Sublethal Effect Concentrations for Nonpolar Narcosis in the Zebrafish Embryo

Abstract

Nonpolar narcosis, also known as baseline toxicity, has been described as the minimal toxicity that an organic chemical may elicit based on its lipophilicity. Although lethal effects of narcosis-inducing chemicals (NICs) have been thoroughly investigated, knowledge of sublethal effects is still very limited. We investigated the effects of 3 well-known NICs (phenanthrene, 1,3,5-trichlorobenzene, and pentachlorobenzene) on a variety of organismal endpoints (malformations, swim bladder inflation, respiration, heart rate, swimming activity, and turning angles), which can be plausibly linked to narcosis in zebrafish embryos. Baseline toxicity recorded as mortality is typically observed in similar exposure ranges in a wide variety of species including fish, corresponding to a chemical activity range between 0.01 and 0.1. In the present study, we found that sublethal effects occurred at concentrations approximately 5 times below lethal concentrations. Altered swimming activity and impaired swim bladder inflation were the most sensitive endpoints occurring at exposure levels below the generally accepted threshold for baseline toxicity for 2 out of 3 compounds. Overall, most effective exposure levels across the sublethal endpoints and compounds did fall within the range typically associated with baseline toxicity, and deviations were generally limited to a factor 10. Although there could be benefit in adding sublethal endpoints to toxicity tests, such as the fish embryo acute toxicity (FET) test, based on the present sublethal endpoints and available evidence from our and other studies, the underestimation of toxicity as a result of the sole assessment of mortality as an endpoint in an FET test may be limited for narcosis.

Optimization of a liquid chromatography-ion mobility-high resolution mass spectrometry platform for untargeted lipidomics and application to HepaRG cell extracts

“…In this regard, the zebrafish (Danio rerio) (embryos, larvae, and adult fish) is a mediumto-high-throughput vertebrate toxicological model that is routinely used to provide relevant information regarding the acute and long-term effects of xenobiotics [4][5][6]. It encompasses multicellular biochemical processes and the conservation of several metabolic and physiological processes also found in mammals (e.g., mitochondrial metabolism, the role of lipid and glucose metabolism in embryonic development, endocrine axes regulating energy metabolism, physiology of the digestive system, etc.…”

Alkyl-phenanthrenes in early life stage fish: differential toxicity in Atlantic haddock (Melanogrammus aeglefinus) embryos

“…Sublethal baseline toxic effects on behavior, growth, and development occur in the concentration range of 0.2–1.6 mmol kg −1 ww (0.4–32 mmol kg −1 lipid), approximately 5–10 fold lower than mortality. 19,59,60 Our results showed toxicity at concentrations that were around the lower limit of this range. Approximately half of the body burdens with the lowest observed sublethal effects occurred below this range when compared on a wet weight basis (Fig.…”

“…These ndings are similar to recent zebrash experiments using passive dosing with PHE, in which sublethal effects were generally within the expected range. 60 Along with the excess mortality, the disparate prole of effects within this homologue series suggests that there are multiple other, more specic, and possibly yet-to-bedetermined modes of action at play. Recent proteomic and metabolomic ndings from exposure to a binary mixture of RET and uoranthene in rainbow trout support this notion that mixture toxicity arises from multiple pathways rather than one.…”

Regrettable substitution? Comparative study of the effect profile of bisphenol A and eleven analogues in an in vitro test battery

“…Baseline toxicity, also referred to as non-polar narcosis or non-specific toxicity, describes the minimal toxicity of a chemical [57,58]. Although the precise molecular mechanism has not yet been conclusively resolved [59], it is widely accepted as a disturbance of the cell membrane caused by the partitioning of hydrophobic chemicals into the membrane lipids [57] and their accumulation [60], resulting in failing integrity and function of the membrane [59].…”