Trophic transfer of carbon-14 from algae to zebrafish leads to its blending in biomolecules and the dysregulation of metabolism via isotope effect

Carbon-14 (C-14) has been a major contributor to the human radioactive exposure dose, as it is released into the environment from the nuclear industry in larger quantities compared to other radionuclides. This most abundant nuclide enters the biosphere as organically bound C-14 (OBC-14), posing a potential threat to public health. Yet, it remains unknown how this relatively low radiotoxic nuclide induces health risks via chemical effects, such as isotope effect. By establishing a trophic transfer model involving algae (<i>Scenedesmus obliquus</i>), daphnia (<i>Daphnia magna</i>) and zebrafish (<i>Danio rerio</i>), we demonstrate that rapid incorporation and transformation of inorganic C-14 by algae into OBC-14 facilitates the blending of C-14 into the biomolecules of zebrafish. We find that internalized C-14 is persistently retained in the brain of zebrafish, affecting DNA methylation and causing alterations in neuropathology. Global isotope tracing metabolomics with C-14 exposure further reveals the involvement of C-14 in various critical metabolic pathways, including one-carbon metabolism and nucleotide metabolism. We thus characterize the kinetic isotope effects for ¹²C/¹⁴C in the key reactions of these metabolic pathways through kinetic experiments and density functional theory computations, showing that the isotopic substitution of carbon in biochemicals regulates metabolism by disrupting reaction ratios via isotope effects. Our results suggest that inorganic C-14 discharged by the nuclear industry can be biotransformed into OBC-14 to impact metabolism via isotope effects, providing new insights into understanding the health risk of C-14, which is traditionally considered as a low radiotoxic nuclide.