DNA damage at an early developmental stage affects neurodevelopment in sterlet (Acipenser ruthenus)

Exposure to DNA damaging agents during fish embryogenesis can induce malformations and developmental disorders. However, there is scarcity of knowledge on dynamics of embryonic DNA repair and its effect on organogenesis. To address this knowledge gap, we exposed sterlet (Acipenser ruthenus) embryos to DNA-alkylating agent, methyl methanesulfonate (MMS), during blastulation (from 2 to 24 h post-fertilization (hpf)) and observed the effects at hatching (8 days post-fertilization (dpf)) and post-hatching stage (10 dpf).

In contrast to control, DNA alkylation damage in treated embryos significantly persisted up to 3 dpf but was resolved by 8 dpf. These observations coincided with a significant increase in expression of key base excision repair (BER) genes (apex1, ogg1, polβ, xrcc1, lig3) and 1.5-fold increase in APE1 protein levels by hatching. These findings suggest that sterlet embryos activate functional BER pathway in response to DNA alkylation. Despite successful DNA repair, embryos exhibited disrupted retinal layers differentiation and reduced expression of tyrosine hydroxylase (TH) at 10 dpf.

Collectively, our results suggest that DNA alkylation can interfere with organogenesis, potentially through misregulation of DNA repair proteins during critical developmental windows. We speculate that DNA alkylation can affect expression of genes critical for early brain and eye development indicating an organ-specific DNA damage response. Notably, this study emphasizes that future studies should address the link between activation of BER pathway and developmental abnormalities when sterlet embryos are genotoxically challenged.