Skip to main content
SpringerLink
Log in

Embryotoxicity Produced by the Mixture of Aluminum, Metformin and Penicillin on Common Carp (Cyprinus carpio): a Study of Interactions

  • Published:
Water, Air, & Soil Pollution Aims and scope Submit manuscript

Abstract

Penicillin, metformin, and aluminum are commonly used substances and their presence in the environment has increased due to their widespread use. In water bodies, the combined presence of xenobiotics leads to additive, synergistic, or antagonistic interactions that significantly modify the toxic response, being more evident in the early stages of development of individuals. These interactions can be evaluated through biomarkers such as the activity and expression of antioxidant enzymes and the production of congenital malformations in exposed organisms. However, little is known about the effects that mixtures of drugs such as penicillin, metformin, and metals such as aluminum can produce on aquatic species that are constantly exposed to these xenobiotics such as common carp. The objective of this study was to determine the toxicity and type of interaction produced on Cyprinus carpio embryos exposed to these pollutants isolated and in mixtures. Here we show that the mixture of these pollutants produces antagonism and synergism at high and low concentrations respectively. In addition, toxicity results show that in embryos subacutely exposed (NOAEL) to the mixture of contaminants, the activity of antioxidant enzymes and their gene expression (PCR-RT) is increased, embryonic development is modified, and teratogenesis occurs. As can be observed, the mixture of the contaminants influenced the toxic response, evidencing the importance of continuing to study interactions; since this is the way, they are usually found in contaminated bodies of water.

Highlights

1. Exposure of Cyprinus carpio embryos to the mixture of metformin, penicillin and aluminum at high concentrations (LC50) produces an antagonistic type of interaction.

2. Exposure of Cyprinus carpio embryos to the mixture of metformin, penicillin and aluminum at sublethal concentrations (NOAEL) produces a synergistic type interaction.

3. Antioxidant enzyme activity of Cyprinus carpio embryos exposed to NOAEL-equivalent concentrations of metformin, penicillin and aluminum is modified by simultaneous exposure to the toxicants.

4. Gene expression of antioxidant enzymes in Cyprinus carpio embryos exposed to NOAEL-equivalent concentrations of metformin, penicillin and aluminum is increased by simultaneous exposure to the toxicants during the first hours of development.

5. The embryonic developmental score of Cyprinus carpio is decreased by simultaneous exposure to metformin, penicillin and aluminum.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  • Ahmed, N., Soufiane, J., Fehmi, B., Amor, H., Ezzeddine, M., Patricia, A., Naceur, E., & Hamouda, B. (2015). Effects of increasing levels of pharmaceutical penicillin G contamination on structure of free living nematode communities in experimental microcosms. Environmental Toxicology and Pharmacology, 40, 215–219.

    Google Scholar 

  • Aksakal, F. I. (2020). Evaluation of boscalid toxicity on Daphnia magna by using antioxidant enzyme activities, the expression of genes related to antioxidant and detoxification systems, and life-history parameters. Comparative Biochemistry and Physiology Part c: Toxicology & Pharmacology, 237, 108830.

    CAS  Google Scholar 

  • Aksakal, F. I., & Ciltas, A. (2018). Developmental toxicity of penconazole in Zebrfish (Danio rerio) embryos. Chemosphere, 200, 8–15.

    Google Scholar 

  • Ambrosio-Albuquerque, E. P., Cusioli, L. F., Bergamasco, R., Sinópolis Gigliolli, A. A., Lupepsa, L., Paupitz, B. R., Barbieri, P. A., Borin-Carvalho, L. A., & de Brito Portela-Castro, A. L. (2021). Metformin environmental exposure: A systematic review. Environmental Toxicology and Pharmacology, 83, 103588.

    CAS  Google Scholar 

  • Andreu, V., Gimeno-García, E., Pascual, J. A., Vazquez-Roig, P., & Picó, Y. (2016). Presence of pharmaceuticals and heavy metals in the waters of a Mediterranean coastal wetland: Potential interactions and the influence of the environment. Science of the Total Environment, 540, 278–286.

    CAS  Google Scholar 

  • Banti, C. N., Ketikidis, I., Hadjikakou, S. K., Hatzidimitriou, A. G., Grześkiewicz, A. M., Kubicki, M., & Hadjiliadis, M. (2020). Study of penicillin degradation mechanism upon interaction with silver(I) ions. Inorganica Chimica Acta, 509, 119683.

    CAS  Google Scholar 

  • Benavides, M., Fernandez-Lodeiro, J., Coelho, P., Lodeiro, C., & Diniz, M. S. (2016). Single and combined effects of aluminum (Al2O3) and zinc (ZnO) oxide nanoparticles in a freshwater fish. Carassius Auratus Environ Sci Pollut Res, 23, 24578–24591.

    CAS  Google Scholar 

  • Bownik, A., Ślaska, B., Bochra, J., Gumieniak, K., & Gałek, K. (2019). Procaine penicillin alters swimming behaviour and physiologicalparameters ofDaphnia magna. Environmental Science and Pollution Research, 26, 18662–18673.

