Reproductive toxicity in male juvenile rats: Antagonistic effects between isolated agrochemicals and in binary or ternary combinations.

The management of agrochemicals in Brazilian agriculture impacts global environmental sustainability and food security, since this country is one of the major agro-food exporters in the world. Acephate, carbendazim, and dithiocarbamates (DTCs) such as mancozeb, are among the most detected agrochemicals in Brazilian agro-food products, occurring in combination in several crops, especially in fruit cultures. The present study evaluated the impact of the exposure to isolated agrochemicals and all the combined possible mixtures (binary and ternary forms) on the reproductive parameters of male juvenile rats, known to be a vulnerable biological system and developmental window. Data were analyzed using Generalized Linear Models (GzLM), considering each agrochemical as an independent factor. The study revealed higher reproductive toxicity exerted by isolated agrochemicals when compared to the combined treatments, which exhibited mostly an antagonistic effect. Results suggest endocrine disruptive effects of each one separately on the weight of reproductive organs and testicular histomorphometry, besides changes in testicular SOD activity. The full factorial experimental design employed here allowed us to conclude that it is not possible to scale-up the effects of the isolated treatments to the mixtures, showing how difficult it is to know beforehand the response and cross-talk among the multiple physiological mechanisms disturbed by complex mixtures. Considering that food products are shared on a global scale and that some of these three agrochemicals have already been prohibited in EU countries, the consumption of some Brazilian products puts global human health at risk, that of children.

Biochemical and histopathological responses in peripubertal male rats exposed to agrochemicals isolated or in combination: A multivariate data analysis study.

The widespread use of agrochemicals results in the exposure of the general human population, including children, to several of these chemicals simultaneously. In the present preclinical study, it was investigated the hepatic damages caused by exposure to acephate, carbendazim and mancozeb when administered alone or in different combinations (binary and ternary). Juvenile male Wistar rats were exposed to agrochemicals from post-natal day 53, by gavage. The doses of agrochemicals applied here were determined from previous studies whose results showed no signs of systemic toxicity. All exposures provoked a significant increase in DNA damage (except for acephate alone) and activation of the xenobiotic biotransformation system (except for the ternary mixture). Interestingly, the ternary mixture did not exhibit an exacerbation in adverse effects caused by agrochemicals isolated or in binary combination, even though they are sharing genotoxicity damage induction as a common toxicity pathway. Conversely, some effects observed for isolated or binary combinations of agrochemicals were not observed for ternary combination, suggesting a chemical interaction that could imply antagonism character. Using a multivariate data analysis approach, exposure to isolated agrochemicals were related to a group of adverse effects characterized by hepatic lesion and the attempt of the tissue to mobilize defense cells and increase mitotic rates to minimize damages. Binary mixtures also share similarities in relation to the effects they exhibited, mainly a moderate to high increase in the GST activity and in histopathological alterations suggesting that binary combinations trigger an increased response of the mechanism of xenobiotics biotransformation. Together, obtained results bring important insights regarding adverse effects and possible interaction of the three agrochemicals whose residues are commonly detected in agro-food products.