Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

Changes in gut microbiota and metabolites of mice with intravenous graphene oxide-induced embryo toxicity

  • Xiaojing Liu (Department of Occupational and Environmental Health, School of Public Health, Cheeloo College of Medicine, Shandong University) ;
  • Zengjin Wang (Department of Occupational and Environmental Health, School of Public Health, Cheeloo College of Medicine, Shandong University) ;
  • Chuanfeng Teng (School of Chemistry and Chemical Engineering, Shandong University) ;
  • Zhiping Wang (Department of Occupational and Environmental Health, School of Public Health, Cheeloo College of Medicine, Shandong University)
  • Received : 2023.12.22
  • Accepted : 2024.04.24
  • Published : 2024.10.15
⟨ Previous Next ⟩

Abstract

The expanding applications of graphene oxide (GO) nanomaterials have attracted interest in understanding their potential adverse effects on embryonic and fetal development. Numerous studies have revealed the importance of the maternal gut microbiota in pregnancy. In this study, we established a mouse GO exposure model to evaluate embryo toxicity induced by intravenous administration of GO during pregnancy. We also explored the roles of gut microbiota and fecal metabolites using a fecal microbiota transplantation (FMT) intervention model. We found that administration of GO at doses up to 1.25 mg/kg caused embryo toxicity, characterized by significantly increased incidences of fetal resorption, stillbirths, and decreased birth weight. In pregnant mice with embryo toxicity, the richness of the maternal gut microbiota was dramatically decreased, and components of the microbial community were disturbed. FMT alleviated the decrease in birth weight by remodeling the gut microbiota, especially via upregulation of the Firmicutes/Bacteroidetes ratio. We subsequently used untargeted metabolomics to identify characteristic fecal metabolites associated with GO exposure. These metabolites were closely correlated with the phyla Actinobacteria, Proteobacteria, and Cyanobacteria. Our findings offer new insights into the embryo toxic effects of GO exposure during pregnancy; they emphasize the roles of gut microbiota-metabolite interactions in adverse pregnancy outcomes induced by GO or other external exposures, as demonstrated through FMT intervention.

Keywords

Acknowledgement

This work was supported by Beijing Natural Science Foundation (No. 7234401) and China Postdoctoral Science Foundation (No. 88014Y0226), and National Natural Science Foundation of China (No. 81472950).

