Plasma Retinoid Concentrations Are Altered in Pregnant Women

Lindsay C Czuba, Emily E Fay, Jeffrey LaFrance, Chase K Smith, Sara Shum, Sue L Moreni, Jennie Mao, Nina Isoherranen, Mary F Hebert, Lindsay C Czuba, Emily E Fay, Jeffrey LaFrance, Chase K Smith, Sara Shum, Sue L Moreni, Jennie Mao, Nina Isoherranen, Mary F Hebert

Abstract

Vitamin A is vital to maternal-fetal health and pregnancy outcomes. However, little is known about pregnancy associated changes in maternal vitamin A homeostasis and concentrations of circulating retinol metabolites. The goal of this study was to characterize retinoid concentrations in healthy women (n = 23) during two stages of pregnancy (25-28 weeks gestation and 28-32 weeks gestation) as compared to ≥3 months postpartum. It was hypothesized that plasma retinol, retinol binding protein 4 (RBP4), transthyretin and albumin concentrations would decline during pregnancy and return to baseline by 3 months postpartum. At 25-28 weeks gestation, plasma retinol (-27%), 4-oxo-13-cis-retinoic acid (-34%), and albumin (-22%) concentrations were significantly lower, and all-trans-retinoic acid (+48%) concentrations were significantly higher compared to ≥3 months postpartum in healthy women. In addition, at 28-32 weeks gestation, plasma retinol (-41%), retinol binding protein 4 (RBP4; -17%), transthyretin (TTR; -21%), albumin (-26%), 13-cis-retinoic acid (-23%) and 4-oxo-13-cis-retinoic acid (-48%) concentrations were significantly lower, whereas plasma all-trans-retinoic acid concentrations (+30%) were significantly higher than ≥3 months postpartum. Collectively, the data demonstrates that in healthy pregnancies, retinol plasma concentrations are lower, but all-trans-retinoic acid concentrations are higher than postpartum.

Keywords: postpartum; pregnancy; retinoid; retinol-binding protein 4 (RBP4); transthyretin (TTR); vitamin A.

Conflict of interest statement

N.I. reports consultancy agreements with Boehringer-Ingelheim and Johnson and Johnson. None of the other authors have conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
The average vitamin A intake (IU) for each participant was calculated based on self-reported food logs for the three days prior to SD1, SD2, and SD3 visits and were not significantly different between visits.
Figure 2
Figure 2
The plasma retinoid ((A) retinol (B) atRA (C) 13cisRA (D) 4oxo13cisRA) concentrations are altered in normal healthy pregnancies (n = 23) at 25–28 weeks gestation (SD1) and 28–32 weeks gestation (SD2) compared to 3–4 months PP (SD3). The ratio of (E) atRA to 13cisRA was higher during pregnancy while the ratio of (F) 4oxo13cisRA to 13cisRA was lower during pregnancy. In each analysis, one subject was excluded from the statistical comparison due to insufficient sample quantity in SD3 (red symbols).
Figure 3
Figure 3
The plasma (A) RBP4 and (B) TTR concentrations at 25–28 weeks gestation (SD1), 28–32 weeks gestation (SD2), and 3–4 months PP (SD3) were measured from 23 healthy pregnant women. The ratio of (C) retinol to RBP4 and (D) retinol to TTR were lower on both SD1 and SD2 in comparison to SD3. In panels C,D, one subject had insufficient sample to measure SD3 retinol concentrations (red symbols) and was excluded from the statistical comparison (n = 22 pregnant women).
Figure 4
Figure 4
Plasma (A) albumin was measured on each study visit during 25–28 weeks gestation (SD1), 28–32 weeks gestation (SD2), and 3–4 months PP (SD3). Plasma retinoid concentrations were normalized to the albumin concentration and shown as a ratio in (B–D). In panels B–D, one subject was excluded for statistical comparisons due insufficient sample for SD3 retinoid concentrations (red symbols) (n = 22 pregnant women).