    CAS  Google Scholar 

  • Bradford, M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry, 72(1–2), 248–254.

    CAS  Google Scholar 

  • Brooks, P. (2005). Mitochondrial H+ leak and ROS generation: An odd couple. Free Radical Biology and Medicine, 38(1), 12–23.

    Google Scholar 

  • Büyükgüzel, E., & Kalender, Y. (2007). Penicillin-induced oxidative stress: Effects on antioxidative response of midgut tissues in instars of Galleria mellonella. Journal of Economic Entomology, 5, 533–541.

    Google Scholar 

  • Canli, E., & Canli, M. (2020). Effects of aluminum, copper and titanium nanoparticles on the liver antioxidant enzymes of the Nile fish (Oreochromis niloticus). Energy Reports, 6(Supplement 8), 62–67.

    Google Scholar 

  • Cano-Viveros, S., Galar-Martínez, M., Gasca-Pérez, E., García-Medina, S., Ruiz-Lara, K., Gómez-Oliván, L. M., & Islas-Flores, H. (2021). The relationship between embryotoxicity and oxidative stress produced by aluminum, iron, mercury, and their mixture on Cyprinus carpio. Water, Air, and Soil Pollution, 232, 376.

    CAS  Google Scholar 

  • Capriello, T., Félix, L. M., Monteiro, S. M., Santos, D., Cofone, R., & Ferrandino, I. (2021). Exposure to aluminium causes behavioural alterations and oxidative stress in the brain of adult zebrafish. Environ Toxicol Pharmacol, 85, 103636.

    CAS  Google Scholar 

  • Carmo, T. L. L., Azevedo, V. C., de Siqueira, P. R., Galvao, T. D., dos Santos, F. A., Martinez, C. B. D., et al. (2018). Reactive oxygen species and other biochemical and morphological biomarkers in the gills and kidneys of the neotropical freshwater fish, prochilodus lineatus, exposed to titanium dioxide (TiO2) nanoparticles. Environmental Science and Pollution Research, 25, 22963–22976.

    Google Scholar 

  • Castaldo, G., Nguyễn, T., Town, R. M., Bervoets, L., Blust, R., & De Boeck, G. (2021). Common carp exposed to binary mixtures of Cd(II) and Zn(II): A study on metal bioaccumulation and ion-homeostasis. Aquatic Toxicology, 237, 105875.

    CAS  Google Scholar 

  • Chen F., Liu SS., Duan XT., Xiao QF (2014) Predicting the mixture effects of three pesticides by integrating molecular simulation with concentration addition modeling. RSC Advances 32256–32262.

  • Cheng, D., Ngo, H. H., Guo, W., Chang, S. W., Nguyen, D. D., Liu, Y., Wei, Q., & Wei, D. (2020). A critical review on antibiotics and hormones in swine wastewater: Water pollution problems and control approaches. Journal of Hazardous Materials, 387, 121682.

  • Chou, TC, Martin, N. (2005) CompuSyn for drug combinations: PC Software and User's Guide: a computer program for quantitation of synergism and antagonism in drug combinations, and the determination of IC50 and ED50 and LD50 values. Paramus (NJ): ComboSyn

  • Cleuvers, M. (2003). Aquatic ecotoxicity of pharmaceuticals including the assessment of combination effects. Toxicology Letters, 3, 185–194.

    Google Scholar 

  • Cui, C., Xiang, Z., Yang, W., Shiying, L., Huijun, L., Qi, H., Waqas, A., Yan, C., Xilin, L., Lingjiu, L., Fengfeng, S., Yanyan, L., Ke, Z., FeiFei, Z., Yangzhen, X., Pan, H., Yansong, L., Honglin, R., Ningyi, J., & Zengshan, L. (2018). Acute and chronic toxicity assessment of benzylpenicillin G residue in heat-treated animal food products. Chemosphere, 202, 757–767.

  • Dandan Y, Zhenbiao X, Minmin F, Zelong Z, Dahu C, Linxia S (2022) Genotoxicity evaluation of metformin in freshwater planarian Dugesia japonica by the comet assay and RAPD analysis. BioMed Research International, Volume 2022.

  • Daniluk, J., Daniluk, U., Rusak, M., Dabrowska, M., Reszec, J., Garbowicz, M., … Dabrowski, A (2017) The effect of penicillin administration in early life on murine gut microbiota and blood lymphocyte subsets. Anaerobe. 47, 18–24.

  • Dhage, P. A., Kamble, L. K., & Bhargava, S. Y. (2017). Localization and distribution of superoxide dismutase-1 in the neural tube morphogenesis of chick embryo. International Journal of Developmental Neuroscience., 56, 1–9.

    CAS  Google Scholar 

  • Diario Oficial de la Federación (DOF). Norma Mexicana NMX-AA-051-SCFI-2016. December 7th 2016, Mexico.

