Pyrethroid insecticide lambda-cyhalothrin induces hepatic cytochrome P450 enzymes, oxidative stress and apoptosis in rats

https://doi.org/10.1016/j.scitotenv.2018.03.030Get rights and content

Highlights

  • Lambda-cyhalothrin induced hepatic CYP1A1/2, CYP2B1/2, CYP3A1/2, CYP4A1/2 activities in rats.

  • Similarly, an increase of hepatic CYP1A1/2, 2A1, 2B1/2, 2E1, 3A1/2 and 4A1 mRNA levels was observed.

  • IL-1β, NFκB, Nrf2, p53, caspase-3 and Bax gene expressions were also affected.

  • PCR array showed greater fold change on the up-regulated ALDH1A1, CYP2B2, CYP2C80 and CYP2D4 genes.

  • IPA groups genes into toxicological mechanisms related to fatty acid and xenobiotic metabolism.

Abstract

This study aimed to examine in rats the effects of the Type II pyrethroid lambda-cyhalothrin on hepatic microsomal cytochrome P450 (CYP) isoform activities, oxidative stress markers, gene expression of proinflammatory, oxidative stress and apoptosis mediators, and CYP isoform gene expression and metabolism phase I enzyme PCR array analysis. Lambda-cyhalothrin, at oral doses of 1, 2, 4 and 8 mg/kg bw for 6 days, increased, in a dose-dependent manner, hepatic activities of ethoxyresorufin O-deethylase (CYP1A1), methoxyresorufin O-demethylase (CYP1A2), pentoxyresorufin O-depentylase (CYP2B1/2), testosterone 7α- (CYP2A1), 16β- (CYP2B1), and 6β-hydroxylase (CYP3A1/2), and lauric acid 11- and 12-hydroxylase (CYP4A1/2). Similarly, lambda-cyhalothrin (4 and 8 mg/kg bw, for 6 days), in a dose-dependent manner, increased significantly hepatic CYP1A1, 1A2, 2A1, 2B1, 2B2, 2E1, 3A1, 3A2 and 4A1 mRNA levels and IL-1β, NFκB, Nrf2, p53, caspase-3 and Bax gene expressions. PCR array analysis showed from 84 genes examined (P < 0.05; fold change > 1.5), changes in mRNA levels in 18 genes: 13 up-regulated and 5 down-regulated. A greater fold change reversion than 3-fold was observed on the up-regulated ALDH1A1, CYP2B2, CYP2C80 and CYP2D4 genes. Ingenuity Pathway Analysis (IPA) groups the expressed genes into biological mechanisms that are mainly related to drug metabolism. In the top canonical pathways, Oxidative ethanol degradation III together with Fatty Acid α-oxidation may be significant pathways for lambda-cyhalothrin. Our results may provide further understanding of molecular aspects involved in lambda-cyhalothrin-induced liver injury.

Introduction

Lambda-cyhalothrin [α-cyano-3-phenoxybenzyl 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate] is a Type II pyrethroid insecticide with a high level of activity against a wide range of Lepidoptera, Hemiptera, Diptera, and Coleoptera species. Lambda-cyhalothrin has found extensive uses in public and animal health applications as well as in around buildings where it effectively controls a broad spectrum of insects and ectoparasites, including cockroaches, flies, lice, mosquitos, and ticks (Davies et al., 2000; Kroeger et al., 2003). Studies have demonstrated that Type II pyrethroids, that contain an α-cyano-3-phenoxybenzyl alcohol and a halogen group in the acid moiety, are readily absorbed from the respiratory tract following inhalation (Kavlock et al., 1979) and from the gastrointestinal tract following oral administration (Anadón et al., 1996, Anadón et al., 2006) and detoxified by cytochrome P450 (CYP)-mediated oxidation and esterase-mediated hydrolysis followed by conjugation (Ruzo et al., 1979; Shono et al., 1979; Dayal et al., 2003). Studies in vivo and in vitro and epidemiological data have shown that pyrethroids undergo extensive metabolism by carboxylesterases and CYPs (Anand et al., 2006; Godin et al., 2006, Godin et al., 2007; Nishi et al., 2006; Crow et al., 2007; Scollon et al., 2009).

