Niclosamide Is a Much More Potent Toxicant of Mitochondrial Respiration than TFM in the Invasive Sea Lamprey (Petromyzon marinus)

Abstract

Invasive sea lampreys in the Laurentian Great Lakes are controlled by applying TFM (3-trifluoromethyl-4-nitrophenol) and niclosamide to streams infested with their larvae. Both agents uncouple oxidative phosphorylation in the mitochondria, but TFM specifically targets lampreys, which have a lower capacity to detoxify the lampricide. Niclosamide lacks specificity and is more potent than TFM. However, its greater potency is poorly understood. We tested the hypothesis that niclosamide is a stronger uncoupler of mitochondrial oxidative phosphorylation than TFM by measuring oxygen consumption rates in isolated liver mitochondria exposed to physiologically relevant concentrations of TFM, niclosamide, or their mixture (100 TFM:1 niclosamide) at environmentally relevant temperatures (7, 13, and 25 °C). Niclosamide increased State 4 respiration and decreased the respiratory control ratio (RCR) at much lower concentrations than TFM. Calculations of the relative EC 50 values, the amount of TFM or niclosamide required to decrease the RCR by 50%, indicated that niclosamide was 40−60 times more potent than TFM. Warmer temperature did not appear to decrease the sensitivity of mitochondria to niclosamide or TFM, as observed in the intact sea lamprey exposed to TFM in warmer waters. We conclude that the extreme sensitivity of mitochondria to niclosamide contributes to its greater in vivo toxicity in the whole animal.

Transcriptomic impacts and potential routes of detoxification in a lampricide-tolerant teleost exposed to TFM and niclosamide

“…Historically, niclosamide has been used primarily to treat tapeworm and other parasitic worm infections (Dawson, 2003), by uncoupling oxidative phosphorylation in the target species (Jones, 1979; Pampori et al, 1984; Pearson and Hewlett, 1985; Weinbach and Garbus, 1969). This mode of action has also been shown in vertebrates (Borowiec et al, 2022), which causes increased reliance on anaerobic metabolism to meet basic ATP demands (reviewed in Wilkie et al, 2019; Lawrence et al 2021; Ionescu et al 2020a,b). In fishes, this is typified by reductions in tissue ATP, glycogen, glucose, and phosphocreatine levels (PCr; Lawrence et al, 2021; Shoman, 2001; Zhu et al, 2020; Ionescu et al 2022a,b).…”

“…A GO term enrichment analysis approach has already been used to identify effects on detoxification systems and cellular growth/death processes associated with TFM and niclosamide exposures separately in fishes (Lawrence and Grayson et al, 2022; Zhu et al, 2020). As previous work has identified both TFM and niclosamide as targeting oxidative phosphorylation and affecting cell growth and death processes (Borowiec et al, 2022; Lawrence and Grayson et al, 2022), we hypothesized that both niclosamide and a TFM:niclosamide mixture would disrupt cellular energy metabolism and cell cycle processes in bluegill. We predicted that this effect would be more pronounced in the mixture group.…”

“…Lampricide applications are not restricted to TFM, which is often co-applied with 1-2 % niclosamide (tradename Bayluscide®; previously known as Bayer 73), which increases TFM’s effectiveness without loss of specificity (Barber and Steeves, 2021; Dawson et al, 1982; McDonald and Kolar, 2007). The use of lampricide mixtures is advantageous in control efforts as these two compounds typically act in a synergistic or greater than additive fashion (e.g., Borowiec et al, 2022; Hepditch et al, 2021; Lawrence et al, 2021; Marking and Dawson, 1975), making lampricide applications more effective and economical.…”

“…The effects of TFM alone are fairly well characterized as it acts as a mitochondrial uncoupler in fishes (Birceanu et al, 2011; Borowiec et al, 2022; Huerta et al, 2020). Whole transcriptome responses in TFM-exposed bluegill and sea lamprey were characterized by an enrichment of processes related to an arrest of cellular growth and proliferation, increased apoptosis, and an inflammatory response (Lawrence and Grayson et al 2022).…”

Investigating Immunotoxicity in Black Carp (Mylopharyngodon piceus) Fingerlings Exposed to Niclosamide

“…The significant presence of residues in the environment can have detrimental impacts on non-target environmental organisms, necessitating further investigation into the potentially harmful effects of niclosamide residues on aquatic organisms. Previous research has shown Life 2024, 14, 544 2 of 14 that niclosamide exposure can lead to impaired embryonic development, endocrine and metabolic disruptions, and oxidative damage in zebrafish [6][7][8][9]. Niclosamide has been documented to induce liver, gut, and gill toxicity in black carp [10].…”