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Long-term low-dose exposure of permethrin induces liver and kidney damage in rats
BMC Pharmacology and Toxicology volume 23, Article number: 46 (2022)
Permethrin is one of the pyrethroid insecticides, which is widely used in agriculture and public health. Although acute toxicity of the insecticide has been studied, the chronic toxicity upon the long-term exposure has not been clear yet. The purpose of the current study is to investigate the organ toxicities of permethrin following its long-term low-dose exposure.
Male Wistar rats were daily administrated orally with permethrin (75 mg/kg body weight/day, gavage) for 90 days, and then the samples of biofluids (blood and urine) and organs including liver and kidney were collected. The serum and urine samples were measured by biochemical assay and the tissues of kidney and liver were examined and analyzed by histopathological method.
The results showed that no change was found in serum and urine biochemical parameters for the toxicity; however, significant changes including hyperchromatic nuclei swollen in the hepatic parenchymal cells and the swelling proximal tubules in the kidneys were observed in the tissue structures of liver and kidneys in the histopathological sections.
These results indicate that low-dose long-term exposure of permethrin can cause chronic toxicity with slight liver and kidney damage.
Synthetic pyrethroids are a group of insecticides widely used in agriculture and public health, which comprise over one-third of all insecticides in the world . Pyrethroid insecticides demonstrate a selective toxicity toward insects. They are mainly used for mosquito eradication and pests control [1,2,3,4,5]. Pyrethroid insecticides are considered to be one of the safest pesticides available, but the potential toxicity risk of the insecticides following long-term exposure has been concerned and debated [6, 7]. Recent studies have suggested that the pyrethroid pesticides are not entirely safe to mammals’ health [8, 9]. Permethrin is one of the most used pyrethroid insecticides, which is characterized by low toxicity to vertebrates including mammals but high toxic against target insects. It is known that permethrin produces toxicity through targeting the important site of sodium channels to induce a decrease of the activity of the channels in nervous system [10,11,12,13]. The long-term wide use of this insecticide produces an increasing concern for the health of humans .
Some investigations have been carried out on the high-dose short-term toxicity of permethrin [15, 16]. In reality, however, the actual exposure to the insecticide is usually at low-level and for long-term [17, 18]. The majority of previous investigations on permethrin have focused on the target toxicities, for example, the neurotoxicity [4, 19,20,21]; however, there has been minimal study conducted on the organ toxicity of the insecticide to mammals after low-dose and long-term exposure. In this investigation, we studied the effect of permethrin on the liver and kidney functions in rats following 90-day low-dose oral exposure.
Materials and methods
Permethrin (40 60 cis trans isomer ratio, 95% purity) was purchased from Ronch Chemical Co. (Nanjing, China). Hematoxylin, eosin, and other chemicals were obtained from Sigma Chemical Co. (St. Louis, MO, USA).
Animals and treatment
Ten male Wistar rats (200 ± 20 g) were obtained from Weitong Lihua Laboratory Animal Technology Company (Beijing, China) and were housed individually in cages. All animals were acclimatized for at least 1 week prior to the study . During the experiment, the animal rooms were maintained at 22 ± 2 °C temperature and 50–60% humidity and a light/dark cycle of 12 h. Animals had free access to water and the diet. The rats were randomly divided into 2 groups (control and permethrin treatment groups) with 5 animals in each group. Previous studies showed that acute oral half-lethal dose (LD50) of permethrin was 1500 mg/kg for male rats . In this study we chose the value of 1/20 LD50 as the dose (75 mg/kg body weight/day) for the pesticide treatment rats.
The pesticide was dissolved in corn oil (it is difficult to be dissolved in water) and then orally administered daily via gavage to rats (1 ml/kg body weight). Rats were given permethrin daily (once a day) for 90 days. The rats in control group received daily an equivalent dose of corn oil. The body weight of each rat was recorded daily, and symptoms and conditions of the rats were monitored daily throughout the experiment.
All animal procedures were performed in accordance with current China legislation and approved by the Animal and Medical Ethics Committee from Institute of Zoology, Chinese Academy of Sciences.