  • Drzymała, J., & Kalka, J. (2020). Ecotoxic interactions between pharmaceuticals in mixtures: Diclofenac and sulfamethoxazole. Chemosphere, 259, 127407.

    Google Scholar 

  • Duis, K., & Oberemm, A. (2001). Aluminium and calcium - Key factors determining the survival of vendace embryos and larvae in post-mining lakes? Limnologica, 31, 3–10.

    CAS  Google Scholar 

  • Eggen, T., Asp, T. N., Grave, K., & Hormazabal, V. (2011). Uptake and translocation of metformin, ciprofloxacin and narasin in forage- and crop plants. Chemosphere, 85(1), 26–33.

    CAS  Google Scholar 

  • Elizalde-Velázquez, G. A., & Gómez-Oliván, L. M. (2020). Occurrence, toxic effects and removal of metformin in the aquatic environments in the world: Recent trends and perspectives. Science of the Total Environment, 1(702), 134924.

    Google Scholar 

  • Elizalde-Velázquez, A., Gómez-Oliván, L. M., García-Medina, S., Islas-Flores, H., Hernández-Navarro, M. D., & Galar-Martínez, M. (2021). Antidiabetic drug metformin disrupts the embryogenesis in zebrafish through an oxidative stress mechanism. Chemosphere, 285, 131213.

    Google Scholar 

  • Elizalde-Velázquez, G. A., Gómez-Oliván, L. M., García-Medina, S., Rosales-Pérez, K. E., Orozco-Hernández, J. M., Islas-Flores, H., Galar-Martínez, M., & Hernández-Navarro, M. D. (2022). Chronic exposure to realistic concentrations of metformin prompts a neurotoxic response in Danio rerio adults. Science of the Total Environment, 849, 157888.

    Google Scholar 

  • Fernández-Dávila, M. L., Razo-Estrada, A. C., García-Medina, S., Gómez-Oliván, L. M., Piñón-López, M. J., Ibarra, R. G., & Galar-Martínez, M. (2012). Aluminum-induced oxidative stress and neurotoxicity in grass carp (Cyprinidae–Ctenopharingodon idella). Ecotoxicology and Environmental Safety, 76(2), 87–92.

    Google Scholar 

  • Ferrandino, I., Capriello, T., Félix, L. M., Meglio, G., Santos, D., & Monteiro, S. M. (2022). Histological alterations and oxidative stress in adult zebrafish muscle after aluminium exposure. Environmental Toxicology and Pharmacology, 94, 103934.

    CAS  Google Scholar 

  • Gaaied, S., Oliveira, M., Le Bihanic, F., Cachot, J., & Banni, M. (2019). Gene expression patterns and related enzymatic activities of detoxification and oxidative stress systems in zebrafish larvae exposed to the 2,4-dichlorophenoxyacetic acid herbicide. Chemosphere, 224, 289–297.

    CAS  Google Scholar 

  • Gabriel Correia, T. (2021). Vanessa Aparecida Rocha OliveiraVieiraAmandade Moraes NarcizoRicardo AndradeZampieriLucile MariaFloeter-WinterRenata GuimarãesMoreira. Endocrine disruption caused by the aquatic exposure to aluminum and manganese in Astyanax altiparanae (Teleostei: Characidae) females during the final ovarian maturation. Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology, 249, 109132.

    Google Scholar 

  • García-Medina, S., Razo-Estrada, A. C., Gómez-Oliván, L. M., et al. (2010). Aluminum-induced oxidative stress in lymphocytes of common carp (Cyprinus carpio). Fish Physiology and Biochemistry, 36, 875–882.

    Google Scholar 

  • García-Medina, S., Razo-Estrada, C., Galar-Martinez, M., Cortéz-Barberena, E., Gómez-Oliván, L. M., Alvarez-González, I., & Madrigal-Bujaidar, E. (2011). Genotoxic and cytotoxic effects induced by aluminum in the lymphocytes of the common carp (Cyprinus carpio). Comparative Biochemistry and Physiology Part c: Toxicology & Pharmacology, 153(1), 113–118.

    Google Scholar 

  • García-Medina, S., et al. (2013). The relationship of cytotoxic and genotoxic damage with blood aluminum levels and oxidative stress induced by this metal in common carp (Cyprinus Carpio) erythrocytes. Ecotoxicology and Environmental Safety, 1, 191–7.

    Google Scholar 

  • Gimenes, L. L. S., Freschi, G. P. G., Bianchini, J. I., & Cunha Santino, M. B. (2020). Growth of the aquatic macrophyte Ricciocarpos natans (L) Corda in different temperatures and in distinct concentrations of aluminum and manganese. Aquatic Toxicology, 224, 105484.

    CAS  Google Scholar 

  • Godoy, A. A., Domingues, I., Arsénia Nogueira, A. J., & Kummrow, F. (2018). Ecotoxicological effects, water quality standards and risk assessment for the anti-diabetic metformin. Environmental Pollution, 243(Pt A), 534–542.

