Extended exposure to antineoplastic drugs 5-fluorouracil and methotrexate in environmentally relevant concentrations: evaluation of testicular toxicity and DNA damage of rats

• Grant number: 19/04108-7
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): June 01, 2019
• Effective date (End): October 31, 2021
• Field of knowledge: Biological Sciences - Morphology - Histology
• Principal Investigator: Juliana Elaine Perobelli
• Grantee: Paloma da Cunha de Medeiros
• Host Institution: Instituto de Saúde e Sociedade (ISS). Universidade Federal de São Paulo (UNIFESP). Campus Baixada Santista. Santos , SP, Brazil

Abstract

Antineoplastic drugs, used to treat cancer, act to prevent tumor growth by controlling cell divisions. They may interact with the DNA of cancer cells, causing metabolic and morphological changes, leading to cell death. However, they do not act selectively, resulting in undesirable side effects such as genotoxicity, mutagenicity and even carcinogenicity. It is known that the consumption of this class of drugs has increased worldwide due to the increasing rates of cancer incidence in the population, the early diagnosis and the use of medications in combination (polichemotherapy). 5-fluorouracil (5-FU) and methotrexate (MTX) are among the most widely consumed antineoplastic drugs in the world and can be constantly detected in the environment. After consumed they are excreted by faeces and/ or urine in a mixture of compounds and metabolites. Inthis way, they enter the aquatic environment through domestic and hospital effluent treatment plants, which still have low efficiency in drug removal. Therefore, these drugs are known as emerging pollutants, being found in concentrations ranging from ng/L tomg/L in water flows. Considering the increased consumption of antineoplastic drugs, as well as the inefficiency of removal of these drugs and their metabolites during the conventional effluent treatment process, the present study aims to investigate the potential impact of extended exposure to these antineoplastic drugs in environmentally relevant concentrations. Male Wistar rats (70 days old) will be distributed into 4 groups (n = 10 / group): control, who will receive only vehicle (filtered water); MTX that will receivemethotrexate at 10 ng/L in drinking water; 5-FU which will receive 5-fluorouracil at 10 ng/L in drinking water; and MTX + 5FU, which will receive the combination of methotrexate and 5-fluorouracil at a concentration of 10 ng/L each in drinking water. Theconcentration was chosen according to its environmental relevance, based on reports of the European Medicines Agency. The treatment period will be from post natal day (PND)70 to 160, when the animals will be euthanized for evaluation of testicular toxicity(histomorphometric analysis, oxidative damage and changes in endocrine signaling) and DNA damage (cytotoxicity, genotoxicity and mutagenicity). (AU)