Samples collection and preparation
The sample collection and preparation were carried out in the similar way as our earlier report . Briefly, after the last administration, 24-hour urine samples of each rat were collected into an ice-cold vessel containing 0.1 ml of 1% sodium azide to prevent bacterial contamination and the samples were stored at − 80 °C prior to biochemical analysis.
All rats were anesthetized with pentobarbital sodium and decapitated twenty-four hours after the last administration. Blood samples were collected and then centrifuged to obtain the serum for biochemical assays. Weights of organs were immediately measured after they were isolated from the body.
For histopathological analysis, the kidney and liver tissues of the rats were dissected immediately at the end of the 90-day exposure to the pesticide, and then were fixed in a solution of 10% formalin. After fixation, the specimens were dehydrated with 80, 95, 100% gradient alcohol, and then soaked in melted wax, and finally embedded in paraffin . After that, the paraffin blocks were cut into 4-μm-thickness sections using a microtome (Microm HM 340E, Thermo Fisher Scientific, USA), then were stained with hematoxylin and eosin. The histological changes in the kidney and liver tissue sections were examined in a microscope (Olympus, Tokyo, Japan) and evaluated by a pathologist blinded to the different treatment groups.
Serum and urine biochemistry
All biochemical parameters of serum and urine samples were analyzed on an Autolab-PM4000 automatic analyzer (AMS Co.), according to the standard spectrophotometric methods. Values of the biochemical parameters were expressed as the mean ± SD.
Student’s t-test was used to assess the statistical significance of differences in measured parameters between the two groups. P < 0.05 was considered statistically significant. SPSS 18.0 software (SPSS, Inc., Chicago, MI, USA) was employed for the statistical evaluation.
Effects of permethrin on body weight and organ weight
During the 90-day experimental period, no obvious toxic sign was observed in the control rats and the permethrin-treated rats. And no animal was found dead during the whole experimental period of the study.
The weights of liver, kidneys, and other organs in permethrin-treated rats were not changed significantly after the 90-day exposure compared with those in control rats (Table 1), although the body weight of the treated rats decreased. The slight decrease (about 12%) of the body weight in permethrin-treated rats was perhaps due to the less feed intake.
Effect of permethrin on the clinical biochemistry
The changes of the biochemical parameters in serum and urine of the rats are shown in Table 2. We found that there was no significant change in the biochemical parameters of the serum and urine samples. These results indicate that the typical serum and urine biochemistry did not display obvious toxicity after 90-day exposure of permethrin.
Effect of permethrin on histopathology of liver and kidneys
Photomicrographs of the liver and kidney tissues are shown in Figs. 1 and 2, respectively. The microscope examination of liver sections displayed that the hyperchromatic nuclei were swollen in the hepatic parenchymal cells from the rats exposed to permethrin (Fig. 1), suggesting that permethrin induced slight liver damage after 90-day exposure at the dose of 75 mg/kg body weight/day. In the kidney sections, the swelling proximal tubules were observed (Fig. 2), which suggests that the long-term low-dose exposure of permethrin could also induce the kidney damage.
Permethrin which is used as a pyrethroid insecticide can affect sodium channels in the insect nervous system. The symptoms of acute toxicity for human and other vertebrates is vomiting, dyspnea, cough and bronchospasm, and skin effects . There is a lot of evidence that exposure to permethrin can cause reproductive toxicity, and endocrine disrupting . However, the long-term health implications of exposure to pyrethroids, especially the effects of the insecticide on important organs and tissues, are still unclear.
