Cu(II)-Dependent Spine Development Injury in Zebrafish (Danio rerio) with Organ Heterogeneous Cu Imbalance

Growing
evidence suggests that the imbalance of Cu leads to multiorgan
diseases or other adverse effects, but the underlying mechanisms remain
largely unknown. Herein, we used zebrafish to uncover the mystery
of organ heterogeneous responses to Cu stress and Cu(II)-dependent
spine developmental injury in the early organogenesis stage. We first
demonstrated that Cu(I) was distributed in the entire body, but high
contents of Cu(II) were accumulated in the yolk sac and eye in normal
zebrafish larvae. Cu exposure from birth to 144 hpf caused no obvious
damage to Cu-metabolizing organs (liver and intestine), despite the
elevated Cu(I) and Cu(II) levels. However, the spine was more sensitive
to the Cu exposure. In the spine region, the Cu(I) level remained
stable, whereas the level of Cu(II) significantly increased, which
was highly associated with spine development injury. A significant
negative correlation between Cu(II) and the spine-related parameters
was identified. Moreover, cuproptosis caused spine development deformation
during the early embryogenesis stage. Spine-related pathways such
as somitegenesis significantly changed in the early embryogenesis
period, and 5 spine-related pathways were significantly altered in
the larval stage at 96 hpf. Our study suggested that Cu stress induced
organ heterogeneous Cu imbalance and Cu(II)-dependent spine development
injury in zebrafish.