O-19 IMPLICATIONS OF GLYPHOSATE ON NON-ALCOHOLIC FATTY LIVER DISEASE IN MICE

Introduction and Objectives

Non-alcoholic fatty liver disease (NAFLD) affects ∼25% of the world's population, presenting a multiaxis pathogenesis closely related to westernized dietary (WD) patterns, and to metabolic comorbidities. In addition to WD, individuals are frequently exposed to crops and dairy products presenting glyphosate (Glypho) residues, the most used broad-spectrum herbicide worldwide. This study aimed to evaluate whether chronic Glypho exposure promotes WD-induced NAFLD.

Materials and Methods

Male C57BL/6J mice were fed WD (chow containing 20% lard, 0.2% cholesterol, 20% sucrose, and high sugar solution with 23.1/18.9 g/L of D-fructose/D-glucose), and received glyphosate (0.05, 5 or 50 mg/kg/day) by gavage (5 × /week) for six months. Doses were below/within the regulatory limits (Acceptable Daily Intake or No Observed Adverse Effect Level).

Results

Glypho did not promote WD-induced obesity, hypercholesterolemia, and glucose intolerance, as this herbicide did not exert major effects on WD-induced hepatic macro/micro vesicular steatosis and perivascular fibrosis. Nonetheless, Glypho at the higher dose (50 mg) exerted the most pronounced effects on enhancing CD68+ macrophage density, p65 (NF-B), TNF-, and IL-6 protein levels in the liver. Furthermore, this dose also decreased hepatic Nrf2 levels, while enhanced lipid peroxidation in the liver and adipose tissue. The hepatic RNASeq analysis revealed that Glypho at 50 mg upregulated 212 genes, while downregulated 731 compared to WD counterpart. Glypho upregulated genes associated to “xenobiotic metabolic process” (Cyp2c37, Cyp2c23, Cyp2c54, Cyp2b10, Cyp2c50, and Cyp2e1), directly involved in oxidative stress, as well as “positive regulation of immune response”-related mRNAs (Egfr, Ccl7, Cfd, C6, C8a, and C8b). Moreover, Glypho downregulated key “cell cycle”-related genes (as Mki67 and Cdk1).

Conclusions

In essence, our results are innovative on demonstrating that Glypho – in a dose within the regulatory limits – impaired the hepatic inflammation/redox dynamics at the morphological, biochemical and transcriptomic levels.