A toxicology study to evaluate the embryotoxicity of metformin compared with the hypoglycemic drugs, the anticancer drug, the anti‐epileptic drug, the antibiotic, and the cyclo‐oxygenase (COX)‐2 inhibitor: 评价二甲双胍与降糖药、抗癌药、抗癫痫药、抗菌药以及环氧合酶‐2抑制剂相比的胚胎毒性的毒理学研究
Abstract
Background: The safe use of medications in pregnant females, their embryos and in offspring is important. The aim of the present study was to evaluate embryotoxicity of metformin (MET) compared with other hypoglycemic drugs (rosiglitazone [RSG] and glimepiride [GLIM]), the anticancer drug 5‐fluorouracil (5‐FU), the anti‐epileptic drug diphenylhydantoin (DPH), the antibiotic penicillin G (P en G), and the cyclo‐oxygenase (COX)‐2 inhibitor nimesulide (NIM) in an embryonic stem cell test (EST). Methods: Differences in the expression of developmental marker genes following treatment with the test compounds during the course of differentiation (from embryonic stem cell D 3 (D 3 cells) to myocardial cells) were determined using real‐time quantitative polymerase chain reaction. In these studies, 5‐FU was used as a positive control and P en G was used as a negative control. The cytotoxicity of these drugs against D 3 cells and 3 T 3 fibroblasts was determined by the 3‐(4,5‐dimethyl‐2 thiazoyl)‐2,5‐diphenyl‐2 H‐tetrazolium bromide (MTT) assay. Embryotoxicity was classified according to the prediction model of EST. Results: At concentrations >800 μ g/mL MET had a greater cytotoxic effect on D 3 cells than 3 T 3 fibroblasts. At the highest concentration of MET(5 mg/mL), the cell viability of D 3 cells and 3 T 3 fibroblasts was <10% and >30%, respectively. The size of the embryonic body (EB) differentiation area was almost the same over the concentration range 50–200 μ g/mL MET, and there was no significant difference in EB differentiation area until a concentration of 400 μ g/mL MET. At a concentration of 800 μ g/mL MET, the size of EB outgrowth was significantly reduced. The same assays revealed GLIM,RSG, and NIM to be weakly embryotoxic substances. Conclusions: Based on the EST,MET can be classified as a weakly embryotoxic substance, which suggests that it should be prescribed with caution to pregnant women with gestational diabetes.
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Metformin is weakly toxic towards embryonic stem cells.
“One study suggests that metformin, the most prescribed antidiabetic drug, is weakly toxic towards embryonic stem cells, and should be prescribed with caution to pregnant women [15].”
From Evaluating Traditional Chinese Medicine and Herbal Products for the Treatment of Gestational Diabetes Mellitus (2019) · cites this paper as [15]
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
The Principles of Humane Experimental Technique
(1960) · The Medical Journal of Australia · doi:10.5694/j.1326-5377.1960.tb73127.x · Cited by 5,002 · see citing works
Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes
Nissen, S. E., & Wolski, K. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa072761 · Cited by 4,675 · see citing works
Genschow, E., Spielmann, H., Scholz, G., Seiler, A. E. M., Brown, N. A., Piersma, A. H., Brady, M. C., Clemann, N., Huuskonen, H., Paillard, F., et al. (2002) · Alternatives to Laboratory Animals · doi:10.1177/026119290203000204 · Cited by 382 · see citing works
Genschow, E., Spielmann, H., Scholz, G., Pohl, I., Seiler, A. E. M., Clemann, N., Bremer, S., & Becker, K. (2004) · Alternatives to Laboratory Animals · doi:10.1177/026119290403200305 · Cited by 339 · see citing works
Use and Application of Stem Cells in Toxicology
Davila, J. C. (2004) · Toxicological Sciences · doi:10.1093/toxsci/kfh100 · Cited by 281 · see citing works
Cardiac specific differentiation of mouse embryonic stem cells
Sachinidis, A. (2003) · Cardiovascular Research · doi:10.1016/s0008-6363(03)00248-7 · Cited by 230 · see citing works
Spielmann, H. (1998) · Environmental Health Perspectives · doi:10.1289/ehp.98106571 · Cited by 228 · see citing works
An in vitro assay for teratogens with cultures of rat embryo midbrain and limb bud cells
Flint, O. P., & Orton, T. C. (1984) · Toxicology and Applied Pharmacology · doi:10.1016/0041-008x(84)90020-6 · Cited by 221 · see citing works
Ijäs, H., Vääräsmäki, M., Morin-Papunen, L. C., Keravuo, R., Ebeling, T., Saarela, T., & Raudaskoski, T. (2010) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.2010.02763.x · Cited by 215 · see citing works
Seiler, A. E. M., Visan, A., Buesen, R., Genschow, E., & Spielmann, H. (2004) · Reproductive Toxicology · doi:10.1016/j.reprotox.2003.10.015 · Cited by 189 · see citing works
Mouse embryonic stem cells express the cardiac myosin heavy chain genes during development in vitro.