    CAS  Google Scholar 

  • Gómez-Oliván, L. M., Mendoza-Zenila, Y. P., SanJuan-Reyes Nely Galar-Martínez, M., Ramírez-Durán, N., Rodríguez Martín-Doimeadios, R. C., Rodríguez-Fariñas, N., Islas-Flores, H., Elizalde-Velázquez, A., García-Medina, S., & Pérez-Pastén Borja, R. (2017). Geno and cytotoxicity induced on Cyprinus carpio by aluminum, iron, mercury and mixture thereof. Ecotoxicology and Environmental Safety, 135, 98–105.

    Google Scholar 

  • Gudiño, M. E., Blanco-Touriñán, N., Arbona, V., Gómez-Cadenas, A., Blázquez, M. A., Navarro-García, F. (2018) β-Lactam antibiotics modify root architecture and indole glucosinolate metabolism in Arabidopsis thaliana. Plant and Cell Physiology, 59(10), 2086–2098.

  • Havelkova, B., Beklova, M., Kovacova, V., Hlavkova, D., & Pikula, J. (2016). Ecotoxicity of selected antibiotics for organisms of aquatic and terrestrial ecosystems. Neuro Endocrinol Lett, 37(Suppl1), 38–44.

    CAS  Google Scholar 

  • He, F., Liu, Q., Jing, M., Wana, J., Huoa, C., Zong, W., Tang, J., Liu, R., et al. (2021). Toxic mechanism on phenanthrene-induced cytotoxicity, oxidative stress and activity changes of superoxide dismutase and catalase in earthworm (Eisenia foetida): A combined molecular and cellular study. Journal of Hazardous Materials, 418(15), 126302.

    CAS  Google Scholar 

  • Hermesz, E., & Ferencz, Á. (2009). Identification of two phospholipid hydroperoxide glutathione peroxidase (gpx4) genes in common carp. Comp Biochem Physiol C Toxicol Pharmacol, 150(1), 101–106.

    Google Scholar 

  • Hermsen, S. A., van den Brandhof, E. J., van der Ven, L. T., & Piersma, A. H. (2011). Relative embryotoxicity of two classes of chemicals in a modified zebrafish embryotoxicity test and comparison with their in vivo potencies. Toxicology in Vitro, 25(3), 745–753.

    CAS  Google Scholar 

  • Hou, X., Song, J., Li, X. N., Zhang, L., Wang, X., Chen, L., & Shen, Y. H. (2010). Metformin reduces intracellular reactive oxygen species levels by upregulating expression of the antioxidant thioredoxin via the AMPK-FOXO3 pathway. Biochem Biophys Res Commun, 396(2), 199–205.

    CAS  Google Scholar 

  • Jing, M., Han, G., Wan, J., Zhang, S., Yang, J., Zong, W. S., Niu, Q., & Liu, R. (2020). Catalase and superoxide dismutase response and the underlying molecular mechanism for naphthalene. Science of the Total Environment., 736(20), 139567.

    CAS  Google Scholar 

  • Ketikidis, I., Banti, C. N., Kourkoumelis, N., Tsiafoulis, C. G., Papachristodoulou, C., Kalampounias, A. G., & Hadjikakou, S. K. (2020). Conjugation of penicillin-G with silver(I) ions expands its antimicrobial activity against gram negative bacteria. Antibiotics, 9, 25.

    CAS  Google Scholar 

  • Kimmel, C. B., Ballard, W. W., Kimmel, S. R., Ullmann, B., & Schilling, T. F. (1995). Stages of embryonic development of the zebrafish. Developmental Dynamics, 203, 253–310.

    CAS  Google Scholar 

  • Komijani, M., Shamabadi, N. S., Shahin, K., Eghbalpour, F., Tahsili, M. R., & Bahram, M. (2021). Heavy metal pollution promotes antibiotic resistance potential in the aquatic environment. Environmental Pollution, 274, 116569.

    CAS  Google Scholar 

  • Kovacic, P., & Somanathan, R. (2006). Mechanism of teratogenesis: Electron transfer, reactive oxygen species, and antioxidants. Birth Defects Research. Part c, Embryo Today, 78(4), 308–325.

    CAS  Google Scholar 

  • Kovalakova, P., Cizmas, L., McDonald, T. J., Marsalek, B., Feng, M., Virender, K., & Sharma, C. (2020). Occurrence and toxicity of antibiotics in the aquatic environment: A review. Chemosphere, 251, 126351.

    CAS  Google Scholar 

  • Lankoff, A., Banasik, A., Duma, A., Ochniak, E., Lisowska, H., Kuszewski, T., Góźdź, S., & Wojcik, A. (2006). A comet assay study reveals that aluminium induces DNA damage and inhibits the repair of radiation-induced lesions in human peripheral blood lymphocytes. Toxicol Lett, 161(1), 27–36.