References

  1. Yu W, Sisi L, Haiyan Y, Jie L (2020) Progress in the functional modification of graphene/graphene oxide: a review. RSC Adv 10:15328-15345. https://doi.org/10.1039/d0ra01068e
  2. Zhao H, Ding R, Zhao X, Li Y, Qu L, Pei H, Yildirimer L, Wu Z, Zhang W (2017) Graphene-based nanomaterials for drug and/or gene delivery, bioimaging, and tissue engineering. Drug Discov Today 22:1302-1317. https://doi.org/10.1016/j.drudis.2017.04.002
  3. Dasari Shareena TP, McShan D, Dasmahapatra AK, Tchounwou PB (2018) A Review on Graphene-Based Nanomaterials in Biomedical Applications and Risks in Environment and Health. Nanomicro Lett 10:53. https://doi.org/10.1007/s40820-018-0206-4
  4. Wild CP (2012) The exposome: from concept to utility. Int J Epidemiol 41:24-32. https://doi.org/10.1093/ije/dyr236
  5. Chen Z, Yu C, Khan IA, Tang Y, Liu S, Yang M (2020) Toxic effects of different-sized graphene oxide particles on zebrafish embryonic development. Ecotoxicol Environ Saf 197:110608. https://doi.org/10.1016/j.ecoenv.2020.110608
  6. Zhao Y, Wu Q, Wang D (2016) An epigenetic signal encoded protection mechanism is activated by graphene oxide to inhibit its induced reproductive toxicity in Caenorhabditis elegans. Biomaterials 79:15-24. https://doi.org/10.1016/j.biomaterials.2015.11.052
  7. Chatterjee N, Kim Y, Yang J, Roca CP, Joo SW, Choi J (2017) A systems toxicology approach reveals the Wnt-MAPK crosstalk pathway mediated reproductive failure in Caenorhabditis elegans exposed to graphene oxide (GO) but not to reduced graphene oxide (rGO). Nanotoxicology 11:76-86. https://doi.org/10.1080/17435390.2016.1267273
  8. Zhang X, Zhou Q, Zou W, Hu X (2017) Molecular mechanisms of developmental toxicity induced by graphene oxide at predicted environmental concentrations. Environ Sci Technol 51:7861-7871. https://doi.org/10.1021/acs.est.7b01922
  9. Sandoval-Motta S, Aldana M, Martinez-Romero E, Frank A (2017) The Human Microbiome and the Missing Heritability Problem. Front Genet 8:80. https://doi.org/10.3389/fgene.2017.00080
  10. Edwards SM, Cunningham SA, Dunlop AL, Corwin EJ (2017) The Maternal Gut Microbiome During Pregnancy. Am J Matern Child Nurs 42:310-317. https://doi.org/10.1097/NMC.0000000000000372
  11. Koren O, Goodrich J, Cullender T, Spor A, Laitinen K, Backhed HK, Gonzalez A, Werner J, Angenent L, Knight R (2012) Host Remodeling of the Gut Microbiome and Metabolic Changes during Pregnancy. Cell 150:470-480. https://doi.org/10.1016/j.cell.2012.07.008
  12. Chang Y, Chen Y, Zhou Q, Wang C, Chen L, Di W, Zhang Y (2020) Short-chain fatty acids accompanying changes in the gut microbiome contribute to the development of hypertension in patients with preeclampsia. Clin Sci 134:289-302. https://doi.org/10.1042/cs20191253
  13. Dorrestein PC, Mazmanian SK, Knight R (2014) Finding the missing links among metabolites, microbes, and the host. Immunity 40:824-832. https://doi.org/10.1016/j.immuni.2014.05.015
  14. Zhang F, Cui B, He X, Nie Y, Wu K, Fan D, Group FM (2018) Microbiota transplantation: concept, methodology and strategy for its modernization. Protein Cell 9:462-473. https://doi.org/10.1007/s13238-018-0541-8
  15. Weingarden AR, Vaughn BP (2017) Intestinal microbiota, fecal microbiota transplantation, and inflammatory bowel disease. Gut microbes 8:238-252. https://doi.org/10.1080/19490976.2017.1290757
  16. Chen D, Wu J, Jin D, Wang B, Cao H (2019) Fecal microbiota transplantation in cancer management: Current status and perspectives. Int J Cancer 145:2021-2031. https://doi.org/10.1002/ijc.32003
  17. Vendrik KEW, Ooijevaar RE, de Jong PRC, Laman JD, van Oosten BW, van Hilten JJ, Ducarmon QR, Keller JJ, Kuijper EJ, Contarino MF (2020) Fecal microbiota transplantation in neurological disorders. Front Cell Infect Microbiol 10:98. https://doi.org/10.3389/fcimb.2020.00098
