Cytosine arabinoside exposure induced cytotoxic effects and neural tube defects in mice and embryo stem cells

Zhen Guan; Yingchao Liang; Zhiqiang Zhu; Aiyun Yang; Shen Li; Jin Guo; Fang Wang; Huimin Yang; Na Zhang; Xiuwei Wang; Jianhua Wang

doi:10.1016/j.ecoenv.2023.115141

Cytosine arabinoside exposure induced cytotoxic effects and neural tube defects in mice and embryo stem cells

Ecotoxicol Environ Saf. 2023 Jun 13:262:115141. doi: 10.1016/j.ecoenv.2023.115141. Online ahead of print.

Authors

Zhen Guan¹, Yingchao Liang¹, Zhiqiang Zhu¹, Aiyun Yang¹, Shen Li¹, Jin Guo², Fang Wang², Huimin Yang³, Na Zhang⁴, Xiuwei Wang⁵, Jianhua Wang⁶

Affiliations

¹ Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing 100020, China.
² Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China.
³ Growth and Development Department, Capital Institute of Pediatrics, Beijing 100020, China.
⁴ Key Laboratory of Environmental and Viral Oncology, College of Life Science and Chemistry, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China. Electronic address: nanatonglei@bjut.edu.cn.
⁵ Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing 100020, China. Electronic address: wangxiuwei1010@126.com.
⁶ Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing 100020, China. Electronic address: fywjh@163.com.

PMID: 37320917
DOI: 10.1016/j.ecoenv.2023.115141

Abstract

Cytosine arabinoside (Ara-C) is one of the most widely used chemotherapeutic agents for hematological malignancies. The residues of Ara-C have been detected in wastewater and river water with increased usage and discharge. As the ability to cross the placenta and the teratogenicity at low ng/L levels, the toxic effects on pregnant women and infants have been concerned. The toxicity of Ara-C exposure on early embryonic neurodevelopment has not been fully elucidated. In this study, pregnant C57BL/6 mice were injected with different doses of Ara-C on Gestation day (GD) 7.5 and assessed on GD11.5 and GD13.5 to explore the neural developmental effects of Ara-C. HE staining, immunofluorescence, western blot, EdU assay, and flow cytometry were utilized to determine the toxic effects of Ara-C in vivo and in vitro. Our results showed that Ara-C (15-22.5 mg/kg body weight) induced the occurrence of neural tube defects (NTDs). The expression of PH3 was markedly reduced in embryos with Ara-C-induced NTDs, compared to the control group (P < 0.05). In contrast, cell apoptosis was markedly increased. Increased expression levels of GFAP and decreased Nestin were observed in the embryonic brain tissues in Ara-C induced NTDs. The level of β-catenin was also decreased on both GD11.5 and GD13.5. These results were confirmed in vitro using mouse Sv129 embryonic stem cells (mESC). Ara-C at a dose comparable to the environment level (0.05 nM) had cytotoxicity. Impaired Wnt/β-catenin signaling pathway is involved in Ara-C exposure induced imbalance between cell proliferation, apoptosis, and differentiation, which might contribute to Ara-C-induced occurrence of NTDs. Our data indicated the environmental concentration of Ara-C had cytotoxicity and that maternal exposure to Ara-C induced NTDs. These results might provide more information to understand the environmental toxic impact of Ara-C on neurodevelopment.

Keywords: Cytosine arabinoside; Cytotoxicity; Neural tube defects.