Effects of lithium on developmental toxicity, teratogenicity and transcriptome in medaka embryos

Abstract

In this study, we assessed embryonic developmental toxicity and teratogenicity of lithium (Li) on medaka (Oryzias latipes) and predict the molecular mechanisms of their effects using a nanosecond pulsed electric field (nsPEF) technique and bioinformatics analysis. The microscopic observation revealed that the 1 mg/L LiCl treatment causes the most severe deformation effects, such as thrombus, heart hypertrophy, deformation of eyes, and growth retardation to embryos. The RNA-seq analysis identified 2,483 up-and down-regulated genes, such as histogenesis and organ growth related genes, in 2 day post-fertilization embryos after treatment with nsPEF and 1 mg/L LiCl. In addition, bioinformatic analyses showed that LiCl affects several aspects of gene ontology, such as molecular functions and cellular components, and some pathways, such as spliceosome, cell cycle, selenocompound metabolism, TGF-β signaling, and RNA degradation. The upregulation of GSK3B (signal transduction and cell growth), BAX (apoptosis), and MAP3K8 (cell death, arrest of cell cycle, and inflammation) genes were also observed in embryos exposed to LiCl. Our results suggest that the incorporation of Li compounds into medaka eggs using nsPEF shows adverse effects to the development and teratogenicity, and that these toxic effects may be affected by the alterations of certain gene expression in medaka embryos.

Electroporation of thalidomide to medaka (<i>Oryzias latipes</i>) embryo for evaluation of developmental toxicity

“…However, long-term immersion is required in a high-concentration solution, owing to which the window of exposure becomes unclear. Notably, nsPEF treatment is a potent method for incorporation of chemical compounds into medaka eggs (Tominaga et al, 2010(Tominaga et al, , 2019Yamaguchi et al, 2018Yamaguchi et al, , 2020. Using this method, chemical substances that are difficult to introduce via osmosis alone can be easily introduced inside medaka eggs with shells.…”

“…We previously developed an electroporation method using a nanosecond pulsed electric field (nsPEF) to facilitate the introduction of substances into medaka eggs. We attempted to assess teratogenicity and embryonic developmental toxicity; moreover, we determined some endpoints that included not only survival, growth, and developmental abnormalities but also changes in the gene expression levels for the assessment of toxicity of 17β-estradiol, lithium, and benzo(a)pyrene using medaka and nsPEF treatment (Yamaguchi et al, 2018(Yamaguchi et al, , 2020Tominaga et al, 2019).…”