Assessing the effects of uracil-based pesticides on hepatic metabolic dysfunctions in low-cost three-dimensional multicellular spheroids.

Pesticides are used worldwide and cause several pathologies as metabolic dysfunction-associated steatotic liver disease. Steatosis is a mark of the disease beginning; however, the mechanisms by which pesticides act on this dysfunction require further understanding. Thus, this work presents a sensitive and responsive low-cost hepatic multicellular spheroid useful to detail metabolic routes in hepatic dysfunction. Using those spheroids, the effects of pesticides bromacil and terbacil were assessed. Pesticides doses near the acceptable daily intake in Brazil changes energetic, oxidative and the one-carbon metabolism. Moreover, pesticide-specific effects were observed as increased expression of FASN, PPARs, CYP1A1, AHR, DNMTs among others, and changes in the methylation pattern of DNA, RNA and histones. Combined, the results were alarming, considering the long-lasting effects of the evaluated pesticides in agriculture fields. In addition, we can suggest that our spheroid model could be useful for large scale investigation of the effects of pesticides in liver metabolism.