References

    1. Carazo A., Macáková K., Matoušová K., Krčmová L.K., Protti M., Mladěnka P. Vitamin a Update: Forms, Sources, Kinetics, Detection, Function, Deficiency, Therapeutic Use and Toxicity. Nutrients. 2021;13:1703. doi: 10.3390/nu13051703.
    1. Li Y., Wongsiriroj N., Blaner W.S. The multifaceted nature of retinoid transport and metabolism. Hepatobiliary Surg. Nutr. 2014;3:126–139. doi: 10.3978/j.issn.2304-3881.2014.05.04.
    1. Jing J., Isoherranen N., Robinson-Cohen C., Petrie I., Kestenbaum B.R., Yeung C.K. Chronic Kidney Disease Alters Vitamin A Homeostasis via Effects on Hepatic RBP4 Protein Expression and Metabolic Enzymes. Clin. Transl. Sci. 2016;9:207–215. doi: 10.1111/cts.12402.
    1. Key T.J., Appleby P.N., Allen N.E., Travis R.C., Roddam A.W., Jenab M., Egevad L., Tjønneland A., Johnsen N.F., Overvad K., et al. Plasma Carotenoids, Retinol, and Tocopherols and the Risk of Prostate Cancer in the European Prospective Investigation into Cancer and Nutrition Study. Am. J. Clin. Nutr. 2007;86 doi: 10.1093/ajcn/86.3.672.
    1. Bell E.C., John M., Hughes R.J., Pham T. Ultra-Performance Liquid Chromatographic Determination of Tocopherols and Retinol in Human Plasma. J. Chromatogr. Sci. 2014;52:1065–1070. doi: 10.1093/chromsci/bmt161.
    1. Suzuki M., Wang T., Garretto D., Isasi C., Cardoso W., Greally J., Quadro L. Disproportionate Vitamin A Deficiency in Women of Specific Ethnicities Linked to Differences in Allele Frequencies of Vitamin A-Related Polymorphisms. Nutrients. 2021;13:1743. doi: 10.3390/nu13061743.
    1. Söderlund M.B., Fex G., Nilsson-Ehle P. Decreasing serum concentrations of all-trans, 13-cis retinoic acids and retinol during fasting and caloric restriction. J. Intern. Med. 2003;253:375–380. doi: 10.1046/j.1365-2796.2003.01114.x.
    1. Bastos Maia S., Rolland Souza A.S., Costa Caminha M.D., Lins da Silva S., Callou Cruz R.D., Carvalho dos Santos C., Batista Filho M. Vitamin A and Pregnancy: A Narrative Review. Nutrients. 2019;11:681. doi: 10.3390/nu11030681.
    1. Arnold S.L., Amory J., Walsh T.J., Isoherranen N. A sensitive and specific method for measurement of multiple retinoids in human serum with UHPLC-MS/MS. J. Lipid Res. 2012;53:587–598. doi: 10.1194/jlr.D019745.
    1. N’Soukpoé-Kossi C., Sedaghat-Herati R., Ragi C., Hotchandani S., Tajmir-Riahi H. Retinol and retinoic acid bind human serum albumin: Stability and structural features. Int. J. Biol. Macromol. 2007;40:484–490. doi: 10.1016/j.ijbiomac.2006.11.005.
    1. Stevison F., Kosaka M., Kenny J.R., Wong S., Hogarth C., Amory J., Isoherranen N. Does In Vitro Cytochrome P450 Downregulation Translate to In Vivo Drug-Drug Interactions? Preclinical and Clinical Studies with 13-cis-retinoic acid. Clin. Transl. Sci. 2019;12:350–360. doi: 10.1111/cts.12616.
    1. Gannon B.M., Jones C., Mehta S. Vitamin A Requirements in Pregnancy and Lactation. Curr. Dev. Nutr. 2020;4:nzaa142. doi: 10.1093/cdn/nzaa142.
    1. Quadro L., Spiegler E.K. Maternal-Fetal Transfer of Vitamin A and Its Impact on Mammalian Embryonic Development. In: Asson-Batres M.A., Rochette-Egly C., editors. The Biochemistry of Retinoid Signaling III: Vitamin A and Retinoic Acid in Embryonic Development. Springer International Publishing; Cham, Switzerland: 2020. pp. 27–55.
