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"Implications of exposure to nitrosodimethylamine in rats: effects on toxicological and reproductive parameters"

Grant number: 23/04536-4
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): December 01, 2023
Effective date (End): January 31, 2025
Field of knowledge:Biological Sciences - Pharmacology - Toxicology
Principal Investigator:Arielle Cristina Arena
Grantee:Lívia Trippe Nagaoka Gonçalves
Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

N-nitrosamines are agents with mutagenic/carcinogenic potential which can be present in food, cigarettes, cosmetics, and water. Recently, high levels of this compound have been detected in widely used drugs, which have attracted the attention of Anvisa and regulatory agencies around the world. These compounds are metabolically activated by the cytochrome P450 system, leading to the generation of alkylating agents and reactive oxygen species. Thus, recurrent exposure to N-nitrosamines may increase the risk of cancer occurrence as well as impact reproductive health in several species. Although the carcinogenic potential of N-nitrosamines is well established, few studies have investigated their adverse effects on reproduction, especially at low dosages, those that are still considered acceptable by regulatory agencies. Studies have shown that different types of N-nitrosamines have compromised fertility in rabbits and rodents, through hormonal, sperm and histological changes, and decreased activity of the 17²-HSD enzyme, suggesting that these compounds may act as endocrine disruptors. However, data on the adverse effects resulting from female and male exposure to low doses of nitrosamines are insufficient. Thus, this study aims to evaluate the consequences of male, female and combined (male and female) exposure to Nitrosodimethylamine (NDMA), one of the most commonly found in the environment, on toxicological and reproductive parameters of male and female rats. Males will be exposed to NDMA (0 and 7.2 ng/kg/day; gavage) from the preconceptional period until mating. Females will be exposed to the same doses in the preconceptional, during mating and gestational/lactational periods. The males and females will constitute the following groups: 1) Control (control females X control males); 2) NDMA females (NDMA females X control males); 3) NDMA males (control females X NDMA males); 4) NDMA combined (NDMA females X NDMA males). Males will be euthanized after the mating period and females after the end of the lactation period for hemato-biochemical, sperm, histological, hormonal, gene expression of steroidogenic and antioxidant enzymes. The offspring will be destined to another project. This study may contribute to the re-evaluation of current toxicological limits, which will help guide public health policies.

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