/266

  • Cynober LA (2002) Plasma amino acid levels with a note on membrane transport: characteristics, regulation, and metabolic significance. Nutrition 18(9):761–766

    Article  CAS  PubMed  Google Scholar 

  • Di Giulio A, Carelli S, Castoldi R, Gorio A, Taricco E, Cetin I (2004) Plasma amino acid concentrations throughout normal pregnancy and early stages of intrauterine growth restricted pregnancy. J Matern Fetal Neonatal Med 15(6):356–362

    Article  PubMed  CAS  Google Scholar 

  • Diaz SLO, Pinto J, Graça GA, Duarte IF, Barros ANS, Galhano EI, Carreira IM (2011) Metabolic biomarkers of prenatal disorders: an exploratory NMR metabonomics study of second trimester maternal urine and blood plasma. J Proteome Res 10(8):3732–3742

    Article  CAS  PubMed  Google Scholar 

  • Diaz SO, Barros ANS, Goodfellow BJ, Duarte IF, Carreira IM, Galhano EI, Gil AM (2013) Following healthy pregnancy by nuclear magnetic resonance (NMR) metabolic profiling of human urine. J Proteome Res 12(2):969–979

    Article  CAS  PubMed  Google Scholar 

  • Doyle W, Crawford M, Wynn A, Wynn S (1990) The association between maternal diet and birth dimensions. J Nutr Med 1(1):9–17

    Google Scholar 

  • ECETOC (2004) Influence of maternal toxicity in studies on developmental toxicity. ECETOC WORKSHOP REPORT No. 4. (Brussels), p, 1(43), 114–115

  • Eckhardt ER, Wang DQH, Donovan JM, Carey MC (2002) Dietary sphingomyelin suppresses intestinal cholesterol absorption by decreasing thermodynamic activity of cholesterol monomers. Gastroenterology 122(4):948–956

    Article  CAS  PubMed  Google Scholar 

  • Farina A, Caramelli E, Concu M, Sekizawa A, Ruggeri R, Bovicelli L, Carinci P (2002) Testing normality of fetal DNA concentration in maternal plasma at 10–12 completed weeks’ gestation: a preliminary approach to a new marker for genetic screening. Prenatal Diagn 22(2):148–152

    Article  CAS  Google Scholar 

  • Ferraris RP (2001) Dietary and developmental regulation of intestinal sugar transport. Biochem J 360(2):265–276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gall WE, Beebe K, Lawton KA, Adam K-P, Mitchell MW, Nakhle PJ, Camastra S (2010) α-Hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population. PLoS ONE 5(5):e10883

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Giavini E, Menegola E (2012) The problem of maternal toxicity in developmental toxicity studies. Regul Toxicol Pharmacol 62(3):568–570. https://doi.org/10.1016/j.yrtph.2011.11.021

    Article  CAS  PubMed  Google Scholar 

  • Handelman SK, Romero R, Tarca AL, Pacora P, Ingram B, Maymon E, Erez O (2019) The plasma metabolome of women in early pregnancy differs from that of non-pregnant women. PLoS ONE 14(11):e0224682. https://doi.org/10.1371/journal.pone.0224682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hastie T, Tibshirani R, Narasimhan B, Chu G (2020) Impute: impute: Imputation for microarray data. R package version 1.54. 0

  • Hauguel S, Desmaizieres V, Challier J (1986) Glucose uptake, utilization, and transfer by the human placenta as functions of maternal glucose concentration. Pediatr Res 20(3):269–273

    Article  CAS  PubMed  Google Scholar 

  • Heitmann R, Bergman E (1978) Glutamine metabolism, interorgan transport and glucogenicity in the sheep. Am J Physiol-Endocrinol Metab 234(2):E197

    Article  CAS  Google Scholar 

  • Herrera E (2000) Metabolic adaptations in pregnancy and their implications for the availability of substrates to the fetus. Eur J Clin Nutr 54(1):S47–S51

    Article  CAS  PubMed  Google Scholar 

  • Herrera E (2002) Lipid metabolism in pregnancy and its consequences in the fetus and newborn. Endocrine 19(1):43–55

