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A Two-Generation Reproductive Toxicity Study of Cerium Nitrate in Sprague–Dawley Rats

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Abstract

A two-generation reproductive toxicity study was performed to evaluate the effects of cerium nitrate on the development of the parent, offspring, and third generation of Sprague–Dawley (SD) rats. A total of 240 SD rats (30 rats/sex/group) were randomly divided into four dosage groups according to body weight: 0 mg/kg, 30 mg/kg, 90 mg/kg, and 270 mg/kg. The rats were administered different dosages of cerium nitrate by oral gavage. There were no observed changes related to cerium nitrate in body weight, food consumption, sperm survival rate, motility, mating rate, conception rate, abortion rate, uterine plus fetal weight, uterine weight, corpus luteum number, implantation rate, live fetus number (rate), stillbirth number (rate), absorbed fetus number (rate), appearance, visceral, and skeletal in rats of each generation dosage group. In addition, the pathological findings showed no significant lesions associated with cerium nitrate toxicity in all tissues and organs, including reproductive organs. In conclusion, the present study showed that long-term oral gavage of cerium nitrate at 30 mg/kg, 90 mg/kg, and 270 mg/kg had no significant effect on reproduction and the developmental ability of their offspring in rats. The no-observed-adverse-effect level (NOAEL) of cerium nitrate in SD rats was higher than 270 mg/kg.

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Data Availability

Some or all data, models, or code generated or used during the study are available from the corresponding author by request.

References

  1. Kowalczyk E, Givelet L, Amlund H, Sloth JJ, Hansen M (2022) Risk assessment of rare earth elements, antimony, barium, boron, lithium, tellurium, thallium and vanadium in teas. EFSA J 20(Suppl 1):e200410. https://doi.org/10.2903/j.efsa.2022.e200410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Willbold E, Gu X, Albert D et al (2015) Effect of the addition of low rare earth elements (lanthanum, neodymium, cerium) on the biodegradation and biocompatibility of magnesium. Acta Biomater 11:554–562. https://doi.org/10.1016/j.actbio.2014.09.041

    Article  CAS  PubMed  Google Scholar 

  3. Carpenter D, Boutin C, Allison JE, Parsons JL, Ellis DM (2015) Uptake and effects of six rare earth elements (REEs) on selected native and crop species growing in contaminated soils. PLoS One 10(6):e0129936. https://doi.org/10.1371/journal.pone.0129936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hu Z, Richter H, Sparovek G, Schnug E (2004) Physiological and biochemical effects of rare earth elements on plants and their agricultural significance: a review. J Plant Nutr 27(1)

  5. Tommasi F, Thomas PJ, Pagano Get al (2021) Review of rare earth elements as fertilizers and feed additives: a knowledge gap analysis. Arch Environ Contam Toxicol 81:531–540

  6. Liang G, Wang H, Shi H et al (2020) Recent progress in the development of upconversion nanomaterials in bioimaging and disease treatment. J Nanobiotechnology 18(1):154. https://doi.org/10.1186/s12951-020-00713-3

    Article  PubMed  PubMed Central  Google Scholar 

  7. Ogata H, Fukagawa M, Hirakata H et al (2021) Effect of treating hyperphosphatemia with lanthanum carbonate vs calcium carbonate on cardiovascular events in patients with chronic kidney disease undergoing hemodialysis: the LANDMARK randomized clinical trial. JAMA 325(19):1946–1954. https://doi.org/10.1001/jama.2021.4807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Egler SG, Niemeyer JC, Correia FV, Saggioro EM (2022) Effects of rare earth elements (REE) on terrestrial organisms: current status and future directions. Ecotoxicology 31(5):689–699. https://doi.org/10.1007/s10646-022-02542-6

    Article  CAS  PubMed  Google Scholar 

  9. Samonova OA, Aseyeva EN, Chernitsova OV (2020) Data on rare earth elements in different particle size fractions of topsoil for two small erosional landforms in central European Russia. Data Brief 30:105450. https://doi.org/10.1016/j.dib.2020.105450

    Article  CAS  PubMed  Google Scholar 

  10. Gwenzi W, Mangori L, Danha C, Chaukura N, Dunjana N, Sanganyado E (2018) Sources, behaviour, and environmental and human health risks of high-technology rare earth elements as emerging contaminants. Sci Total Environ 636:299–313. https://doi.org/10.1016/j.scitotenv.2018.04.235

    Article  CAS  PubMed  Google Scholar 

  11. Yan L, Gao F, Shi W et al (2022) A two-generation reproductive toxicity study of lanthanum nitrate in SD rats. Biol Trace Elem Res 200(5):2268–2282. https://doi.org/10.1007/s12011-021-02841-9