    CAS  Google Scholar 

  • Lee, J. W., Shin, Y. J., Kim, H., Kim, H., Kim, J., Min, S. A., Kim, P., Yu, S. D., & Park, K. (2019). Metformin-induced endocrine disruption and oxidative stress of Oryzias latipes on two-generational condition. Journal of Hazardous Materials, 5(367), 171–181.

    Google Scholar 

  • Liao, G., Wang, P., Zhu, J., Weng, X., Lin, S., Huang, J., Xu, Y., Zhou, F., Zhang, H., Tse, L., Zou, F., & Meng, F. (2021). Joint toxicity of lead and cadmium on the behavior of zebrafish larvae: An antagonism. Aquatic Toxicology, 238, 105912.

    CAS  Google Scholar 

  • Liu, K., Song, J., Chi, W., Liu, H., Ge, S., & Daode, Y. (2021). Developmental toxicity in marine medaka (Oryzias melastigma) embryos and larvae exposed to nickel. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 248, 109082.

    CAS  Google Scholar 

  • Long, X., Wang, D., Lin, Z., Qin, M., Song, C., & Liu, Y. (2016). The mixture toxicity of environmental contaminants containing sulfonamides and other antibiotics in Escherichia coli: Differences in both the special target proteins of individual chemicals and their effective combined concentration. Chemosphere, 158, 193–203.

    CAS  Google Scholar 

  • Luja-Mondragón, M., Gómez-Oliván, L. M., SanJuan-Reyes, N., Islas-Flores, H., Orozco-Hernández, J. M., Heredia-García, G., Galar-Martínez, M., & Dublán-García, O. (2019). Alterations to embryonic development and teratogenic effects induced by a hospital effluent on Cyprinus carpio oocytes. Science of the Total Environment, 660(10), 751–764.

    Google Scholar 

  • Marinello, P., Carolina Panis, T. N. X., Silva, B. R., Abdelhay, E., Rodrigues, J. A., Mencalha, A. L., Lopesa, N. M. D., Borgese, F. H., Luiz, R. C., & Rubens Cecchinie, A. L. (2020). Oxidative stress and TGF-β1 induction by metformin in MCF-7 and MDA-MB-231 human breast cancer cells are accompanied with the downregulation of genes related to cell proliferation, invasion and metastasis. Pathology - Research and Practice, 216(10), 153135.

    CAS  Google Scholar 

  • Mendieta-Serrano, M. A., Schnabel, D., Lomelí, H., & Salas-Vidal, E. (2015). Spatial and temporal expression of zebrafish glutathione peroxidase 4 a and b genes during early embryo development. Gene Expression Patterns, 19(1–2), 98–107.

    CAS  Google Scholar 

  • Merck © Darmstadt, Grmany. HPLC Analysis of penicillin G and phenoxymethylpenicillinic acid on Ascentis® C18. 2022, February 3th. Retrieved from https://www.sigmaaldrich.com/MX/es/technical-documents/protocol/analytical-chemistry/small-molecule-hplc/hplc-analysis-of-penicillin-g-and-phenoxymethylpenicillinic-acid-on-Ascentis.

  • Monteiro-Fernandes R., Gonçalves Corrêa M., Bragança Aragão W., Cunha Nascimento P., Cartágenes CS., Azulay Rodrigues C., Sarmiento LF., Chagas Monteiro M., FerrazMaia CS., Crespo-López ME., RodriguesLima R (2020) Preclinical evidences of aluminum-induced neurotoxicity in hippocampus and pre-frontal cortex of rats exposed to low doses 206, 111139

  • Monteiro-Fernandes R., GuimarãesEiró L., dos Santos-Chemelo V., Paz Alvarenga MO., Rodrigues-Lima R (2021) Chapter 14 - Aluminum toxicity and oxidative stress. Toxicology Oxidative Stress and Dietary Antioxidants 127–135.

  • Montvida, O., Shaw, J., Atherton, J. J., Stringer, F., & Sanjoy, K. P. (2018). Long-term trends in antidiabetes drug usage in the U.S.: Real-world Evidence in Patients Newly Diagnosed With Type 2 Diabetes. Diabetes Care, 41, 69–78.

    Google Scholar 

  • Niemuth, N. J., & Klaper, R. D. (2015). Emerging wastewater contaminant metformin causes intersex and reduced fecundity in fish. Chemosphere, 135, 38–45.

    CAS  Google Scholar 

  • Niemuth, N. J., Jordan, R., Crago, J., Blanksma, C., Johnson, R., & Klaper, R. D. (2015). Metformin exposure at environmentally relevant concentrations causes potential endocrine disruption in adult male fish. Environ ToxicolChem, 34, 291–6.

    CAS  Google Scholar 

  • Oertel, R., Baldauf, J., & Rossmann, J. (2018). Development and validation of a hydrophilic interaction liquid chromatography-tandem mass spectrometry method for the quantification of the antidiabetic drug metformin and six others pharmaceuticals in wastewater. J Chromatogr A, 1556, 73–80.