    Article  CAS  PubMed  Google Scholar 

  • Herrera E, Knopp RH, Freinkel N (1969) Carbohydrate metabolism in pregnancy: VI. Plasma fuels, insulin, liver composition, gluconeogenesis, and nitrogen metabolism during late gestation in the fed and fasted rat. J Clin Investig 48(12):2260–2272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herrera E, Palacin M, Martin A, Lasuncion MA (1985) Relationship between maternal and fetal fuels and placental glucose transfer in rats with maternal diabetes of varying severity. Diabetes 34(Supplement 2):42–46

    Article  CAS  PubMed  Google Scholar 

  • Herrera E, Ramos P, Lopez-Luna P, Lasuncion M (1994) Metabolic interactions during pregnancy in preparation for lactation. In: Serrano Rios M, Sastre A, Perez Juez MA, Entrala A, De Sabesti C (eds) Dairy products in human health and nutrition. Balkema, Rotterdam, pp 189–197. ISBN 90 5410 359 0

  • Herrera E, Amusquivar E, Lopez-Soldado I, Ortega H (2006) Maternal lipid metabolism and placental lipid transfer. Hormone Res Paediatr 65(Suppl. 3):59–64

    Article  CAS  Google Scholar 

  • Jang C, Oh SF, Wada S, Rowe GC, Liu L, Chan MC, Ibrahim A (2016) A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat Med 22(4):421–426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kalhan S, Rossi K, Gruca L, Burkett E, O’Brien A (1997) Glucose turnover and gluconeogenesis in human pregnancy. J Clin Investig 100(7):1775–1781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamlage B, Maldonado SG, Bethan B, Peter E, Schmitz O, Liebenberg V, Schatz P (2014) Quality markers addressing preanalytical variations of blood and plasma processing identified by broad and targeted metabolite profiling. Clin Chem 60(2):399–412

    Article  CAS  PubMed  Google Scholar 

  • Kamp H, Strauss V, Wiemer J, Leibold E, Walk T, Mellert W, Krennrich G (2012) Reproducibility and robustness of metabolome analysis in rat plasma of 28-day repeated dose toxicity studies. Toxicol Lett 215(2):143–149

    Article  CAS  PubMed  Google Scholar 

  • Keller J, Mellert W, Sperber S, Kamp H, Jiang X, Fabian E, van Ravenzwaay B (2019) Added value of plasma metabolomics to describe maternal effects in rat maternal and prenatal toxicity studies. Toxicol Lett 301:42–52. https://doi.org/10.1016/j.toxlet.2018.10.032

    Article  CAS  PubMed  Google Scholar 

  • Khera KS (1984) Maternal toxicity—a possible factor in fetal malformations in mice. Teratology 29:411–416

    Article  CAS  PubMed  Google Scholar 

  • Khera KS (1987) Maternal toxicity in humans and animals: effects on fetal development and criteria for detection. Teratog Carcinog Mutagen 7:287–295

    Article  CAS  PubMed  Google Scholar 

  • Kim G, Chevli K, Fitch C (1983) Fasting modulates creatine entry-into skeletal muscle in the mouse. Experientia 39(12):1360–1362

    Article  CAS  PubMed  Google Scholar 

  • Knopp RH, MontesChildsLiMabuchi AMJRH (1981) Metabolic adjustments in normal and diabetic pregnancy. Clin Obstet Gynecol 24(1):21–49

    Article  CAS  PubMed  Google Scholar 

  • Kuhlbäuck B, Widholm O (1966) Plasma creatinine in normal pregnancy. Scand J Clin Lab Invest 18(6):654–656

    Article  Google Scholar 

  • Leone TC, Weinheimer CJ, Kelly DP (1999) A critical role for the peroxisome proliferator-activated receptor α (PPARα) in the cellular fasting response: the PPARα-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci 96(13):7473–7478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li P, Wu G (2018) Roles of dietary glycine, proline, and hydroxyproline in collagen synthesis and animal growth. Amino Acids 50(1):29–38

    Article  CAS  PubMed  Google Scholar 

  • Lindon JC, Holmes E, Nicholson JK (2004) Toxicological applications of magnetic resonance. Prog Nucl Magn Reson Spectrosc 1(45):109–143

    Article  CAS  Google Scholar 

  • Lindon JC, Holmes E, Nicholson JK (2006) Metabonomics techniques and applications to pharmaceutical research & development. Pharm Res 23(6):1075–1088