In this study, we used Wister rat to study the organ toxicity of pesticide permethrin. Rat has been using as a test animal for the study of hepatotoxicity and nephrotoxicity of chemicals since rat is in similar toxicological symptom and tissue structure change to human. In this investigation, we determined the changes of body weight and organ weight, biochemical parameters of serum and urine, and the histopathological changes of the kidneys and liver from the rats following 90-day exposure to low-dose permethrin. The dose used (75 mg/kg body weight/day, 1/20 LD50) was comparable to the reported chronic no-observed-adverse-effect level (NOAEL) in rats . It was inferred from the results, combined with the data from the previous reports that pesticide permethrin exposure even at low dose could affect the organs functions, although no obvious pathological change was found in liver and kidneys of the rats exposed to permethrin for a relatively shorter time [24, 29, 30]. In our study, some of the nuclei are massively enlarged, abnormally stained in the sections of liver from the permethrin-treated rats. The morphological changes in the sections of kidney revealed the swelling of the proximal tubules, suggesting the histology of megakaryocytic interstitial nephritis. The results in this study suggested that permethrin could cause the damage of liver and kidneys even at low dose after long-term exposure and even at that time no any apparent toxic symptom or abnormal change of the biochemical parameters could be observed.
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. All data generated or analyzed during this study are included in this published article.
Prasanthi K, Rajini P. Fenvalerate-induced oxidative damage in rat tissues and its attenuation by dietary sesame oil. Food Chem Toxicol. 2005;43:299–306.
Lawrence LJ, Casida JE. Stereospecific action of pyrethroid insecticides on the gamma-aminobutyric acid receptor-ionophore complex. Science. 1983;221:1399–401.
Casida J, Quistad G. Golden age of insecticide research: past, present, or future? Annu Rev Entomol. 1998;43:1–16.
Soderlund DM, Clark JM, Sheets LP, Mullin LS, Piccirillo VJ, Sargent D, et al. Mechanisms of pyrethroid neurotoxicity: implications for cumulative risk assessment. Toxicology. 2002;171:3–59.
Bradberry SM, Cage SA, Proudfoot AT, Vale JA. Poisoning due to pyrethroids. Toxicol Rev. 2005;24:93–106.
Kolaczinski J, Curtis C. Chronic illness as a result of low-level exposure to synthetic pyrethroid insecticides: a review of the debate. Food Chem Toxicol. 2004;42:697–706.
Spencer J, O’Malley M. Pyrethroid illnesses in California, 1996-2002. Rev Environ Contam Toxicol. 2006;186:57–72.
Nicolopoulou-Stamati P, Maipas S, Kotampasi C, Stamatis P, Hens L. Chemical pesticides and human health: the urgent need for a new concept in agriculture. Front Public Health. 2016;4:148.
Chrustek A, Hołyńska-Iwan I, Dziembowska I, Bogusiewicz J, Wróblewski M, Cwynar A, et al. Current research on the safety of pyrethroids used as insecticides. Medicina (Kaunas). 2018;54:61.
Lawrence LJ, Casida JE. Pyrethroid toxicology: mouse intracerebral structure-toxicity relationships. Pestic Biochem Physiol. 1982;18:9–14.
Michelangeli F, Robson MJ, East JM, Lee AG. The conformation of pyrethroids bound to lipid bilayers. Biochim Biophys Acta. 1990;1028:49–57.
Vais H, Williamson MS, Devonshire AL, Usherwood PNR. The molecular interactions of pyrethroid insecticides with insect and mammalian sodium channels. Pest Manag Sci. 2001;57:877–88.
DeMicco A, Cooper KR, Richardson JR, White LA. Developmental neurotoxicity of pyrethroid insecticides in zebrafish embryos. Toxicol Sci. 2010;113:177–86.
Morgan MK, Sheldon LS, Croghan CW, Jones PA, Chuang JC, Wilson NK. An observational study of 127 preschool children at their homes and daycare centers in Ohio: environmental pathways to cis-and trans-permethrin exposure. Environ Res. 2007;104:266–74.
Zhu Q, Yang Y, Lao Z, Zhong Y, Zhang K, Zhao S. Acute and chronic toxicity of deltamethrin, permethrin, and dihaloacetylated heterocyclic pyrethroids in mice. Pest Manag Sci. 2020;76:4210–21.
Ishmael J, Lithfield MH. Chronic toxicity and carcinogenic evaluation of permethrin in rats and mice. Fundam Appl Toxicol. 1988;11:308–22.
Fenske RA, Kedan G, Lu C, Fisker-Andersen JA, Curl CL. Assessment of organophosphorus pesticide exposures in the diets of preschool children in Washington state. J Expo Anal Environ Epidemiol. 2002;12:21–8.