Robbins, J. M., Gulick, J. M., Sanchez, A., Howles, P. N., & Doetschman, T. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)38485-6 · Cited by 172 · see citing works
Rohwedel, J., Guan, K., Hegert, C., & Wobus, A. M. (2001) · Toxicology in Vitro · doi:10.1016/s0887-2333(01)00074-1 · Cited by 168 · see citing works
Benefits and Risks of Oral Diabetes Agents Compared With Insulin in Women With Gestational Diabetes
Nicholson, W. K., Bolen, S. D., Witkop, C. T., Neale, D. M., Wilson, L. M., & Bass, E. B. (2009) · Obstetrics and Gynecology · doi:10.1097/aog.0b013e318190a459 · Cited by 160 · see citing works
Management of Diabetes in Pregnancy
Ballas, J., Moore, T. R., & Ramos, G. A. (2011) · Current Diabetes Reports · doi:10.1007/s11892-011-0249-0 · Cited by 143 · see citing works
Prevalidation of the Embryonic Stem Cell Test (EST)—A New In Vitro Embryotoxicity Test
Scholz, G., Genschow, E., Pohl, I., Bremer, S., Paparella, M., Raabe, H.-M., Southee, J. A., & Spielmann, H. (1999) · Toxicology in Vitro · doi:10.1016/s0887-2333(99)00046-6 · Cited by 141 · see citing works
Nieden, N. I. Z., Kempka, G., & Ahr, H. J. (2003) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2003.09.019 · Cited by 140 · see citing works
Piersma, A. H., Genschow, E., Verhoef, A. J., Spanjersberg, M. Q. I., Brown, N. A., Brady, M. C., Burns, A. K., Clemann, N., Seiler, A. E. M., & Spielmann, H. (2004) · Alternatives to Laboratory Animals · doi:10.1177/026119290403200307 · Cited by 131 · see citing works
Ijäs, H., Vääräsmäki, M., Saarela, T., Keravuo, R., & Raudaskoski, T. (2014) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/1471-0528.12964 · Cited by 127 · see citing works
Myosin heavy chain gene expression in mouse embryoid bodies. An in vitro developmental study.
Sánchez, A., Jones, W. K., Gulick, J. M., Doetschman, T., & Robbins, J. M. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)54589-0 · Cited by 122 · see citing works
Verwei, M., van Burgsteden, J. A., Krul, C. A. M., van de Sandt, J. J. M., & Freidig, A. P. (2006) · Toxicology Letters · doi:10.1016/j.toxlet.2006.01.017 · Cited by 109 · see citing works
First steps in establishing a developmental toxicity test method based on human embryonic stem cells
Adler, S., Pellizzer, C., Hareng, L., Härtung, T., & Bremer, S. (2007) · Toxicology in Vitro · doi:10.1016/j.tiv.2007.07.013 · Cited by 109 · see citing works
COX-2 selective inhibitors cardiac toxicity: getting to the heart of the matter.