    1. Roberts C. Regulating Retinoic Acid Availability during Development and Regeneration: The Role of the CYP26 Enzymes. J. Dev. Biol. 2020;8:6. doi: 10.3390/jdb8010006.
    1. Topletz A.R., Zhong G., Isoherranen N. Scaling in vitro activity of CYP3A7 suggests human fetal livers do not clear retinoic acid entering from maternal circulation. Sci. Rep. 2019;9:4620. doi: 10.1038/s41598-019-40995-8.
    1. Spiegler E., Kim Y.-K., Wassef L., Shete V., Quadro L. Maternal–fetal transfer and metabolism of vitamin A and its precursor β-carotene in the developing tissues. Biochim. Biophys. Acta (BBA)-Mol. Cell Biol. Lipids. 2012;1821:88–98. doi: 10.1016/j.bbalip.2011.05.003.
    1. Li Y., Tajima A., Mattie F.J., Green M.H., Ross A.C. Pregnancy and Lactation Alter Vitamin A Metabolism and Kinetics in Rats under Vitamin A-Adequate Dietary Conditions. Nutrients. 2021;13:2853. doi: 10.3390/nu13082853.
    1. Radhika M.S., Bhaskaram P., Balakrishna N., Ramalakshmi B.A., Devi S., Siva Kumar B. Effects of Vitamin A Deficiency during Pregnancy on Maternal and Child Health. BJOG Int. J. Obstet. Gynaecol. 2002;109:689–693. doi: 10.1111/j.1471-0528.2002.01010.x.
    1. Hanson C., Lyden E., Abresch C., Anderson-Berry A. Serum Retinol Concentrations, Race, and Socioeconomic Status in of Women of Childbearing Age in the United States. Nutrients. 2016;8:508. doi: 10.3390/nu8080508.
    1. Hanson C., Lyden E., Anderson-Berry A., Kocmich N.I., Rezac A., Delair S., Furtado J., Van Ormer M., Izevbigie N., Olateju E.K., et al. Status of Retinoids and Carotenoids and Associations with Clinical Outcomes in Maternal-Infant Pairs in Nigeria. Nutrients. 2018;10:1286. doi: 10.3390/nu10091286.
    1. Baker H., DeAngelis B., Holland B., Gittens-Williams L., Barrett T., Jr. Vitamin Profile of 563 Gravidas during Trimesters of Pregnancy. J. Am. Coll. Nutr. 2002;21:33–37. doi: 10.1080/07315724.2002.10719191.
    1. Krzyzanowska K., Zemany L., Krugluger W., Schernthaner G.H., Mittermayer F., Schnack C., Rahman R., Brix J., Kahn B.B., Schernthaner G. Serum concentrations of retinol-binding protein 4 in women with and without gestational diabetes. Diabetologia. 2008;51:1115–1122. doi: 10.1007/s00125-008-1009-9.
    1. Sapin V., Alexandre M.C., Chaïb S., Bournazeau J.A., Sauvant P., Borel P., Jacquetin B., Grolier P., Lémery D., Dastugue B., et al. Effect of Vitamin A Status at the End of Term Pregnancy on Thesaturation of Retinol Binding Protein with Retinol. Am. J. Clin. Nutr. 2000;71:537–543. doi: 10.1093/ajcn/71.2.537.
    1. Inoue S., Takamoto N., Akahori Y., Masumoto A., Nakatsukasa H., Msuyama H., Hiramatsu Y. Elevated level of serum retinol-binding protein 4 in pregnancy-induced hypertension. J. Obstet. Gynaecol. Res. 2009;35:293–300. doi: 10.1111/j.1447-0756.2008.00950.x.
    1. Ueland T., Dalsoren T., Voldner N., Godang K., Henriksen T., Bollerslev J. Retinol-binding protein-4 is not strongly associated with insulin sensitivity in normal pregnancies. Eur. J. Endocrinol. 2008;159:49–54. doi: 10.1530/EJE-07-0682.
    1. Mendola P., Ghassabian A., Mills J., Zhang C., Tsai M., Liu A., Yeung E.H. Retinol-Binding Protein 4 and Lipids Prospectively Measured During Early to Mid-Pregnancy in Relation to Preeclampsia and Preterm Birth Risk. Am. J. Hypertens. 2017;30:569–576. doi: 10.1093/ajh/hpx020.