    Article  CAS  PubMed  Google Scholar 

  12. Montini T, Melchionna M, Monai M, Fornasiero P (2016) Fundamentals and catalytic applications of CeO2-based materials. Chem Rev 116(10):5987–6041. https://doi.org/10.1021/acs.chemrev.5b00603

    Article  CAS  PubMed  Google Scholar 

  13. Jiang DG, Yang J, Zhang S, Yang DJ (2012) A survey of 16 rare Earth elements in the major foods in China. Biomed Environ Sci 25(3):267–271. https://doi.org/10.3967/0895-3988.2012.03.003

    Article  CAS  PubMed  Google Scholar 

  14. Zhou R, Liu L, Yue B et al (2014) Dietary intake assessment for rare earth elements from 4th Chinese total diet study. Mod Prev 41(11):1975–1978

    CAS  Google Scholar 

  15. Wang H, Chen X, Ye J, Jia X, Zhang Q, He H (2020) Analysis of the absorption and accumulation characteristics of rare earth elements in Chinese tea. J Sci Food Agric 100(8):3360–3369. https://doi.org/10.1002/jsfa.10369

    Article  CAS  PubMed  Google Scholar 

  16. Geng B, Hu J, Li Y et al (2022) Near-infrared phosphorescent carbon dots for sonodynamic precision tumor therapy. Nat Commun 13(1):5735. https://doi.org/10.1038/s41467-022-33474-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. He B, Wang J, Lin J et al (2021) Association between rare earth element cerium and the risk of oral cancer: a case-control study in Southeast China. Front Public Health 9:647120. https://doi.org/10.3389/fpubh.2021.647120

    Article  PubMed  PubMed Central  Google Scholar 

  18. Qian LW, Evani SJ, Chen P et al (2020) Cerium nitrate treatment provides eschar stabilization through reduction in bioburden, DAMPs, and inflammatory cytokines in a rat scald burn model. J Burn Care Res 41(3):576–584. https://doi.org/10.1093/jbcr/irz199

    Article  PubMed  Google Scholar 

  19. Thakur N, Manna P, Das J (2019) Synthesis and biomedical applications of nanoceria, a redox active nanoparticle. J Nanobiotechnology 17(1):84. https://doi.org/10.1186/s12951-019-0516-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zicari MA, d’Aquino L, Paradiso A, Mastrolitti S, Tommasi F (2018) Effect of cerium on growth and antioxidant metabolism of Lemna minor L. Ecotoxicol Environ Saf 163:536–543. https://doi.org/10.1016/j.ecoenv.2018.07.113

    Article  CAS  PubMed  Google Scholar 

  21. Deveci M, Eski M, Sengezer M, Kisa U (2000) Effects of cerium nitrate bathing and prompt burn wound excision on IL-6 and TNF-alpha levels in burned rats. Burns 26(1):41–45. https://doi.org/10.1016/s0305-4179(99)00107-2

    Article  CAS  PubMed  Google Scholar 

  22. Datta A, Mishra S, Manna K, Saha KD, Mukherjee S, Roy S (2020) Pro-oxidant therapeutic activities of cerium oxide nanoparticles in colorectal carcinoma cells. ACS Omega 5(17):9714–9723. https://doi.org/10.1021/acsomega.9b04006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Colon J, Herrera L, Smith J et al (2009) Protection from radiation-induced pneumonitis using cerium oxide nanoparticles. Nanomedicine 5(2):225–231. https://doi.org/10.1016/j.nano.2008.10.003

    Article  CAS  PubMed  Google Scholar 

  24. Li X, Chen Z, Chen Z, Zhang Y (2013) A human health risk assessment of rare earth elements in soil and vegetables from a mining area in Fujian Province, Southeast China. Chemosphere 93(6):1240–1246. https://doi.org/10.1016/j.chemosphere.2013.06.085

    Article  CAS  PubMed  Google Scholar 

  25. Pagano G, Thomas PJ, Di Nunzio A, Trifuoggi M (2019) Human exposures to rare earth elements: present knowledge and research prospects. Environ Res 171:493–500. https://doi.org/10.1016/j.envres.2019.02.004

    Article  CAS  PubMed  Google Scholar 

  26. Cheng Z, Li N, Cheng J et al (2012) Signal pathway of hippocampal apoptosis and cognitive impairment of mice caused by cerium chloride. Environ Toxicol 27(12):707–718. https://doi.org/10.1002/tox.20696