Davies, N. M., & Jamali, F. (2004) · PubMed · Cited by 106 · see citing works
Brown, N. A. (2002) · Alternatives to Laboratory Animals · doi:10.1177/026119290203000205 · Cited by 99 · see citing works
Metformin for gestational diabetes in routine clinical practice
Goh, J. E. L., Sadler, L. C., & Rowan, J. (2011) · Diabetic Medicine · doi:10.1111/j.1464-5491.2011.03361.x · Cited by 98 · see citing works
Bremer, S., & Härtung, T. (2004) · Current Pharmaceutical Design · doi:10.2174/1381612043383700 · Cited by 96 · see citing works
Beating is necessary for transdifferentiation of skeletal muscle‐derived cells into cardiomyocytes
Iijima, Y., Nagai, T., Mizukami, M., Matsuura, K., Ogura, T., Wada, H., Toko, H., Akazawa, H., Takano, H., Nakaya, H., et al. (2003) · The FASEB Journal · doi:10.1096/fj.02-1048fje · Cited by 89 · see citing works
Kovo, M., Haroutounian, S., Feldman, N., Hoffman, A., & Glezerman, M. (2007) · European Journal of Obstetrics & Gynecology and Reproductive Biology · doi:10.1016/j.ejogrb.2007.01.013 · Cited by 82 · see citing works
(2003) · PubMed · Cited by 79 · see citing works
Erdmann, E., & Wilcox, R. G. (2007) · European Heart Journal · doi:10.1093/eurheartj/ehm529 · Cited by 79 · see citing works
Nonsteroidal Anti-Inflammatory Drugs and Reversible Female Infertility
Stone, S., Khamashta, M. A., & Nelson‐Piercy, C. (2002) · Drug Safety · doi:10.2165/00002018-200225080-00001 · Cited by 72 · see citing works
Establishment of an in vitro reporter gene assay for developmental cardiac toxicity
Bremer, S., Worth, A. P., Paparella, M., Bigot, K., Kolossov, E., Fleischmann, B. K., Hescheler, J., & Balls, M. (2001) · Toxicology in Vitro · doi:10.1016/s0887-2333(01)00007-8 · Cited by 70 · see citing works
Zhu, D., & Lou, Y. (2005) · Acta Pharmacologica Sinica · doi:10.1111/j.1745-7254.2005.00076.x · Cited by 62 · see citing works
Festag, M., Viertel, B., Steinberg, P., & Sehner, C. (2007) · Toxicology in Vitro · doi:10.1016/j.tiv.2007.06.014 · Cited by 58 · see citing works
Preliminary Results of the ECVAM Validation Study on Three In Vitro Embryotoxicity Tests
Spielmann, H., Genschow, E., Scholz, G., Brown, N. A., Piersma, A. H., Brady, M. C., Clemann, N., Huuskonen, H., Paillard, F., Bremer, S., et al. (2001) · Alternatives to Laboratory Animals · doi:10.1177/026119290102900322 · Cited by 38 · see citing works
Burdan, F., Szumiło, J., Marzec, B., Klepacz, R., & Dudka, J. (2005) · Toxicology · doi:10.1016/j.tox.2005.08.009 · Cited by 27 · see citing works
Prenatal effects of DuP-697—the irreversible, highly selective cyclooxygenase-2 inhibitor
Burdan, F., Dudka, J., Szumiło, J., Korobowicz, A., & Klepacz, L. (2003) · Reproductive Toxicology · doi:10.1016/s0890-6238(03)00045-5 · Cited by 27 · see citing works
Unresolved controversies in gestational diabetes
Barbour, L. A. (2014) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000080 · Cited by 27 · see citing works
Ho, F. L., Liew, C.-F., Cunanan, E. C., & Lee, K. (2007) · Annals of the Academy of Medicine Singapore · doi:10.47102/annals-acadmedsg.v36n8p672 · Cited by 26 · see citing works
Effect of metformin on mouse embryo development
Bedaiwy, M. A., Miller, K. F., Goldberg, J. M., Falcone, T., & Nelson, D. R. (2001) · Fertility and Sterility · doi:10.1016/s0015-0282(01)02825-4 · Cited by 22 · see citing works
[Reversible infertility from nonsteroidal anti-inflammatory drugs].
Skomsvoll, J. F., Rødevand, E., Koksvik, H. S., Salvesen, K. Å., von Dûring, V., Rygnestad, T., & Østensen, M. (2005) · PubMed · Cited by 10 · see citing works
Genotoxicity of nimesulide in murine bone marrow cells.
