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Paracetamol affects the expression of detoxification- and reproduction-related genes and alters the life traits of Daphnia magna

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Abstract

Paracetamol (APAP) is a widely used non-steroidal anti-inflammatory drug and has been frequently detected in aquatic environment. However, limited information is provided about the toxic effects and detoxification mechanism of APAP in aquatic invertebrates. In the present study, the change of life traits of Daphnia magna (e.g., body length, growth rate and reproduction) was investigated under the chronic APAP exposure (0–5000 μg/L) for 21 day, and the effects of APAP on the expression of the detoxification- and reproduction-related genes including HR96, CYP360A8, CYP314, MRP4, P-gp, EcR and Vtg in the acute exposure (up to 96 h) were also determined. Results showed that the molting frequency, days to the first brood and days to the first egg production of D. magna were affected under the 50 μg/L concentration of APAP in the chronic exposure test. In the acute test, the transcriptional expression of HR96 was up-regulated under APAP exposure for 24 and 48 h. Similar performances were also observed in the expression of CYP360A8, CYP314, MRP4 and P-gp. However, with exposure time extended to 96 h, the induction of HR96 decreased or even reversed in some cases. It may indicate that the defense system in Daphnia is activated for a short time of exposure or becomes adaptive after longer term of exposure. APAP exposure also affected reproduction-related genes expression, which was related to the exposure time and concentration of APAP. In summary, APAP significantly affected the expression of genes associated with detoxification metabolism and altered some physiological parameters in D. magna.

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References

  • Andersen L, Goto-Kazeto R, Trant JM, Nash JP, Korsgaard B, Bjerregaard P (2006) Short-term exposure to low concentrations of the synthetic androgen methyltestosterone affects vitellogenin and steroid levels in adult male zebrafish (Danio rerio). Aquat Toxicol 76:343–352

    CAS  Google Scholar 

  • Baldwin WS, Marko PB, Nelson DR (2009) The cytochrome P450 (CYP) gene superfamily in Daphnia pulex. BMC Genom 10:169

    Google Scholar 

  • Bertrand S, Brunet FG, Escriva H, Parmentier G, Laudet V, Robinson-Rechavi M (2004) Evolutionary genomics of nuclear receptors: from twenty-five ancestral genes to derived endocrine systems. Mol Biol Evol 21:1923–1937

    CAS  Google Scholar 

  • Boyd GR, Reemtsma H, Grimm DA, Mitra S (2003) Pharmaceuticals and personal care products (PPCPs) in surface and treated waters of Louisiana, USA and Ontario, Canada. Sci Total Environ 311:135–149

    CAS  Google Scholar 

  • Campos B, Pina B, Barata CC (2012) Mechanisms of action of selective serotonin reuptake inhibitors in Daphnia magna. Environ Sci Technol 46:2943–2950

    CAS  Google Scholar 

  • Carlsson C, Johansson AK, Alvan G, Bergman K, Kuhler T (2006) Are pharmaceuticals potent environmental pollutants? Part II: environmental risk assessments of selected pharmaceutical excipients. Sci Total Environ 364:88–95

    CAS  Google Scholar 

  • Choi E, Alsop D, Wilson JY (2018) The effects of chronic acetaminophen exposure on the kidney, gill and liver in rainbow trout (Oncorhynchus mykiss). Aquat Toxicol 198:20–29

    CAS  Google Scholar 

  • Cleuvers M (2003) Aquatic ecotoxicity of pharmaceuticals including the assessment of combination effects. Toxicol Lett 142:185–194

    CAS  Google Scholar 

  • Davis DC, Potter WZ, Jollow DJ, Mitchell JR (1974) Species differences in hepatic glutathione depletion, covalent binding and hepatic necrosis after acetaminophen. Life Sci 14:2099–2109

    CAS  Google Scholar 

  • Han GH, Hur HG, Kim SD (2006) Ecotoxicological risk of pharmaceuticals from wastewater treatment plants in Korea: occurrence and toxicity to Daphnia magna. Environ Toxicol Chem 25:265–271

    CAS  Google Scholar 

  • Hannas BR, Wang YH, Thomson S, Kwon G, Li H, Leblanc GA (2011) Regulation and dysregulation of vitellogenin mRNA accumulation in daphnids (Daphnia magna). Aquat Toxicol 101:351–357

    CAS  Google Scholar 

  • Hernandez JP, Mota LC, Baldwin WS (2009) Activation of CAR and PXR by dietary, environmental and occupational chemicals alters drug metabolism, intermediary metabolism, and cell proliferation. Curr Pharmacogenom Personal Med 7:81–105

    CAS  Google Scholar 

  • Hirohashi T, Suzuki H, Takikawa H, Sugiyama Y (2000) ATP-dependent transport of bile salts by rat multidrug resistance-associated protein 3 (Mrp3). J Biol Chem 275:2905–2910

    CAS  Google Scholar 

  • Houde M, Carter B, Douville M (2013) Sublethal effects of the flame retardant intermediate hexachlorocyclopentadiene (HCCPD) on the gene transcription and protein activity of Daphnia magna. Aquat Toxicol 140:213–219