    Article  CAS  PubMed  Google Scholar 

  • Lippi G, Albiero A, Montagnana M, Salvagno GL, Scevarolli S, Franchi M, Guidi GC (2007) Lipid and lipoprotein profile in physiological pregnancy. Clin Lab 53(3–4):173–178

    CAS  PubMed  Google Scholar 

  • Lo YD, Tein MS, Lau TK, Haines CJ, Leung TN, Poon PM, Hjelm NM (1998) Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet 62(4):768–775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luan H, Meng N, Liu P, Feng Q, Lin S, Fu J, Chen F (2014) Pregnancy-induced metabolic phenotype variations in maternal plasma. J Proteome Res 13(3):1527–1536

    Article  CAS  PubMed  Google Scholar 

  • Lun FM, Chiu RW, Allen Chan K, Yeung Leung T, Kin Lau T, Dennis Lo Y (2008) Microfluidics digital PCR reveals a higher than expected fraction of fetal DNA in maternal plasma. Clin Chem 54(10):1664–1672

    Article  CAS  PubMed  Google Scholar 

  • Lund P, Wiggins D (1986) The ornithine requirement of urea synthesis. Formation of ornithine from glutamine in hepatocytes. Biochem J 239(3):773–776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacFarlane NG (2018) Digestion and absorption. Anaesth Intensive Care Med 19(3):125–127

    Article  Google Scholar 

  • Maes M, Verkerk R, Bonaccorso S, Ombelet W, Bosmans E, Scharpé S (2002) Depressive and anxiety symptoms in the early puerperium are related to increased degradation of tryptophan into kynurenine, a phenomenon which is related to immune activation. Life Sci 71(16):1837–1848

    Article  CAS  PubMed  Google Scholar 

  • Mascioli SR, Bantle JP, Freier EF, Hoogwerf BJ (1984) Artifactual elevation of serum creatinine level due to fasting. Arch Intern Med 144(8):1575–1576

    Article  CAS  PubMed  Google Scholar 

  • Mattes W, Kamp H, Fabian E, Herold M, Krennrich G, Looser R, van Ravenzwaay B (2013) Prediction of clinically relevant safety signals of nephrotoxicity through plasma metabolite profiling. BioMed Res Int 2013:202497

  • Mattes W, Davis K, Fabian E, Greenhaw J, Herold M, Looser R, Moeller N (2014) Detection of hepatotoxicity potential with metabolite profiling (metabolomics) of rat plasma. Toxicol Lett 230(3):467–478

    Article  CAS  PubMed  Google Scholar 

  • Mellert W, Kapp M, Strauss V, Wiemer J, Kamp H, Walk T, van Ravenzwaay B (2011) Nutritional impact on the plasma metabolome of rats. Toxicol Lett 207(2):173–181. https://doi.org/10.1016/j.toxlet.2011.08.013

    Article  CAS  PubMed  Google Scholar 

  • Milano G, Hotston-Moore A, Lobley G (2000) Influence of hepatic ammonia removal on ureagenesis, amino acid utilization and energy metabolism in the ovine liver. Br J Nutr 83(3):307–315

    Article  CAS  PubMed  Google Scholar 

  • Montoya G, Strauss V, Fabian E, Kamp H, Mellert W, Walk T, Peter E (2014) Mechanistic analysis of metabolomics patterns in rat plasma during administration of direct thyroid hormone synthesis inhibitors or compounds increasing thyroid hormone clearance. Toxicol Lett 225(2):240–251

    Article  CAS  PubMed  Google Scholar 

  • Moore PS, Koontz JW (1989) Insulin-mediated regulation of tyrosine aminotransferase in rat hepatoma cells: inhibition of transcription and inhibition of enzyme degradation. Arch Biochem Biophys 275(2):486–495

    Article  CAS  PubMed  Google Scholar 

  • Nicolosi BF, Leite DF, Mayrink J, Souza RT, Cecatti JG, Calderon IDMP (2019) Metabolomics for predicting hyperglycemia in pregnancy: a protocol for a systematic review and potential meta-analysis. Syst Control Found Appl 8(1):218

    Google Scholar 

  • Nieuwenhuizen WF, Duivenvoorden I, Voshol PJ, Rensen PC, van Duyvenvoorde W, Romijn JA, Havekes LM (2007) Dietary sphingolipids lower plasma cholesterol and triacylglycerol and prevent liver steatosis. Eur J Lipid Sci Technol 109(10):994–997