    CAS  Google Scholar 

  • Ommati, M., Mohammadi, H., Mousavi, K., Azarpira, N., Farshad, O., Dehghanic, R., Najibi, A., Kamran, S., Niknahad, H., & Heidari, R. (2021). Metformin alleviates cholestasis-associated nephropathy through regulating oxidative stress and mitochondrial function. Liver Research., 5, 171–180.

    CAS  Google Scholar 

  • Parrott JL., Pacepavicius G., Shires K., Clarence S., Khan H., Gardiner M., Sullivan C., Alaee M (2021) Fathead minnow exposed to environmentally relevant concentrations of metformin for one life cycle show no adverse effects. Facets 998–1023

  • Peng, Y., Luo, Y., Nie, X. P., Liao, W., Yang, Y. F., & Ying, G. G. (2013). Toxic effects of triclosan on the detoxification system and breeding of Daphnia magna. Ecotoxicology, 9, 1384–1394.

    Google Scholar 

  • Pérez-Alvarez, I., Islas-Flores, H., Gómez-Oliván, L. M., Barceló, D., López De Alda, M., Pérez Solsona, S., Sánchez-Aceves, L., San Juan-Reyes, N., & Galar-Martínez, M. (2018). Determination of metals and pharmaceutical compounds released in hospital wastewater from Toluca, Mexico, and evaluation of their toxic impact. Environmental Pollution, 240, 330–341.

    Google Scholar 

  • Pérez-Coyotl, I., Martínez-Vieyra, C., Galar-Martínez, M., Gómez-Oliván, L. M., García-Medina, S., Islas-Flores, H., Pérez-Pasten, B. R., Gasca-Pérez, E., Novoa-Luna, K. A., & Dublán-García, O. (2017). DNA damage and cytotoxicity induced on common carp by pollutants in water from an urban reservoir. Madín reservoir, a case study Chemosphere, 185, 789–797.

    Google Scholar 

  • Pérez-Coyotl, I., Galar-Martínez, M., García-Medina, S., Gómez-Oliván, L. M., Gasca-Pérez, E., Martínez-Galero, E., Islas-Flores, H., Pérez-Pastén, B. R., Barceló, D., López de Alda, M., Pérez-Solsona, S., Serra-Roig, M. P., Montemurro, N., Peña-Herrera, J. M., & Sánchez-Aceves, L. M. (2019). Polluted water from an urban reservoir (Madín dam, México) induces toxicity and oxidative stress in Cyprinus carpio embryos. Environmental Pollution, 251, 510–521.

    Google Scholar 

  • Pillet, M., Castaldo, G., De Weggheleire, S., Bervoets, L., Blust, R., & De Boeck, G. (2019). Limited oxidative stress in common carp (Cyprinus carpio, L, 1758) exposed to a sublethal tertiary (Cu, Cd and Zn) metal mixture. Comparative biochemistry and physiology, 218, 70–80.

    CAS  Google Scholar 

  • Porta, V., Grigoletho-Schramm, S., Kazue-Kano, E., Emiko-Koono, E., Popst-Armando, Y., Fukuda, K., & dos Reis-Serra, C. H. (2008). HPLC-UV determination of metformin in human plasma for application in pharmacokinetics and bioequivalence studies. J Pharm Biomed., 46, 143–147.

    CAS  Google Scholar 

  • Quaile, M. P., Melich, D. H., Jordan, H. L., Nold, J. B., Chism, J. P., Polli, J. W., Smith, G. A., & Rhodes, M. C. (2010). Toxicity and toxicokinetics of metformin in rats. Toxicology and Applied Pharmacology., 243, 340–347.

    CAS  Google Scholar 

  • Quiroga-Santos, E., Galar-Martínez, M., García-Medina, S., Gasca-Pérez, E., Cano-Viveros, S., Ruíz-Lara, K., Gómez-Oliván, L. M., & Islas-Flores, H. (2021). Geno-cytotoxicity and congenital malformations produced by relevant environmental concentrations of aluminum, diclofenac and their mixture on Cyprinus carpio An interactions study. Environmental Toxicology and Pharmacology, 82, 103555.

    CAS  Google Scholar 

  • Radi, R., Turrens, J. F., Chang, L. Y., Bush, K. M., Carpo, J. D., & Freeman, B. A. (1991). Detection of catalase in rat heart mitochondria. Journal of Biological Chemistry, 266, 22028–22034.

    CAS  Google Scholar 

  • Ribeiro, M., Zephyr, N., Silva, J. A. L., Danion, M., Guérin, T., Castanheira, I., Leufroy, A., & Jitaru, P. (2021). Assessment of the mercury-selenium antagonism in rainbow trout fish. Chemosphere, 286, 131749.

    Google Scholar 

  • Ruixue, M., Wang, B., Yin, L., Zhang, Y., Deng, S., Huang, J., Wang, Y., & Gang, Y. (2017). Characterization of pharmaceutically active compounds in Beijing, China: Occurrence pattern, spatiotemporal distribution and its environmental implication. Journal of Hazardous Materials, 323(Part A), 147–155.

