Physiologically Based Pharmacokinetic Model for the Biotransportation of Arsenic in Marine Medaka (Oryzias melastigma)

The toxicity of arsenic (As) targets specific tissues of organisms, while the biotransportation of As among the tissues of fish remains poorly understood. In the present study, radiotracer techniques followed by a physiologically based pharmacokinetic (PBPK) modeling were applied to simulate the biotransportation (absorption, distribution, and elimination) of ⁷³As(V) and biotransformation of As(V) in the marine medaka Oryzias melastigma after waterborne As exposure. Fish were simulated by a six-compartment model by assuming that blood was the intermediate exchange among different compartments (gill, intestine, liver, head, and carcass). Modeling suggested that intestine and gill were the uptake, exchange, as well as elimination sites of waterborne As, while carcass and head were the main storage sites. Intestine played a vital role in the metabolism of As(V) by biotransforming inorganic As into arsenobetaine (AsB), possibly because of the important role of gut microbiota. The correlation between the PBPK model constants and the As speciation (e.g., AsB %, inorganic As %, and methylated As %) indicated that AsB tended to be stored in the tissues rather than being depurated, while inorganic and methylated As were more easily transferred from tissues to the blood and eliminated. Modeling simulation coupling with biotransformation for the first time demonstrated that the fish intestine was the main metabolic site, and synthesis of AsB as mediated by the microbiota in the intestine contributed to the high As bioaccumulation in marine fish.