    Article  CAS  Google Scholar 

  • Norris GH, Blesso CN (2017) Dietary and endogenous sphingolipid metabolism in chronic inflammation. Nutrients 9(11):1180

    Article  PubMed Central  CAS  Google Scholar 

  • Numan M (1988) Maternal behavior. Physiol Reprod 2:1569–1645

    Google Scholar 

  • OECD (1992) Decision of the council concerning the mutual acceptance of data in the assessment of chemicals (C(81)30(Final)). Adopted by the council at its 535th meeting on 12 May 1981

  • OECD (2001) Test No. 414: prenatal development toxicity study. OECD Publishing, Paris

  • OECD (2018) OECD 414 OECD Guideline for testing of chemicals: Prenatal developmental toxicity study. OECD

    Book  Google Scholar 

  • O’Gorman A, Gibbons H, Brennan L (2013) Metabolomics in the identification of biomarkers of dietary intake. Comput Struct Biotechnol J 4(5):e201301004

    Article  PubMed  PubMed Central  Google Scholar 

  • Owen OE, Felig P, Morgan AP, Wahren J, Cahill GF (1969) Liver and kidney metabolism during prolonged starvation. J Clin Investig 48(3):574–583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Palan PR, Shaban DW, Martino T, Mikhail MS (2004) Lipid-soluble antioxidants and pregnancy: maternal serum levels of coenzyme Q10, α-tocopherol and γ-tocopherol in preeclampsia and normal pregnancy. Gynecol Obstet Invest 58(1):8–13

    Article  CAS  PubMed  Google Scholar 

  • Pinto J, Barros ANS, Domingues MRRM, Goodfellow BJ, Galhano EI, Pita C, Gil AM (2015) Following healthy pregnancy by NMR metabolomics of plasma and correlation to urine. J Proteome Res 14(2):1263–1274

    Article  CAS  PubMed  Google Scholar 

  • Pulkkinen M, Hämäläinen MM (1995) Myometrial estrogen and progesterone receptor binding in pregnancy: inhibition by the detergent action of phospholipids. J Steroid Biochem Mol Biol 52(3):287–294

    Article  CAS  PubMed  Google Scholar 

  • RCore T (2016) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria

  • Roessner U, Wagner C, Kopka J, Trethewey RN, Willmitzer L (2000) Technical advance: simultaneous analysis of metabolites in potato tuber by gas chromatography-mass spectrometry. Plant J 23:131–142. https://doi.org/10.1046/j.1365-313x.2000.00774.x

  • Reece EA, Homko C, Wiznitzer A (1994) Metabolic changes in diabetic and nondiabetic subjects during pregnancy. Obstet Gynecol Surv 49(1):64–71

    Article  CAS  PubMed  Google Scholar 

  • Rogers JM, Chernoff N, Keen CL, Daston GP (2005) Evaluation and interpretation of maternal toxicity in Segment II studies: issues, some answers, and data needs. Toxicol Appl Pharmacol 207(2):367–374

    Article  PubMed  CAS  Google Scholar 

  • Ronzaud C, Loffing J, Bleich M, Gretz N, Gröne H-J, Schütz G, Berger S (2007) Impairment of sodium balance in mice deficient in renal principal cell mineralocorticoid receptor. J Am Soc Nephrol 18(6):1679–1687

    Article  CAS  PubMed  Google Scholar 

  • Rubio-Aliaga I, de Roos B, Duthie SJ, Crosley LK, Mayer C, Horgan G, Kremer W (2011) Metabolomics of prolonged fasting in humans reveals new catabolic markers. Metabolomics 7(3):375–387

    Article  CAS  Google Scholar 

  • Schmelz E-M, Crall KJ, Larocque R, Dillehay DL, Merrill AH Jr (1994) Uptake and metabolism of sphingolipids in isolated intestinal loops of mice. J Nutr 124(5):702–712

    Article  CAS  PubMed  Google Scholar 

  • Schmidt JA, Rinaldi S, Scalbert A, Ferrari P, Achaintre D, Gunter MJ, Travis RC (2016) Plasma concentrations and intakes of amino acids in male meat-eaters, fish-eaters, vegetarians and vegans: a cross-sectional analysis in the EPIC-Oxford cohort. Eur J Clin Nutr 70(3):306–312