    1. Söderlund M.B., Fex G.A., Nilsson-Ehle P. Concentrations of retinoids in early pregnancy and in newborns and their mothers. Am. J. Clin. Nutr. 2005;81:633–636. doi: 10.1093/ajcn/81.3.633.
    1. Frederiksen M.C. Physiologic changes in pregnancy and their effect on drug disposition. Semin. Perinatol. 2001;25:120–123. doi: 10.1053/sper.2001.24565.
    1. Czuba L.C., Zhong G., Yabut K.C., Isoherranen N. In: Analysis of Vitamin A and Retinoids in Biological Matrices. Pohl E., editor. Volume 637. Academic Press Inc.; Cambridge, MA, USA: 2020.
    1. U.S. Food and Drug Administration Center for Drug Evaluation and Research [(accessed on 10 February 2022)];Bioanalytical Method Validation Guidance for Industry. 2018 FDA-2013-D-1020-0039. Available online: .
    1. Jing J., Nelson C., Paik J., Shirasaka Y., Amory J., Isoherranen N. Physiologically Based Pharmacokinetic Model of All-trans-Retinoic Acid with Application to Cancer Populations and Drug Interactions. J. Pharmacol. Exp. Ther. 2017;361:246–258. doi: 10.1124/jpet.117.240523.
    1. Fruscalzo A., Londero A.P., Driul L., Henze A., Tonutti L., Ceraudo M., Zanotti G., Berni R., Schweigert F.J., Raila J. First trimester concentrations of the TTR-RBP4-retinol complex components as early markers of insulin-treated gestational diabetes mellitus. Clin. Chem. Lab. Med. 2015;53:1643–1651. doi: 10.1515/cclm-2014-0929.
    1. Belatik A., Hotchandani S., Bariyanga J., Tajmir-Riahi H. Binding sites of retinol and retinoic acid with serum albumins. Eur. J. Med. Chem. 2012;48:114–123. doi: 10.1016/j.ejmech.2011.12.002.
    1. Garretto D., Kim Y.-K., Quadro L., Rhodas R.R., Pimentel V., Crnosija N.A., Nie L., Bernstein P., Tropper P., Neal-Perry G.S. Vitamin A and β-carotene in pregnant and breastfeeding post-bariatric women in an urban population. J. Périnat. Med. 2019;47:183–189. doi: 10.1515/jpm-2018-0142.
    1. Gao F., Guo F., Zhang Y., Yuan Y., Chen D., Bai G. Vitamin A, D, and E Levels and Reference Ranges for Pregnant Women: A Cross-Sectional Study 2017–2019. Front. Nutr. 2021;8:628902. doi: 10.3389/fnut.2021.628902.
    1. Yang C., Chen J., Liu Z., Yun C., Piao J., Yang X. Prevalence and influence factors of vitamin A deficiency of Chinese pregnant women. Nutr. J. 2015;15:12. doi: 10.1186/s12937-016-0131-7.
    1. Chen Y., Li Z.-D., Mao C.-Y., Kang X., Zhang S.-H. An investigation of the levels of vitamins A, D, and E in the serum of Chinese pregnant women. J. Clin. Lab. Anal. 2018;32:e22176. doi: 10.1002/jcla.22176.
    1. Liu J., Zhan S., Jia Y., Li Y., Liu Y., Dong Y., Tang G., Li L., Zhai Y., Cao Z. Retinol and α-tocopherol in pregnancy: Establishment of reference intervals and associations with CBC. Matern. Child Nutr. 2020;16:e12975. doi: 10.1111/mcn.12975.
    1. Yliniemi A., Nurkkala M.-M., Kopman S., Korpimaki T., Kouru H., Ryynanen M., Marttala J. First Trimester Placental Retinol-Binding Protein 4 (RBP4) and Pregnancy-Associated Placental Protein A (PAPP-A) in the Prediction of Early-Onset Severe Pre-Eclampsia. Metabolism. 2015;64:521–526. doi: 10.1016/j.metabol.2014.12.008.
    1. Saucedo R., Zarate A., Basurto L., Hernandez M., Puello E., Galvan R., Campos S. Relationship Between Circulating Adipokines and Insulin Resistance During Pregnancy and Postpartum in Women with Gestational Diabetes. Arch. Med. Res. 2011;42:318–323. doi: 10.1016/j.arcmed.2011.06.009.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren