Embryonic exposure to oxy-polycyclic aromatic hydrocarbon interfere with pancreatic β-cell development in zebrafish via altering DNA methylation and gene expression.

Oxygenated polycyclic aromatic hydrocarbons (OPAHs) are a class of anthropogenic, persistent and very toxic PAH contaminant associated with developmental toxicity. Abnormal glucose metabolism disturbs energy balances that impair the early development of vertebrates, but the mechanisms by which maternal OPAH exposure alters glucose homeostasis in offspring are not well understood. Studies have suggested that epigenetic changes, particularly in DNA methylation, provide a memory of plastic developmental responses to the environment, leading to the generation of novel offspring phenotypes. The objective of this study is to test the hypothesis that embryonic exposure to low-dose OPAH can impair early β-cell differentiation in zebrafish (Danio rerio) by altering DNA methylation and gene expression. The zebrafish embryos were exposed to 0, 0.03, 0.1, 0.3, 1 and 3 μM 9‑fluorenone (9-FLO) at 3 h postfertilization (hpf) until 120 hpf to assess pancreatic organogenesis. 9-FLO exposure reduced total body length, eye length and heart rate, decreased insulin generation, interfered with glucose metabolism, and altered the expression of pancreatic organogenesis-related genes pdx-1, foxa2, isl1 and ptf1a. In particular, low-dose embryonic 9-FLO exposure significantly decreased β-cell differentiation marker gene pdx-1 mRNA levels, indicating that pancreatic endocrine is a more sensitive target response to embryonic low-dose OPAH exposure. Additionally, we found that DNA methyltransferases dnmt1 and dnmt3 were elevated and the DNA methylation at promoter regions of pdx-1 was increased at an early stage of development. These data demonstrated that the low-dose OPAH embryonic exposure can impair pancreatic endocrine development by increasing DNA methylation at the promoter regions of pdx-1 that are essential for β-cell differentiation.

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