Sulfidation is considered as a natural antidote to toxicity of metallic nanoparticles (NPs). The detoxification contribution from sulfidation, however, may vary depending on sulfidation mechanisms. Here we present the dissolution-precipitation instead of direct solid-state-shell mechanism to illustrate the process of CuO-NPs conversion to CuS-NPs in aqueous solutions. Accordingly, the CuS-NPs at environmentally relevant concentrations showed much stronger interference on Japanese medaka (Oryzias latipes) embryo hatching than CuO-NPs, which was probably due to elevated free copper ions released from CuS-NPs, leading to significant increase in oxidative stress and causing toxicity in embryos. The larval length was significantly reduced by CuS-NPs, however, no other obviously abnormal morphological features were identified in the hatched larvae. Co-introduction of a metal ion chelator [ethylene diamine tetraacetic acid (EDTA)] could abolish the hatching inhibition induced by CuS-NPs, indicating free copper ions released from CuS-NPs play an important role in hatching interference. This work documents for the first time that sulfidation as a natural antidote to metallic NPs is being overestimated, which has far reaching implications for risk assessment of metallic NPs in aquatic environment.