Khan, P. K., Amod, K., Haque, M., & Nath, A. (2003) · PubMed · Cited by 10 · see citing works
Is metformin ready for prime time in pregnancy? Probably not yet
Fantus, I. G. (2014) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.2587 · Cited by 6 · see citing works
Jha, A. M., & Abha, A. (2010) · Drug and Chemical Toxicology · doi:10.3109/01480540903390018 · Cited by 6 · see citing works
Long-term Risk of Cardiovascular Events With Rosiglitazone: A Meta-analysis
Singh, S., Loke, Y. K., & Furberg, C. D. (2007) · JAMA · doi:10.1001/jama.298.10.1189 · Cited by 5 · see citing works
Procedures for deriving ES cell lines from the mouse
Brook, F. A. (2006) · doi:10.1093/oso/9780198550006.003.0002 · Cited by 5 · see citing works
Roshdy, H. M., & Kassem, S. M. (2013) · Cited by 3 · see citing works
Flagged first, then by citations
1 of the 48 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
A preclinical overview of metformin for the treatment of type 2 diabetes
Zhou, T., Xu, X., Du, M., Zhao, T., & Wang, J. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.07.085 · Cited by 101 · see citing works
Xu, Y. X. Z., Xi, S., & Qian, X. (2019) · Journal of Diabetes Research · doi:10.1155/2019/9182595 · Cited by 42 · see citing works
Embryotoxicity estimation of commonly used compounds with embryonic stem cell test
Liu, H., Ren, C., Liu, W., Jiang, X., Wang, L., Zhu, B., Jia, W., Lin, J., Tan, J., & Liu, X. (2017) · Molecular Medicine Reports · doi:10.3892/mmr.2017.6552 · Cited by 15 · see citing works
Self-citationXu, Y. D., Liu, Y., He, T., Zhang, Y., Wang, M., Yuan, H., & Yang, M. (2021) · Colloids and Surfaces B Biointerfaces · doi:10.1016/j.colsurfb.2021.112020 · Cited by 13 · see citing works
Adult Stem Cells and Anticancer Therapy
Kalvelytė, A. V., Imbrasaitė, A., Krestnikova, N., & Stulpinas, A. (2017) · Advances in molecular toxicology · doi:10.1016/b978-0-12-812522-9.00004-x · Cited by 13 · see citing works
Wound healing potential of palm oil tocotrienols rich fraction
Ting, T. M., King, J., Ho, K. L., & Lau, H. L. N. (2021) · Food Research · doi:10.26656/fr.2017.5(4).058 · Cited by 3 · see citing works
Bushueva, І. V., Хоменко, К. В., & Полова, Ж. М. (2023) · Ukrainian Journal of Military Medicine · doi:10.46847/ujmm.2023.4(4)-101 · Cited by 1 · see citing works
Topatan, E., Topatan, A. S., Kilic, M., Halici, B., & Çadırcı, E. (2026) · Journal of obstetrics and gynaecology research · doi:10.1111/jog.70256
- Authors
- Li, L., Zhang, X., Wang, L., Chai, Z., Shen, X., Zhang, Z., & Liu, C.
- Affiliations
- Shenyang Pharmaceutical University (CN)
- Tianjin University of Traditional Chinese Medicine (CN)
- Tianjin Center for Drug Safety Assessment and Research Tianjin China
- Corresponding author
- Liu, Changxiao
- Venue
- Journal of Diabetes
- Publisher
- Wiley
- Published
- 2015-03-04
- Volume
- 7
- Issue
- 6
- Pages
- 839-849
- ISSN
- 1753-0393 (ISSN-L)
- 1753-0407
- OpenAlex
- W1940416343
- Cited by
- 8
- References
- 48
- Citations by year
- 2026: 1 · 2023: 1 · 2021: 2 · 2019: 1 · 2018: 1 · 2017: 2
- FWCI
- 0.63
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Basic Research Plan (973 Plan) Foundation of China (2010CB735602)
- National Key Technology R&D Program of Eleventh Five-Year Plan (2007BAI41B03)
- National Science and Technology Major Project for “Major New Drugs Innovation and Development” (2012XZ09505)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pregnancy and Medication Impact
- Keywords
- metformin, embryotoxicity, embryonic stem cell test, antidiabetic drugs, rosiglitazone, glimepiride, 5-fluorouracil, phenytoin, penicillin G, nimesulide, COX-2 inhibitors, gestational diabetes mellitus, drug safety in pregnancy
- MeSH terms
- Rosiglitazone, Animals, Anti-Bacterial Agents, Anticonvulsants, Antineoplastic Agents, Cell Differentiation, Dose-Response Relationship, Drug, Fibroblasts, Fluorouracil, Hypoglycemic Agents, Metformin, Penicillins, Phenytoin, Sulfonamides, Sulfonylurea Compounds, 3T3 Cells, Gene Expression Regulation, Developmental, Risk Assessment, Thiazolidinediones, Mice, Cyclooxygenase 2 Inhibitors, Embryonic Stem Cells
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