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

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: [Figure not available: see fulltext.]