    Google Scholar 

  • Sánchez-Aceves, L., Pérez-Alvarez, I., Gómez-Oliván, L. M., Islas-Flores, H., & Barceló, D. (2021). Long-term exposure to environmentally relevant concentrations of ibuprofen and aluminum alters oxidative stress status on Danio rerio. Comparative Biochemistry and Physiology Part c: Toxicology & Pharmacology, 248, 109071.

    Google Scholar 

  • Schmidt, S., Busch, W., Altenburger, R., & Küster, E. (2016). Mixture toxicity of water contaminants-effect analysis using the zebrafish embryo assay (Danio rerio). Chemosphere, 152, 503–512.

    CAS  Google Scholar 

  • Senzea, M., Kowalska-Góralska, M., & Czyż, K. (2021). Availability of aluminum in river water supplying dam reservoirs in Lower Silesia considering the hydrochemical conditions. Environmental Nanotechnology, Monitoring & Management, 16, 100535.

    Google Scholar 

  • Shuhaimi-Othman M., Nadzifah YakubNur-Amalina RamleAhmad Abas (2011) Sensitivity of the freshwater prawn, Macrobrachium lanchesteri (Crustacea: Decapoda), to heavy metals. Toxicology and Industrial Health 523–30.

  • Silva Pinheiro, J. P., Lima, J., Bertacini, C., deAssis, G., Branco, S., Dal’OlioGomes, A., & GuimarãesMoreira, R. (2021). Paternal exposure to aluminum, acidity, and temperature affect fatty acid seminal profile, embryonic and larval development of Astyanax altiparanae. Chemosphere, 266, 128935.

    Google Scholar 

  • Static Acute Toxicity of Metformin HCl to Bluegill (Lepomis macrochirus) ABC Laboratories, Inc. Report number 41779, July 1994.

  • Tisler S., Zwiener C (2018) Formation and occurrence of transformation products of metformin in wastewater and surface water. Sci Total Environ. 1121–1129.

  • Triggle, C. R., Mohammed, I., Bshesh, K., Marei, I., Ye, K., Ding, H., MacDonald, R., Hollenberg, M. D., & Hill, M. A. (2022). Metformin: Is it a drug for all reasons and diseases? Metabolism, 133, 155223.

    CAS  Google Scholar 

  • Ussery, E, Bridges, KN, Pandelides, Z, Kirkwood, AE, Bonetta, D, Venables, BJ, Guchardi, J, Holdway, D (2018) Effects of environmentally relevant metformin exposure on Japanese medaka (Oryzias latipes). Aquat Toxicol. 58–65.

  • Vilizzi, L., & Copp, G. H. (2017). Global patterns and clines in the growth of common carp Cyprinus carpio. J Fish Biol, 91, 3–40.

    CAS  Google Scholar 

  • Volkova, A., Ruggles, K., Schulfer, A., Gao, Z., Ginsberg, S. D., & Blaser, M. J. (2021). Effects of early-life penicillin exposure on the gut microbiome and frontal cortex and amygdala gene expression. iScience, V24, 102797.

    Google Scholar 

  • Wang, Y., An, H., Liu, T., Qin, C., Sesaki, H., Guo, S., Radovick, S., Hussain, M., Maheshwari, A., Wondisford, F. E., O’Rourke, B., & He, L. (2019). Metformin improves mitochondrial respiratory activity through activation of AMPK. Cell reports, 29, 1511–1523.

    CAS  Google Scholar 

  • Wang, R. F., Zhu, L. M., Zhang, J., An, X. P., Yang, Y. P., Song, M., & Zhang, L. (2020). Developmental toxicity of copper in marine medaka (Oryzias melastigma) embryos and larvae. Chemosphere, 247, 125923.

    CAS  Google Scholar 

  • Wang, T., Zhang, J., Tao, M., Xu, C., & Chen, M. (2021). Quantitative characterization of toxicity interaction within antibiotic-heavy metal mixtures on Chlorella pyrenoidosa by a novel area-concentration ratio method. Science of The Total Environment, 762, 144180.

    CAS  Google Scholar 

  • Watkinson, A. J., Murby, E. J., Kolpin, D. W., & Costanzo, S. D. (2009). The occurrence of antibiotics in an urban watershed: From wastewater to drinking water. Sci Total Environ, 407, 2711–23.

    CAS  Google Scholar 

  • Wu, M., Shariat-Madar, B., Haron, M., Wu, M., Khan, I., & Dasmahapatra, A. (2011). Ethanol-induced attenuation of oxidative stress is unable to alter mRNA expression pattern of catalase, glutathione reductase, glutathione-S-transferase (GST1A), and superoxide dismutase (SOD3) enzymes in Japanese rice fish (Oryzias latipes) embryogenesis. Comp Biochem Physiol C Toxicol Pharmacol, 153, 159–167.