Reffstrup TK, Larsen JC, Meyer O. Risk assessment of mixtures of pesticides. Current approaches and future strategies. Regul Toxicol Pharmacol. 2010;56:174–92.
Choi JS, Soderlund DM. Structure-activity relationships for the action of 11 pyrethroid insecticides on rat Na v 1.8 sodium channels expressed in Xenopus oocytes. Toxicol Appl Pharmacol. 2006;211:233–44.
Breckenridge CB, Holden L, Sturgess N, Weiner M, Sheets L, Sargent D, et al. Evidence for a separate mechanism of toxicity for the type I and the type II pyrethroid insecticides. Neurotoxicology. 2009;(Suppl 1):S17–31.
Field LM, Davies TE, O’reilly AO, Williamson MS, Wallace BA. Voltage-gated sodium channels as targets for pyrethroid insecticides. Eur Biophys J. 2017;46:675–9.
Liang YJ, Wang P, Long DX, Wang HP, Sun YJ, Wu YJ. The progressive alteration of urine metabolomic profiles of rats following long-term and low-dose exposure to permethrin. Biomarkers. 2020;25:94–9.
Cantalamessa F. Acute toxicity of two pyrethroids, permethrin, and cypermethrin in neonatal and adult rats. Arch Toxicol. 1993;67:510–3.
Liang YJ, Wang HP, Long DX, Wu YJ. Applying biofluid metabonomic techniques to analyze the combined subchronic toxicity of propoxur and permethrin in rats. Bioanalysis. 2012;4:2897–907.
Xu MY, Wang P, Sun YJ, Wu YJ. Disruption of kidney metabolism in rats after subchronic combined exposure to low-dose cadmium and chlorpyrifos. Chem Res Toxicol. 2019;32:122–9.
Wolansky MJ, Harrill JA. Neurobehavioral toxicology of pyrethroid insecticides in adult animals: a critical review. Neurotoxicol Teratol. 2008;30:55–78.
Gabbianelli R, Falcioni ML, Nasuti C, Cantalamessa F, Imada I, Inoue M. Effect of permethrin insecticide on rat polymorphonuclear neutrophils. Chem Biol Interact. 2009;182:245–52.
WHO. Report No. 14994: Combined chronic toxicity/carcinogenicity potential of permethrin technical in Wistar rats [online]. Unpublished report sponsored by M/s Tagros Chemicals India Limited, Chennai, India. 2011 Available from: http://www.google.com.hk/url?sa=t&rct=j&q=&esrc=s&source=web&cd=2&cad=rja&uact=8&ved=0ahUKEwjhiKGl26zYAhWBOZQKHWcjDA4QFggtMAE&url=http%3A%2F%2Fwww.who.int%2Fwhopes%2Fquality%2FPermethrin_25_75_specs_eval_WHO_Sep_2011.pdf&usg=AOvVaw2OcxON0xeovJ-lQjqpVd8o) [Access Sep 2011].
Liang YJ, Wang HP, Long DX, Li W, Wu YJ. A metabonomic investigation of the effects of 60 days exposure of rats to two types of pyrethroid insecticides. Chem Biol Interact. 2013;206:302–8.
Wang P, Xu MY, Liang YJ, Wang HP, Sun YJ, Long DX, et al. Subchronic toxicity of low dose propoxur, permethrin, and their combination on the redox status of rat liver. Chem Biol Interact. 2017;272:21–7.
This work was supported in part by the grant from the National Natural Science Foundation of China (No. 31970416).
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All animal procedures were performed in accordance with current China legislation and approved by the Animal and Medical Ethics Committee, which is affiliated to the Institute of Zoology, Chinese Academy of Sciences. All procedures were carried in accordance with the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines.
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Sun, YJ., Liang, YJ., Yang, L. et al. Long-term low-dose exposure of permethrin induces liver and kidney damage in rats. BMC Pharmacol Toxicol 23, 46 (2022). https://doi.org/10.1186/s40360-022-00586-2
- Long-term low-dose exposure