  18. Zhang Z, Mocanu V, Cai C, Dang J, Slater L, Deehan EC, Walter J, Madsen KL (2019) Impact of Fecal Microbiota Transplantation on Obesity and Metabolic Syndrome-A Systematic Review. Nutrients 11:2291. https://doi.org/10.3390/nu11102291
  19. Liu X, Zhang F, Wang Z, Zhang T, Teng C, Wang Z (2021) Altered gut microbiome accompanying with placenta barrier dysfunction programs pregnant complications in mice caused by graphene oxide. Ecotoxicol Environ Saf 207:111143. https://doi.org/10.1016/j.ecoenv.2020.111143
  20. Sajid M, Ilyas M, Basheer C, Tariq M, Daud M, Baig N, Shehzad F (2015) Impact of nanoparticles on human and environment: review of toxicity factors, exposures, control strategies, and future prospects. Environ Sci Pollut Res Int 22:4122-4143. https://doi.org/10.1007/s11356-014-3994-1
  21. Hoseini-Ghahfarokhi M, Mirkiani S, Mozaffari N, Abdolahi Sadatlu MA, Ghasemi A, Abbaspour S, Akbarian M, Farjadian F, Karimi M (2020) Applications of graphene and graphene oxide in smart drug/gene delivery: is the world still fat? Int J Nanomedicine 15:9469-9496. https://doi.org/10.2147/IJN.S265876
  22. Yildiz G, Bolton-Warberg M, Awaja F (2021) Graphene and graphene oxide for bio-sensing: General properties and the effects of graphene ripples. Acta Biomater 131:62-79. https://doi.org/10.1016/j.actbio.2021.06.047
  23. Zare P, Aleemardani M, Seifalian A, Bagher Z, Seifalian AM (2021) Graphene Oxide: Opportunities and Challenges in Biomedicine. Nanomaterials (Basel) 11:1083. https://doi.org/10.3390/nano11051083
  24. Pereira AT, Schneider KH, Henriques PC, Grasl C, Melo SF, Fernandes IP, Kiss H, Martins MCL, Bergmeister H, Goncalves IC (2021) Graphene oxide coating improves the mechanical and biological properties of decellularized umbilical cord arteries. ACS Appl Mater Interfaces 13:32662-32672. https://doi.org/10.1021/acsami.1c04028
  25. Nair A, Morsy MA, Jacob S (2018) Dose translation between laboratory animals and human in preclinical and clinical phases of drug development. Drug Dev Res 79:373-382. https://doi.org/10.1002/ddr.21461
  26. Wen KP, Chen YC, Chuang CH, Chang HY, Lee CY, Tai NH (2015) Accumulation and toxicity of intravenously-injected functionalized graphene oxide in mice. J Appl Toxicol 35:1211-1218. https://doi.org/10.1002/jat.3187
  27. Li B, Zhang XY, Yang JZ, Zhang YJ, Li WX, Fan CH, Huang Q (2014) Infuence of polyethylene glycol coating on biodistribution and toxicity of nanoscale graphene oxide in mice after intravenous injection. Int J Nanomed 9:4697-4707. https://doi.org/10.2147/IJN.S66591
  28. Yang K, Gong H, Shi X, Wan J, Zhang Y, Liu Z (2013) In vivo biodistribution and toxicology of functionalized nano-graphene oxide in mice after oral and intraperitoneal administration. Biomaterials 34:2787-2795. https://doi.org/10.1016/j.biomaterials.2013.01.001
  29. Kinross JM, Darzi AW, Nicholson JK (2011) Gut microbiome-host interactions in health and disease. Genome Med 3:14. https://doi.org/10.1186/gm228
  30. Collado MC, Isolauri E, Laitinen K, Salminen S (2008) Distinct composition of gut microbiota during pregnancy in overweight and normal-weight women. Am J Clin Nutr 88:894-899. https://doi.org/10.1093/ajcn/88.4.894
  31. Iacob S, Iacob DG (2019) Infectious threats, the intestinal barrier, and its trojan horse: dysbiosis. Front Microbiol 10:1676. https://doi.org/10.3389/fmicb.2019.01676
  32. Grigor'eva IN (2020) Gallstone disease, obesity and the firmicutes/bacteroidetes ratio as a possible biomarker of gut dysbiosis. J Pers Med 11:13. https://doi.org/10.3390/jpm11010013
  33. Yang T, Santisteban MM, Rodriguez V, Li E, Ahmari N, Carvajal JM, Zadeh M, Gong M, Qi Y, Zubcevic J (2015) Gut dysbiosis is linked to hypertension. Hypertension 65:1331-1340. https://doi.org/10.1161/hypertensionaha.115.05315