    Google Scholar 

  • Yang, G., Wang, Y., Wang, T., Wang, D., Weng, H., Wang, Q., & Chen, C. (2021). Variations of enzymatic activity and gene expression in zebrafish (Danio rerio) embryos co-exposed to zearalenone and fumonisin B1. Ecotoxicology and Environmental Safety, 222, 112533.

    CAS  Google Scholar 

  • Zhang, Y., Cai, X., Lang, X., Qiao, X., Li, X., & Chen, J. (2012). Insights into aquatic toxicities of the antibiotics oxytetracycline and ciprofloxacin in the presence of metal: Complexation versus mixture. Environmental Pollution., 166, 48–56.

    CAS  Google Scholar 

  • Zhang, J. J., Li, Y. Q., Wang, Y. S., Chen, L., & Wang, X. Z. (2021). Estradiol ameliorates metformin-inhibited Sertoli cell proliferation via AMPK/TSC2/mTOR signaling pathway. Theriogenology, 175, 7–22.

    CAS  Google Scholar 

  • Zheng, J., Zeng, L., Shen, B., Mei-Ying, X., Zhu, A.-Y., & Chang-Wen, W. (2016). Antioxidant defenses at transcriptional and enzymatic levels and gene expression of Nrf2-Keap1 signaling molecules in response to acute zinc exposure in the spleen of the large yellow croaker Pseudosciaena crocea. Fish & Shellfish Immunology, 52, 1–8.

    Google Scholar 

  • Zhong, X., Zhu, Y., Wang, Y., Zhao, Q., & Huang, He. (2021). Effects of three antibiotics on growth and antioxidant response of Chlorella pyrenoidosa and Anabaena cylindrica. Ecotoxicology and Environmental Safety, 211, 111954.

    CAS  Google Scholar 

  • Zhou, C., Ma, Q., Li, S., Zhu, M., Xia, Z., & Yu, W. (2021). Toxicological effects of single and joint sulfamethazine and cadmium stress in soil on pakchoi (Brassica chinensis L). Chemosphere, 263, 128296.

    CAS  Google Scholar 

  • Zoetis, MSD (2015) No. ZT00455 [Online] Florham Park, New Jersey April 23, 2015. https://www.cvear.com/wp-content/uploads/2012/06/R-Pen-SDS-2015.pdf. Accessed 10/11/21.

Download references

Acknowledgements

This study was made possible by financial support from the Secretaría de Investigación y Posgrado of the Instituto Politécnico Nacional (SIP-IPN, project 20211017 and 20220792) and National Council of Science and Technology (CONACyT, FORDECYT-PRONACES/6656/2020). We give thanks to Biologist Gerardo Ontiveros at the Centro Carpícola Tiacaque for supplying the test specimens and giving advice on their care and maintenance.

Author information

Author notes

  1. Marcela Galar-Martínez and Sandra García-Medina declare that they participated in equal parts in the preparation of this paper.

Authors and Affiliations

  1. Laboratory of Aquatic Toxicology, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Unidad Profesional Adolfo López Mateos, AV. Wilfrido Massieu S/N Y Cerrada Manuel Stampa, Col. Industrial Vallejo, 07700, Mexico City, CP, Mexico

    Selene Cano-Viveros, Marcela Galar-Martínez, Sandra García-Medina, Karina Ruiz-Lara & Misael Hernández-Díaz

  2. Laboratory of Environmental Toxicology, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón Intersección Paseo Tollocan S/N. Col. Residencial Colón, 50120, Toluca, Estado de México, Mexico

    Leobardo Manuel Gómez-Oliván & Hariz Islas-Flores

  3. Cátedra CONACYT, Laboratorio de Toxicología Acuática, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Av. Wilfrido Massieu, Esq. Manuel L. Stampa S/N, 07738, Gustavo A. Madero, Mexico City, Mexico

    Eloy Gasca-Pérez

  4. Laboratory of Biochemical Engineering, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Unidad Profesional Adolfo López Mateos, AV. Wilfrido Massieu S/N Y Cerrada Manuel Stampa, Col. Industrial Vallejo, 07700, Mexico City, CP, Mexico

    Cleotilde Juárez-Ramírez

Authors
  1. Selene Cano-Viveros
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcela Galar-Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sandra García-Medina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Karina Ruiz-Lara
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Misael Hernández-Díaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Leobardo Manuel Gómez-Oliván
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hariz Islas-Flores
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eloy Gasca-Pérez
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Cleotilde Juárez-Ramírez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Marcela Galar-Martínez or Sandra García-Medina.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cano-Viveros, S., Galar-Martínez, M., García-Medina, S. et al. Embryotoxicity Produced by the Mixture of Aluminum, Metformin and Penicillin on Common Carp (Cyprinus carpio): a Study of Interactions. Water Air Soil Pollut 233, 463 (2022). https://doi.org/10.1007/s11270-022-05929-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11270-022-05929-7

Keywords

Search

Navigation