High occupational and environmental human exposure to pyrethroid insecticides could interact with the normal metabolism of drugs or xenobiotics (Carlson and Schoening, 1980; Catinot et al., 1989). Induction of CYP enzymes by Type I and Type II pyrethroids has been demonstrated (Delescluse et al., 1998; Morisseau et al., 1999; Heder et al., 2001; Yang et al., 2009). Although CYP enzymes normally generate metabolites with diminished biologic activity and represent a defense for detoxifying the ROS entities O2radical dot and O22radical dot, there are numerous examples where these enzymes catalyze the metabolic activation of chemically inert agents to electrophiles (Ioannides and Parke, 1990; Guengerich et al., 1991; Hinson et al., 1994). The link between P450-mediated metabolism and toxicity of several compounds has been showed (Nyarko et al., 1997; Gonzalez and Gelboin, 1994). Because, to our knowledge, there is limited information on the ability of lambda-cyhalothrin to induce hepatic drug metabolizing enzymes (Yang et al., 2009; Abass et al., 2012), the present study was performed with the objective to establish if lambda-cyhalothrin interacts with microsomal CYP system in rat liver and to analyze whether oxidative stress, proinflammatory and apoptosis mechanisms should be also co-affected by this pyrethroid. To test each of the postulated key events, several parameters were evaluated in the liver of rats following oral pyrethroid exposure: (1) CYP isoform activities, (2) oxidative stress markers (ROS, and enzymatic antioxidant activities), (3) gene expression of proinflammatory (NFκB, IL-1β), oxidative stress and apoptosis (Nrf2, p53, caspase-3, Bax) mediators, and (4) CYP isoform gene expressions and gene expression profile by rat metabolism phase I enzyme PCR array analysis.

Section snippets

Chemicals and reagents

Lambda-cyhalothrin (mixture 1:1 of S and R enantiomers); molecular formula C23H19ClF3NO3. CAS No: 91465-08-6, purity 98.8% w/w were provided by Zeneca Agrochemicals (Syngenta), Bracknell, Berks, England. Aniline, aminopyrine, erythromycin, lauric acid, ethoxy- and pentoxy-resorufin, testosterone, 6β- and 16α-hydroxytestosterone, NADPH, coenzyme A (CoA), all cofactors, bovine serum albumin, sodium azide, glutathione reductase, GSSG, 1-chloro-2,4-dinitrobenzene (CDNB), XTT, xanthine, xanthine

Results

Oral doses of 1, 2, 4 and 8 mg lambda-cyhalothrin/kg bw, for 6 days, did not cause mortality in animals. All animals were observed twice daily (a.m. before treatment and p.m. after treatment). Rats were observed for their general condition of the skin and fur, eyes, nose, oral cavity, abdomen and external genitalia, evaluated for respiration and palpated for masses. Any visible injury, i.e., any clinical signs of dysfunction were observed in any of the animals treated with lambda-cyhalothrin at

Discussion

To our knowledge, this is the first study to show that short-term oral administration of the Type II pyrethroid lambda-cyhalothrin to rats significantly induces hepatic CYP enzymes. This work assess also if there is a correlation of lambda-cyhalothrin effects between hepatic CYP mRNA levels and CYP enzymes activities. The use of mRNA expression profiling increases the throughput and information on the potential of a compound to induce drug metabolizing enzymes. Our data support that there is a

Conclusion

The present study demonstrates, in liver microsomes from rats treated orally with lambda-cyhalothrin, an induction of CYP1A, CYP2E, CYP2B CYP3A and CYP4A subfamilies, results confirmed analyzing mRNA expression by real-time PCR, where mainly CYP2B2 was overexpressed. IPA analysis also showed that several signaling pathways including Oxidative ethanol degradation III, and Fatty acid α-oxidation maybe closely related to adaptive response after lambda-cyhalothrin exposure. Because of the worldwide

Acknowledgements

This work was supported by Project (ALIBIRD-CM Program) Ref. S2013/ABI-2728 from Comunidad de Madrid, and Project Ref. RTA2015-00010-C03-03 from Ministerio de Economía, Industria y Competitividad, Spain.

Conflict of interest

The authors declare that there are no conflicts of interest.

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