Aflatoxin B1 interferes with embryonic liver development: Involvement of p53 signaling and apoptosis in zebrafish

Ya-Chih Cheng; Ting-Shuan Wu; Ying-Tzu Huang; Yung Chang; Jiann-Jou Yang; Feng-Yih Yu; Biing-Hui Liu

doi:10.1016/j.tox.2021.152844

Aflatoxin B1 interferes with embryonic liver development: Involvement of p53 signaling and apoptosis in zebrafish

Toxicology. 2021 Jun 30:458:152844. doi: 10.1016/j.tox.2021.152844. Epub 2021 Jun 29.

Authors

Ya-Chih Cheng¹, Ting-Shuan Wu¹, Ying-Tzu Huang¹, Yung Chang¹, Jiann-Jou Yang², Feng-Yih Yu³, Biing-Hui Liu⁴

Affiliations

¹ Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
² Department of Biomedical Sciences, Chung Shan Medical University, Taiwan.
³ Department of Biomedical Sciences, Chung Shan Medical University, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address: fengyu@csmu.edu.tw.
⁴ Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: biingliu@ntu.edu.tw.

PMID: 34214637
DOI: 10.1016/j.tox.2021.152844

Abstract

Aflatoxin B₁ (AFB₁), a naturally occurring mycotoxin, is present in human placenta and cord blood. AFB₁ at concentrations found in contaminated food commodities (0.25 and 0.5 μM) did not alter the spontaneous movement, heart rate, hatchability, or morphology of embryonic zebrafish. However, around 86 % of 0.25 μM AFB₁-treated embryos had livers of reduced size, and AFB₁ disrupted the hepatocyte structures, according to histological analysis. Additionally, AFB₁ treatment that begins at any stage before 72 h post-fertilization (hpf) effectively reduced the size of embryonic livers. In hepatic areas, AFB₁ suppressed the expression of Hhex and Prox1, which are two critical transcriptional factors for initiating hepatoblast specification. KEGG analysis based on transcriptome profiling indicated that p53 signaling and apoptosis are the only observed pathways in AFB₁-treated embryos. AFB₁ at 0.5 μM significantly activated the expression of tp53, mdm2, puma, noxa, pidd1, and gadd45aa genes that are related to the p53 pathway and also that of baxa, casp 8 and casp 3a in the apoptotic process. TUNEL staining demonstrated that AFB₁ triggered the apoptosis of embryonic hepatocytes in a dose-dependent manner. These results indicate that the deficiency of both hhex and prox1 as well as hepatocyte apoptosis via the p53-Puma/Noxa-Bax axis may contribute to the embryonic liver shrinkage that is caused by AFB_1.

Keywords: Aflatoxin B1; Apoptosis; Liver development; Zebrafish embryos; p53 signaling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aflatoxin B1 / toxicity*
Animals
Apoptosis / drug effects*
Apoptosis Regulatory Proteins / drug effects
Apoptosis Regulatory Proteins / genetics
Dose-Response Relationship, Drug
Embryonic Development / drug effects*
Gene Expression Regulation, Developmental / drug effects
Liver / drug effects*
Liver / embryology*
Liver / pathology
MicroRNAs / biosynthesis
MicroRNAs / genetics
RNA, Messenger / biosynthesis
RNA, Messenger / genetics
Signal Transduction / drug effects*
Teratogens / toxicity*
Tumor Suppressor Protein p53 / drug effects*
Zebrafish / physiology*

Substances

Apoptosis Regulatory Proteins
MicroRNAs
RNA, Messenger
Teratogens
Tumor Suppressor Protein p53
Aflatoxin B1