    Article  CAS  PubMed  Google Scholar 

  • Shen G, Li Z, Zhang Y, Wu H, Feng J (2016) 1H NMR-based metabolomics study on the physiological variations during the rat pregnancy process. Mol Cell Endocrinol 423:40–50

    Article  CAS  PubMed  Google Scholar 

  • Sims EA, Krantz KE (1958) Serial studies of renal function during pregnancy and the puerperium in normal women. J Clin Investig 37(12):1764–1774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sola MM, Oliver FJ, Salto R, Gutiérrez M, Vargas A (1994) Citrate inhibition of rat-kidney cortex phosphofructokinase. Mol Cell Biochem 135(2):123–128

    Article  CAS  PubMed  Google Scholar 

  • Strauss V, Wiemer J, Leibold E, Kamp H, Walk T, Mellert W, Krennrich G (2009) Influence of strain and sex on the metabolic profile of rats in repeated dose toxicological studies. Toxicol Lett 191(1):88–95

    Article  CAS  PubMed  Google Scholar 

  • Team R (2015) RStudio: integrated development environment. RStudio, PBC, Boston

    Google Scholar 

  • Teruya T, Chaleckis R, Takada J, Yanagida M, Kondoh H (2019) Diverse metabolic reactions activated during 58-hr fasting are revealed by non-targeted metabolomic analysis of human blood. Sci Rep 9(1):1–11

    Article  CAS  Google Scholar 

  • Townsend MK, Bao Y, Poole EM, Bertrand KA, Kraft P, Wolpin BM, Tworoger SS (2016) Impact of pre-analytic blood sample collection factors on metabolomics. Cancer Epidemiol Prev Biomark 25(5):823–829

    Article  CAS  Google Scholar 

  • Van Ravenzwaay B, Cunha GC-P, Leibold E, Looser R, Mellert W, Prokoudine A, Wiemer J (2007) The use of metabolomics for the discovery of new biomarkers of effect. Toxicol Lett 172(1–2):21–28

    Article  PubMed  CAS  Google Scholar 

  • Van Ravenzwaay B, Cunha G, Fabian E, Herold M, Kamp H, Krennrich G, Mellert W (2010a) The Use of metabolomics in cancer research. In: Cho W (ed) An omics perspective on cancer research. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-2675-0_8

  • Van Ravenzwaay B, Cunha G, Strauss V, Wiemer J, Leibold E, Kamp H, Prokoudine A (2010b) The individual and combined metabolite profiles (metabolomics) of dibutylphthalate and di (2-ethylhexyl) phthalate following a 28-day dietary exposure in rats. Toxicol Lett 198(2):159–170

    Article  PubMed  CAS  Google Scholar 

  • Van Ravenzwaay B, Herold M, Kamp H, Kapp M, Fabian E, Looser R, Strauss V (2012) Metabolomics: a tool for early detection of toxicological effects and an opportunity for biology based grouping of chemicals—from QSAR to QBAR. Mutation Research/genet Toxicol Environ Mutagen 746(2):144–150

    Article  CAS  Google Scholar 

  • Van Ravenzwaay B, Kamp H, Montoya-Parra G, Strauss V, Fabian E, Mellert W, Looser R (2015) The development of a database for metabolomics–looking back on ten years of experience. Int J Biotechnol 14(1):47–68

    Article  Google Scholar 

  • van Ravenzwaay B, Kolle S, Ramirez T, Kamp H (2013) Vinclozolin: a case study on the identification of endocrine active substances in the past and a future perspective. Toxicol Lett 223(3):271–279

    Article  PubMed  CAS  Google Scholar 

  • van Ravenzwaay B, Montoya GA, Fabian E, Herold M, Krennrich G, Looser R, Kamp H (2014) The sensitivity of metabolomics versus classical regulatory toxicology from a NOAEL perspective. Toxicol Lett 227(1):20–28. https://doi.org/10.1016/j.toxlet.2014.03.004

    Article  CAS  PubMed  Google Scholar 

  • Venegas C, Cabrera-Vique C, García-Corzo L, Escames G, Acuña-Castroviejo D, López LC (2011) Determination of coenzyme Q10, coenzyme Q9, and melatonin contents in virgin argan oils: comparison with other edible vegetable oils. J Agric Food Chem 59(22):12102–12108