    Article  CAS  PubMed  Google Scholar 

  27. Wang X, Su J, Zhu L et al (2013) Hippocampal damage and alterations of inflammatory cytokine expression in mice caused by exposure to cerium chloride. Arch Environ Contam Toxicol 64(4):545–553. https://doi.org/10.1007/s00244-012-9870-4

    Article  CAS  PubMed  Google Scholar 

  28. Shrivastava S, Mathur R (2004) Effectiveness of ethylene glycol bis (2-aminoethyl ether) tetraacetic acid (EGTA) against cerium toxicity. Indian J Exp Biol 42(9):876–883

    CAS  PubMed  Google Scholar 

  29. Zhao H, Cheng J, Cai J et al (2012) Liver injury and its molecular mechanisms in mice caused by exposure to cerium chloride. Arch Environ Contam Toxicol 62(1):154–164. https://doi.org/10.1007/s00244-011-9672-0

    Article  CAS  PubMed  Google Scholar 

  30. Nemmar A, Yuvaraju P, Beegam S, Fahim MA, Ali BH (2017) Cerium oxide nanoparticles in lung acutely induce oxidative stress, inflammation, and DNA damage in various organs of mice. Oxid Med Cell Longev 2017:9639035. https://doi.org/10.1155/2017/9639035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Qin F, Shen T, Li J et al (2019) SF-1 mediates reproductive toxicity induced by cerium oxide nanoparticles in male mice. J Nanobiotechnology 17(1):41. https://doi.org/10.1186/s12951-019-0474-2

    Article  PubMed  PubMed Central  Google Scholar 

  32. Liu Y, Wu M, Zhang L et al (2019) Prenatal exposure of rare earth elements cerium and ytterbium and neonatal thyroid stimulating hormone levels: findings from a birth cohort study. Environ Int 133(Pt B):105222. https://doi.org/10.1016/j.envint.2019.105222

    Article  CAS  PubMed  Google Scholar 

  33. Oral R, Bustamante P, Warnau M, D’Ambra A, Guida M, Pagano G (2010) Cytogenetic and developmental toxicity of cerium and lanthanum to sea urchin embryos. Chemosphere 81(2):194–198. https://doi.org/10.1016/j.chemosphere.2010.06.057

    Article  CAS  PubMed  Google Scholar 

  34. USFDA (2000a) Guidelines for reproduction studies. Redbook: Toxicological principles for the safety assessment of food ingredients. IV.C.9.a. Silver Spring, MD: FDA

  35. USFDA (2000b) Guidelines for developmental toxicity studies. Redbook: Toxicological principles for the safety assessment of food ingredients. V.C.9.b. Silver Spring, MD: FDA

  36. Shiva M, Gautam AK, Verma Y et al (2011) Association between sperm quality, oxidative stress, and seminal antioxidant activity. Clin Biochem 44:319–324

    Article  CAS  PubMed  Google Scholar 

  37. Ujházy E, Mach M, Navarová Jet al (2012) Teratology - past, present and future. Interdiscip Toxicol 5:163–168

  38. Ain NU, Khan RA, Mirza Tet al (2022) The Effects of Ficus carica on Male and Female Reproductive Capabilities in Rats. Evid Based Complement Alternat Med 2022:1799431

  39. Yan L, Wang H, Duan W et al (2022) The reproductive toxicity of yttrium nitrate in a two-generation study in Sprague-Dawley rats. J Trace Elem Med Biol 76:127117. https://doi.org/10.1016/j.jtemb.2022.127117

    Article  CAS  PubMed  Google Scholar 

  40. Pagano G, Aliberti F, Guida M et al (2015) Rare earth elements in human and animal health: state of art and research priorities. Environ Res 142:215–220. https://doi.org/10.1016/j.envres.2015.06.039

    Article  CAS  PubMed  Google Scholar 

  41. Cao B, Wu J, Xu C et al (2020) The accumulation and metabolism characteristics of rare earth elements in Sprague-Dawley rats. Int J Environ Res Public Health 17(4). https://doi.org/10.3390/ijerph17041399

  42. Fang HQ, Yu Z, Zhi Y et al (2018) Subchronic oral toxicity evaluation of lanthanum: a 90-day, repeated dose study in rats. Biomed Environ Sci 31(5):363–375. https://doi.org/10.3967/bes2018.047

    Article  CAS  PubMed  Google Scholar 

  43. Wu Y, Tang X, Yang W et al (2019) Subchronic toxicity of cerium nitrate by 90-day oral exposure in wistar rats. Regul Toxicol Pharmacol 108:104474. https://doi.org/10.1016/j.yrtph.2019.104474

