Use of Drosophila melanogaster as an alternative model for the study of hepatic metabolic dysfunctions caused by environmental contaminants present in drinking water and their impact on the functionality of the Mondo protein (ChREBP)

• Grant number: 25/03871-0
• Support Opportunities: Scholarships in Brazil - Master
• Start date: July 01, 2025
• End date: January 31, 2027
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Karen Cristiane Martinez de Moraes
• Grantee: Victor Hugo Cotinguiba Cantador
• Host Institution: Instituto de Biociências (IB). Universidade Estadual Paulista (UNESP). Campus de Rio Claro. Rio Claro , SP, Brazil

Abstract

Metabolism-associated fatty liver diseases (MAFLDs) are a major global public health concern; however, effective therapies are still not avaiable. MAFLDs are characterized by the excessive accumulation of lipids in hepatic cells, which can be triggered by the activation of nuclear receptors that modulate cellular signaling. Among these, the carbohydrate-responsive element-binding protein (ChREBP) is a key transcription factor that regulates genes related to energy metabolism and plays a central role in de novo lipogenesis. MAFLDs have multiple etiologies, including exposure to environmental contaminants, which have the potential to pollute ecosystems and harm human health and other living organisms. Among these contaminants are organochlorines such as chlorothalonil and s-metolachlor, which have been widely used generating residues because of the long-lasting half-life chemicals, which has contributed to the contamination of groundwater and drinking water around the world. However, the real effects of those pesticides to public health, when they are used at doses considered safe for regulatory agencies are still needs to be evaluated. In this context, the fruit fly Drosophila melanogaster emerges as a valuable biotechnological model for studying human diseases, as approximately 70% of metabolism-related human genes have orthologs in D. melanogaster. Therefore, this study aims to evaluate the effects of the pesticides chlorothalonil and s-metolachlor on the metabolism of D. melanogaster, assessing the toxicological impacts of these chemical compounds on energy metabolism, epigenetics, and the functionality of the Mondo protein (ChREBP). To achieve this, wild-type D. melanogaster larvae and/or adults will be fed with diets prepared with different concentrations of the pesticides considered as safe for consumption by the regulatory agencies. The individuals will then undergo behavioral, biochemical, and molecular analyses related to energy metabolism, which are relevant in predictive toxicology to investigate and understand the molecular and cellular mechanisms triggered by organochlorine exposure in homeostasis and in a translational approach analyze correlated effect in liver dysfunctions. Genetic alterations in ChREBP expression through the UAS-GAL4 system silencing or overexpressing the protein are also planned, followed by exposure to pesticide concentrations that induce significant metabolic changes in wild Drosophila strain. Next, the same investigation processed for the wild Drosophilas strain will be performed to verify Mondo protein functional activity in genetically modified files. (AU)