  34. Sharon G, Cruz NJ, Kang DW, Gandal MJ, Wang B, Kim YM, Zink EM, Casey CP, Taylor BC, Lane CJ (2019) Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell 177:1600-1618. https://doi.org/10.1016/j.cell.2019.05.004
  35. Jones SW, Roberts RA, Robbins GR, Perry JL, Kai MP, Chen K, Bo T, Napier ME, Ting JP, Desimone JM, Bear JE (2013) Nanoparticle clearance is governed by Th1/Th2 immunity and strain background. J Clin Invest 123:3061-3073. https://doi.org/10.1172/JCI66895
  36. Chen H, Zhao R, Wang B, Zheng L, Ouyang H, Wang H, Zhou X, Zhang D, Chai Z, Zhao Y (2018) Acute oral administration of single-walled carbon nanotubes increases intestinal permeability and inflammatory responses: association with the changes in gut microbiota in mice. Adv Healthc Mater 7:e1701313. https://doi.org/10.1002/adhm.201701313
  37. Wang WW, Zhang Y, Huang XB, You N, Zheng L, Li J (2017) Fecal microbiota transplantation prevents hepatic encephalopathy in rats with carbon tetrachloride-induced acute hepatic dysfunction. World J Gastroenterol 23:6983-6994. https://doi.org/10.3748/wjg.v23.i38.6983
  38. Cui M, Xiao H, Li Y, Zhou L, Zhao S, Luo D, Zheng Q, Dong J, Zhao Y, Zhang X (2017) Faecal microbiota transplantation protects against radiation-induced toxicity. EMBO Mol Med 9:448-461. https://doi.org/10.15252/emmm.201606932
  39. Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V (2016) Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease. Cell 167:1469-1480. https://doi.org/10.1016/j.cell.2016.11.018
  40. Li Z, Lu G, Li Z, Wu B, Luo E, Qiu X, Guo J, Xia Z, Zheng C, Su Q (2021) Altered Actinobacteria and Firmicutes Phylum Associated Epitopes in Patients With Parkinson's Disease. Front Immunol 12:632482. https://doi.org/10.3389/fmmu.2021.632482
  41. Zhu S, Xu J, Adhikari B, Lv W, Chen H (2023) Nostoc sphaeroides Cyanobacteria: a review of its nutritional characteristics and processing technologies. Crit Rev Food Sci Nutr 63:8975-8991. https://doi.org/10.1080/10408398.2022.2063251
  42. Dicker AJ, Huang JTJ, Lonergan M, Keir HR, Fong CJ, Tan B, Cassidy AJ, Finch S, Mullerova H, Miller BE et al (2021) The sputum microbiome, airway inflammation, and mortality in chronic obstructive pulmonary disease. J Allergy Clin Immunol 147:158-167. https://doi.org/10.1016/j.jaci.2020.02.040
  43. Su J, Li S, Chen J, Jian C, Hu J, Du H, Hai H, Wu J, Zeng F, Zhu J (2022) Glycerophospholipid metabolism is involved in rheumatoid arthritis pathogenesis by regulating the IL-6/JAK signaling pathway. Biochem Biophys Res Commun 600:130-135. https://doi.org/10.1016/j.bbrc.2022.02.003
  44. Foulds LM, Boysen RI, Crane M, Yang Y, Muir JA, Smith AI, de Kretser DM, Hearn MT, Hedger MP (2008) Molecular identification of lyso-glycerophosphocholines as endogenous immunosuppressives in bovine and rat gonadal fluids. Biol Reprod 79:525-536. https://doi.org/10.1095/biolreprod.107.064386
  45. Shellenberg TP, Stoops WW, Lile JA, Rush CR (2020) An update on the clinical pharmacology of methylphenidate: therapeutic efficacy, abuse potential and future considerations. Expert Rev Clin Pharmacol 13:825-833. https://doi.org/10.1080/17512433.2020.1796636
  46. Halder N, Lal G (2021) Cholinergic system and its therapeutic importance in inflammation and autoimmunity. Front Immunol 12:660342. https://doi.org/10.3389/fmmu.2021.660342
  47. Zhang F, Zhang T, Zhu H, Borody TJ (2019) Evolution of fecal microbiota transplantation in methodology and ethical issues. Curr Opin Pharmacol 49:11-16. https://doi.org/10.1016/j.coph.2019.04.004
  48. Abenavoli L, Scarpellini E, Colica C, Boccuto L, Salehi B, Sharif-Rad J, Aiello V, Romano B, De Lorenzo A, Izzo AA (2019) Gut microbiota and obesity: a role for probiotics. Nutrients 11:2690. https://doi.org/10.3390/nu11112690