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In Utero Exposure to Lead is Associated with Neural Tube Defects via Disturbing the Expression of Endocannabinoid Retrograde Signaling-Related Genes

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Abstract

Neural tube defects (NTDs) are a group of severe congenital malformations of the central nervous system, for which environmental causes are not fully known. In a human case–control study, we compared lead (Pb) levels in umbilical cord blood serum from 40 NTD cases and 119 controls. In a toxicology study, we treated Institute of Cancer Research (ICR) mice with different dosage of Pb acetate orally from gestational day (GD) 6.5 through 9.5. At GD10.5, mouse embryos were harvested and examined. RNA-sequencing was conducted on the embryos to detect mRNA profiles. siRNAs were used to pull down target genes in human embryonic stem cells to examine the effects of the aberrant gene expression on neural cells. A higher Pb concentration in cord serum was associated with the odds of NTDs [odds ratio (OR): 4.66 (1.69–15.24)]. Lead acetate induced NTDs in 10.6% of mouse fetuses. RNA expression profiles of Pb-induced NTD mice were different from control embryos, especially in endocannabinoid retrograde signaling genes Plcb2, Nfix, and Gabrg2. Down-regulation of Plcb2 and Nfix influenced neural cell differentiation and impaired the formation of neural rosette-like structures. Together, in utero-Pb exposure is associated with development of NTDs via regulating the expression of endocannabinoid retrograde-signaling genes.

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Data Availability

The datasets generated and/or analyzed during the current study are not publicly available due to ethical and legal reasons but are available from the corresponding author on reasonable request.

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Funding

This work was partly supported by China Postdoctoral Science Foundation (2021M700272 and 2021M690248), National Key Research and Development Program, Ministry of Science and Technology, People’s Republic of China (Grant No. 2021YFC2701101), and the National Natural Science Foundation of China (Nos. 21876002 and 41961134034).

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Author notes

  1. Tian Tian and Huijun Dong have contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Assisted Reproduction (Peking University), Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Department of Obstetrics and Gynecology, Ministry of Education, Center for Reproductive Medicine, National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China

    Tian Tian & Jie Qiao

  2. Department of Epidemiology and Biostatistics, School of Public Health, Institute of Reproductive and Child Health/National Health Commission Key Laboratory of Reproductive Health, Peking University, Beijing, China

    Tian Tian, Shengju Yin, Mengyuan Liu, Yongyan Chen, Linlin Wang & Aiguo Ren

  3. Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China

    Huijun Dong & Kuanhui Xiang

  4. Ministry of Education - Shanghai Key Laboratory of Children’s Environment Health, School of Public Health/Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Shengju Yin

  5. Beijing Advanced Innovation Center for Genomics, Beijing, China

    Jie Qiao

  6. Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China

    Jie Qiao

  7. Institute of Reproductive and Child Health, Peking University Health Science Center, Beijing, 100191, China

    Aiguo Ren

  8. Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China

    Jie Qiao

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  1. Tian Tian
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Contributions

TT: Sample collection, investigation, formal analysis, original draft writing, funding acquisition. HD: Validation, investigation, cell experiment performance. SY: Sample collection, Pb assessment, funding acquisition. ML, YC: Sample collection, mouse experiment. KX: Manuscript revision, cell experiment direction. LW: Conceptualization, manuscript revision, funding acquisition. AR, JQ: Conceptualization, Methodology, Formal analysis, Resources, manuscript review & editing, supervision, project administration.

Corresponding authors

Correspondence to Jie Qiao or Aiguo Ren.

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We declare no competing interests.

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This study was approved by the institutional review board of Peking University (Beijing, China), and written informed consent was obtained from all participants before data collection.

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Tian, T., Dong, H., Yin, S. et al. In Utero Exposure to Lead is Associated with Neural Tube Defects via Disturbing the Expression of Endocannabinoid Retrograde Signaling-Related Genes. Expo Health 16, 431–444 (2024). https://doi.org/10.1007/s12403-023-00564-x

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