    Google Scholar 

  • Hwang DS, Han J, Won EJ, Kim DH, Jeong CB, Hwang UK, Zhou B, Choe J, Lee JS (2016) BDE-47 causes developmental retardation with down-regulated expression profiles of ecdysteroid signaling pathway-involved nuclear receptor (NR) genes in the copepod Tigriopus japonicus. Aquat Toxicol 177:285–294

    CAS  Google Scholar 

  • Karimullina E, Li Y, Ginjupalli GK, Baldwin WS (2012) Daphnia HR96 is a promiscuous xenobiotic and endobiotic nuclear receptor. Aquat Toxicol 116-117:69–78

    CAS  Google Scholar 

  • Kato Y, Kobayashi K, Oda S, Tatarazako N, Watanabe H, Iguchi T(2007) Cloning and characterization of the ecdysone receptor and ultraspiracle protein from the water flea Daphnia magna. J Endocrinol 193:183–194

    CAS  Google Scholar 

  • Kim Y, Choi K, Jung J, Park S, Kim PG, Park J (2007) Aquatic toxicity of acetaminophen, carbamazepine, cimetidine, diltiazem and six major sulfonamides, and their potential ecological risks in Korea. Environ Int 33:370–375

    CAS  Google Scholar 

  • King-Jones K, Horner MA, Lam G, Thummel CS (2006) The DHR96 nuclear receptor regulates xenobiotic responses in Drosophila. Cell Metab 4:37–48

    CAS  Google Scholar 

  • Kretschmer XC, Baldwin WS (2005) CAR and PXR: xenosensors of endocrine disrupters? Chem Biol Interact 155:111–128

    CAS  Google Scholar 

  • Le TH, Lim ES, Lee SK, Park JS, Kim YH, Min J (2011) Toxicity evaluation of verapamil and tramadol based on toxicity assay and expression patterns of Dhb, Vtg, Arnt, CYP4, and CYP314 in Daphnia magna. Environ Toxicol 26:515–523

    CAS  Google Scholar 

  • Li SW, Wang YH, Lin AY (2017) Ecotoxicological effect of ketamine: evidence of acute, chronic and photolysis toxicity to Daphnia magna. Ecotoxicol Environ Saf 143:173–179

    CAS  Google Scholar 

  • Liu S, Ding R, Nie X (2019) Assessment of oxidative stress of paracetamol to Daphnia magna via determination of Nrf1 and genes related to antioxidant system. Aquat Toxicol 211:73–80

    CAS  Google Scholar 

  • Liu Y, Wang L, Pan B, Wang C, Bao S, Nie X (2017) Toxic effects of diclofenac on life history parameters and the expression of detoxification-related genes in Daphnia magna. Aquat Toxicol 183:104–113

    CAS  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408

    CAS  Google Scholar 

  • Matozzo V, Gagne F, Marin MG, Ricciardi F, Blaise C (2008) Vitellogenin as a biomarker of exposure to estrogenic compounds in aquatic invertebrates: a review. Environ Int 34:531–545

    CAS  Google Scholar 

  • Meinertz JR, Schreier TM, Bernardy JA, Franz JL (2010) Chronic toxicity of diphenhydramine hydrochloride and erythromycin thiocyanate to daphnia, Daphnia magna, in a continuous exposure test system. Bull Environ Contam Toxicol 85:447–451

    CAS  Google Scholar 

  • Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB (1973) Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther 187:211–217

    CAS  Google Scholar 

  • OECD (2004) OECD guideline for testing of chemicals 202-Daphnia sp. acute immobilisation test Organization for the Economic Cooperation and Development. OECD, Paris

    Google Scholar 

  • Ramos AS, Correia AT, Antunes SC, Goncalves F, Nunes B (2014) Effect of acetaminophen exposure in Oncorhynchus mykiss gills and liver: detoxification mechanisms, oxidative defence system and peroxidative damage. Environ Toxicol Pharmacol 37:1221–1228

    CAS  Google Scholar 

  • Rewitz KF, Gilbert LI (2008) Daphnia Halloween genes that encode cytochrome P450s mediating the synthesis of the arthropod molting hormone: evolutionary implications. BMC Evolut Biol 8:60

    Google Scholar 

  • Saide K, Sherwood V, Wheeler GN (2019) Paracetamol-induced liver injury modelled in Xenopus laevis embryos. Toxicol Lett 302:83–91

    CAS  Google Scholar 

  • Scheffer GL, Kool M, de Haas M, de Vree JM, Pijnenborg AC, Bosman DK, Elferink RP, van der Valk P, Borst P, Scheper RJ (2002) Tissue distribution and induction of human multidrug resistant protein 3. Lab Investig 82:193–201

    CAS  Google Scholar 

  • Schmidt AM, Sengupta N, Saski CA, Noorai RE, Baldwin WS (2017) RNA sequencing indicates that atrazine induces multiple detoxification genes in Daphnia magna and this is a potential source of its mixture interactions with other chemicals. Chemosphere 189:699–708

