Acute Exposure to Permethrin Modulates Behavioral Functions, Redox, and Bioenergetics Parameters and Induces DNA Damage and Cell Death in Larval Zebrafish

Abstract

Permethrin (PM) is a synthetic pyrethroid insecticide widely used as domestic repellent. Damage effects to nontarget organisms have been reported, particularly in the early stages of development. Studies indicate redox unbalance as secondary PM effect. Therefore, our goal was to investigate the acute PM effects on larval zebrafish. Larvae (6 days postfertilization) were exposed to PM (25–600 μg/L) during 24 hours, and 50% lethal concentration was estimated. For subsequent assays, the sublethal PM concentrations of 25 and 50 μg/L were used. PM increased anxiety-like behaviors according to the Novel Tank and Light-Dark tests. At the molecular level, PM induced increased ROS, which may be related to the increased lipid peroxidation, DNA damage, and apoptosis detected in PM-exposed organisms. In parallel, upregulation of the antioxidant system was detected after PM exposure, with increased superoxide dismutase, glutathione S-transferase and glutathione reductase activities, and thiol levels. The increased of Nrf2 target genes and the activation of an electrophile response element-driven reporter Tg(EPRE:LUC-EGFP) suggest that the Nrf2 pathway can mediate a fast response to PM, leading to antioxidant amplification. By using high-resolution respirometry, we found that exposure to PM decreased the oxygen consumption in all respiratory stages, disrupting the oxidative phosphorylation and inhibiting the electron transfer system, leading to decrease in bioenergetics capacity. In addition, PM led to increases of residual oxygen consumption and changes in substrate control ratio. Glucose metabolism seems to be affected by PM, with increased lactate dehydrogenase and decreased citrate synthase activities. Taken together, our results demonstrated the adverse effects of acute sublethal PM concentrations during larval development in zebrafish, causing apparent mitochondrial dysfunction, indicating a potential mechanism to redox unbalance and oxidative stress, which may be linked to the detected cell death and alterations in normal behavior patterns caused by acute PM exposure.

Salinity Changes the Dynamics of Pyrethroid Toxicity in Terms of Behavioral Effects on Newly Hatched Delta Smelt Larvae

“…Indeed, their research has shown that exposure of Delta Smelt larvae to 50 ng/L permethrin and 2 ng/L bifenthrin, for 96 h, resulted in significant hyperactivity, as well as a decrease in thigmotaxis (wall hugging). Similar observations have been reported for Zebrafish larvae exposed to permethrin at 50 μg/L for 24 h, resulting in alterations in nonmotor behavioral patterns, such as decreased defensive behaviors linked to thigmotaxis and scototaxis (dark/light preference) [ 44 ]. Direct links of these effects on survival in the field and overall fitness are difficult to predict, but these behavior alterations are likely to cause changes in ability to avoid predation, capture prey and subsequently affect reproduction success, leading to a decrease in population abundance [ 23 , 49 ].…”

“…An increase in the amount of time in the center or open zone, depending on the test, is considered to be reflective of an anxiolytic response to a compound such as caffeine [ 57 ]. Nunes et al (2019) also advanced the hypothesis that permethrin exposure (50 μg/L) may have decreased the anxiety-like behavior in Zebrafish larvae, altering the normal preference of the periphery in favor of the central area [ 44 ]. This change of anxiety related behavior after a pyrethroid exposure may be a threat to the survival of these larvae in terms of predator avoidance and food capture.…”

“…Among the several locomotor behavioral assays, the light and dark locomotion test, in which various swimming activity endpoints are measured, has been used to evaluate and screen numerous compounds for potential neuroactive properties [ 41 , 42 ]. At sublethal concentrations, pyrethroids are found to induce changes in the protein metabolism and/or behavior in larval fish such as Zebrafish, Inland Silversides and Delta Smelt [ 43 , 44 , 45 , 46 , 47 , 48 ]. Mundy et al (2020), have recently adapted a light and dark cycle behavioral test, routinely used on Zebrafish species, for Delta Smelt larvae and used it to assess sensitive alterations in swimming activity due to environmentally relevant pyrethroid concentrations [ 47 , 48 ].…”

Exposure to Sub-Lethal Doses of Permethrin Is Associated with Neurotoxicity: Changes in Bioenergetics, Redox Markers, Neuroinflammation and Morphology

“…This increases reactive oxygen species (ROS) production and inhibits mitochondrial complex I. Thus, the deficit of antioxidant enzymes in different organs leads to protein, lipid and DNA damage [25,28,31]. However, there is little information about PERM neurotoxicity after exposure to low doses and for short periods.…”

“…Recent studies have shown that exposure to different permethrin concentrations can alter the function of mitochondria, with the consequent increase in oxidative stress and inflammatory processes [27,28,30]. PERM can adversely affect cognitive and mood function either directly or indirectly via reduced hippocampal neurogenesis [27][28][29][30][31]. In the present study, we evaluated neurotoxicity induced by subacute exposure to PERM in sublethal doses and its effects on the immune systems, bioenergetic redox and morphology of the brain using an animal model.…”