    Article  CAS  PubMed  Google Scholar 

  • Walker JB (1963) End-product repression in the creatine pathway of the developing chick embryo. Adv Enzyme Regul 1:151–168

    Article  CAS  PubMed  Google Scholar 

  • Wang Q, Würtz P, Auro K, Mäkinen V-P, Kangas AJ, Soininen P, Santalahti K (2016) Metabolic profiling of pregnancy: cross-sectional and longitudinal evidence. BMC Med 14(1):1–14

    Article  CAS  Google Scholar 

  • Wang M, Xia W, Li H, Liu F, Li,Y, Sun X, Xu S (2018) Normal pregnancy induced glucose metabolic stress in a longitudinal cohort of healthy women: novel insights generated from a urine metabolomics study. Medicine 97(40):e12417

  • Weiner ID, Verlander JW (2013) Renal ammonia metabolism and transport. Compr Physiol 3(1):201–220

    Article  PubMed  PubMed Central  Google Scholar 

  • Welbourne T, Childress D, Givens G (1986) Renal regulation of interorgan glutamine flow in metabolic acidosis. Am J Physiol-Regul Integr Comp Physiol 251(5):R859–R866

    Article  CAS  Google Scholar 

  • Wickham H (2016) ggplot2: elegant graphics for data analysis. Springer

    Book  Google Scholar 

  • Yamada H, Yamahara A, Yasuda S, Abe M, Oguri K, Fukushima S, Ikeda-Wada S (2002) Dansyl chloride derivatization of methamphetamine: a method with advantages for screening and analysis of methamphetamine in urine. J Anal Toxicol 26(1):17–22

    Article  CAS  PubMed  Google Scholar 

  • Yunoki K, Renaguli M, Kinoshita M, Matsuyama H, Mawatari S, Fujino T, Ohnishi M (2010) Dietary sphingolipids ameliorate disorders of lipid metabolism in Zucker fatty rats. J Agric Food Chem 58(11):7030–7035

    Article  CAS  PubMed  Google Scholar 

  • Zhang F, Rick D, Kan L, Perala A, Geter D, LeBaron M, Bartels M (2011) Simultaneous quantitation of testosterone and estradiol in human cell line (H295R) by liquid chromatography/positive atmospheric pressure photoionization tandem mass spectrometry. Rapid Commun Mass Spectrom 25(20):3123–3130

    Article  CAS  PubMed  Google Scholar 

  • Zhang C, Feng Y-CA, Fiehn O, Tsai MY, Zhu Y, Albert P, Liang L (2018) Plasma metabolomics reveal novel metabolites in early pregnancy in association with gestational diabetes risk. Am Diabetes Assoc

    Book  Google Scholar 

  • Zheng X, Zhou K, Zhang Y, Han X, Zhao A, Liu J, Hernandez B (2018) Food withdrawal alters the gut microbiota and metabolome in mice. FASEB J 32(9):4878–4888

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was funded by the internal company resources.

Author information

Authors and Affiliations

  1. Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen, Germany

    S. Ramirez-Hincapie, V. Giri, J. Keller, H. Kamp & B. van Ravenzwaay

  2. BASF Metabolome Solution GmbH, Berlin, Germany

    V. Haake

  3. Food Chemistry and Toxicology, Department of Chemistry, University of Kaiserslautern, Kaiserslautern, Germany

    E. Richling

Authors
  1. S. Ramirez-Hincapie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. Giri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Keller
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H. Kamp
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. V. Haake
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E. Richling
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B. van Ravenzwaay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B. van Ravenzwaay.

Ethics declarations

Conflicts of interest/Competing interests

The author(s) declare(s) that there is no conflict of interest.

Ethics approval

All ethics approvals are included in the methods section of the manuscript.

Consent to participate and Consent for publication

All authors have approved the manuscript and agree with its submission.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 267 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ramirez-Hincapie, S., Giri, V., Keller, J. et al. Influence of pregnancy and non-fasting conditions on the plasma metabolome in a rat prenatal toxicity study. Arch Toxicol 95, 2941–2959 (2021). https://doi.org/10.1007/s00204-021-03105-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-021-03105-0

Keywords

Search

Navigation