    Article  CAS  PubMed  Google Scholar 

  44. Zhang X, Wang L, Ma Y et al (2022) CEP128 is involved in spermatogenesis in humans and mice. Nat Commun 13(1):1395. https://doi.org/10.1038/s41467-022-29109-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hosseinalipour E, Karimipour M, Ahmadi A (2021) Detrimental effects of cerium oxide nanoparticles on testis, sperm parameters quality, and in vitro fertilization in mice: an experimental study. Int J Reprod Biomed 19:801–810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wei J, Wang C, Yin S et al (2020) Concentrations of rare earth elements in maternal serum during pregnancy and risk for fetal neural tube defects. Environ Int 137:105542. https://doi.org/10.1016/j.envint.2020.105542

    Article  CAS  PubMed  Google Scholar 

  47. Popov AL, Popova NR, Selezneva II, Akkizov AY, Ivanov VK (2016) Cerium oxide nanoparticles stimulate proliferation of primary mouse embryonic fibroblasts in vitro. Mater Sci Eng C Mater Biol Appl 68:406–413. https://doi.org/10.1016/j.msec.2016.05.103

    Article  CAS  PubMed  Google Scholar 

  48. Lee J, Jeong JS, Kim SY et al (2020) Safety assessment of cerium oxide nanoparticles: combined repeated-dose toxicity with reproductive/developmental toxicity screening and biodistribution in rats. Nanotoxicology 14(5):696–710. https://doi.org/10.1080/17435390.2020.1751322

    Article  CAS  PubMed  Google Scholar 

  49. Saifi MA, Sangomla S, Khurana A, Godugu C (2019) Protective effect of nanoceria on cisplatin-induced nephrotoxicity by amelioration of oxidative stress and pro-inflammatory mechanisms. Biol Trace Elem Res 189(1):145–156. https://doi.org/10.1007/s12011-018-1457-0

    Article  CAS  PubMed  Google Scholar 

  50. Park K, Park J, Lee H, Choi J, Yu WJ, Lee J (2018) Toxicity and tissue distribution of cerium oxide nanoparticles in rats by two different routes: single intravenous injection and single oral administration. Arch Pharm Res 41(11):1108–1116. https://doi.org/10.1007/s12272-018-1074-7

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank all the technicians who conducted the studies.

Funding

This research was supported by the Innovation Action Plan of Shanghai Science and Technology (Grant No. 20140900700), the National Natural Science Foundation of China (Grant No. 82173908 and 82173649), the Social Development Science and Technology research project of Shanghai (Grant No. 21dz1200302 and 20dz1200102), and Strengthening basic disciplines plan (21 M0902).

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Author notes

  1. Lijun Ren, Wenjing Shi and Yijun Tian contributed equally to this work.

Authors and Affiliations

  1. Department of Health Toxicology, Faculty of Naval Medicine, Naval Medical University, No. 800, Xiangyin Road, Yangpu District, Shanghai, 200433, China

    Lijun Ren, Yijun Tian, Bin Zhang, Bijiang Geng, Jingjing Mao, Jiqianzhu Zhang, Xiaoyu Dai, Jifeng Li, Xiaofang Zhang, Jikuai Chen, Jiangbo Zhu & Lang Yan

  2. Department of Naval Nutrition and Food Hygiene, Faculty of Naval Medicine, Naval Medical University of the People’s Liberation Army, Shanghai, 200433, China

    Wenjing Shi

  3. School of Basic Medicine, Anhui Medical University, Anhui, 230032, China

    Tiantian Zhang

  4. Navy Medical Center of PLA, Naval Medical University of the People’s Liberation Army, Shanghai, 200433, China

    Jingjing Fang

  5. Department of Marine Radiation Medicine, Faculty of Naval Medicine, Naval Medical University of the People’s Liberation Army, Shanghai, 200433, China

    Haoneng Wang

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  1. Lijun Ren
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Contributions

Jikuai Chen, Jiangbo Zhu, and Lang Yan designed this study. Bin Zhang conducted experiments. Tiantian Zhang, Bijiang Geng, Jingjing Mao, Haoneng Wang, Xiaofang Zhang, and Jingjing Fang collected and analyzed the data. Lijun Ren, Wenjing Shi, and Yijun Tian wrote the manuscript. Jiqianzhu Zhang and Xiaoyu Dai checked and reanalyzed the data. All the authors read and approved the final manuscript.

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Correspondence to Jikuai Chen, Jiangbo Zhu or Lang Yan.

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Ren, L., Shi, W., Tian, Y. et al. A Two-Generation Reproductive Toxicity Study of Cerium Nitrate in Sprague–Dawley Rats. Biol Trace Elem Res 202, 597–614 (2024). https://doi.org/10.1007/s12011-023-03692-2

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