    CAS  Google Scholar 

  • Sekimoto T, Iwami M, Sakurai S (2006) Coordinate responses of transcription factors to ecdysone during programmed cell death in the anterior silk gland of the silkworm, Bombyx mori. Insect Mol Biol 15:281–292

    CAS  Google Scholar 

  • Sengupta N, Litoff EJ, Baldwin WS (2015) The HR96 activator, atrazine, reduces sensitivity of Daphnia magna to triclosan and DHA. Chemosphere 128:299–306

    CAS  Google Scholar 

  • Shen B, Dong HQ, Tian HS, Ma L, Li XL, Wu GL, Zhu CL (2003) Cytochrome P450 genes expressed in the deltamethrin-susceptible and -resistant strains of Culex pipiens pallens. Pestic Biochem Physiol 75:19–26

    CAS  Google Scholar 

  • Stuer-Lauridsen F, Birkved M, Hansen LP, Lutzhoft HC, Halling-Sorensen B (2000) Environmental risk assessment of human pharmaceuticals in Denmark after normal therapeutic use. Chemosphere 40:783–793

    CAS  Google Scholar 

  • Sturm A, Cunningham P, Dean M (2009) The ABC transporter gene family of Daphnia pulex. BMC Genom 10:170

    Google Scholar 

  • Subramoniam T (2000) Crustacean ecdysteriods in reproduction and embryogenesis. Comp Biochem Physiol 125:135–156

    CAS  Google Scholar 

  • Ternes TA, Meisenheimer M, McDowell D, Sacher F, Brauch HJ, Haist-Gulde B, Preuss G, Wilme U, Zulei-Seibert N (2002) Removal of pharmaceuticals during drinking water treatment. Environ Sci Technol 36:3855–3863

    CAS  Google Scholar 

  • van Leeuwen CJ, Vermeire TG (2007) Risk Assessment of Chemicals—An Introduction. Part 3. Effects assessment and risk characterization. Springer, Dordrecht. The Netherlands, pp 209–308

    Google Scholar 

  • Viehoever A (1936) Daphnia—the biological reagent. J Am Pharm Assoc 25:1112–1117

    CAS  Google Scholar 

  • Wang L, Peng Y, Nie X, Pan B, Ku P, Bao S (2016) Gene response of CYP360A, CYP314, and GST and whole-organism changes in Daphnia magna exposed to ibuprofen. Comp Biochem Physiol 179:49–56

    CAS  Google Scholar 

  • Whyte-Allman SK, Hoque MT, Jenabian MA, Routy JP, Bendayan R (2017) Xenobiotic nuclear receptors pregnane X receptor and constitutive androstane receptor regulate antiretroviral drug efflux transporters at the blood-testis barrier. J Pharmacol Exp Ther 363:324–335

    CAS  Google Scholar 

  • Wollenberger L, Halling-Sorensen B, Kusk KO (2000) Acute and chronic toxicity of veterinary antibiotics to Daphnia magna. Chemosphere 40:723–730

    CAS  Google Scholar 

  • Xu JJ, Hendriks BS, Zhao J, de Graaf D (2008) Multiple effects of acetaminophen and p38 inhibitors: towards pathway toxicology. FEBS Lett 582:1276–1282

    CAS  Google Scholar 

  • Yamano S, Tatsuno J, Gonzalez FJ (1990) The CYP2A3 gene product catalyzes coumarin 7-hydroxylation in human liver microsomes. Biochemistry 29:1322–1329

    CAS  Google Scholar 

  • Yan Q, Gao X, Peng XY (2012) Research and progress in removal of nonsteroidal anti-inflammatory drugs (NSAIDS) in wastewater treatment plants. Technol Water Treat 38:13–19

    CAS  Google Scholar 

  • Yang X, Chen F, Meng F, Xie Y, Chen H, Young K, Luo W, Ye T, Fu W (2013) Occurrence and fate of PPCPs and correlations with water quality parameters in urban riverine waters of the Pearl River Delta, South China. Environ Sci Pollut Res Int 20:5864–5875

    CAS  Google Scholar 

  • Yin D, Jin H, Yu L, Hu S (2003) Deriving freshwater quality criteria for 2,4-dichlorophenol for protection of aquatic life in China. Environ Pollut 122:217–222

    CAS  Google Scholar 

  • Zhang L (2002) Market analysis of paracetamol. China Pharm 30:11–12.

    CAS  Google Scholar 

  • Zhong Z, Xie QL (2015) Occurence and screening-level risk assessment of pharmaceuticals and personal care products in Liuxi river. Guangdong Chem Ind 42:58–59

    CAS  Google Scholar 

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Acknowledgements

This work was supported by National Natural Science Foundation of China (NSFC 31770554; 41576110).

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Correspondence to Xiangping Nie.

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Ding, R., Liu, S., He, C. et al. Paracetamol affects the expression of detoxification- and reproduction-related genes and alters the life traits of Daphnia magna. Ecotoxicology 29, 398–406 (2020). https://doi.org/10.1007/s10646-020-02199-z

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