Tibaldi, E. | Search bioRxiv

bioRxiv2023

Leukemia in Sprague-Dawley Rats Exposed Long-term from Prenatal Life to Glyphosate and Glyphosate-Based Herbicides

BackgroundGlyphosate-based herbicides (GBHs) are the worlds most widely used weed control agents. There has been intense and increasing public health concern about glyphosate and GBHs since the International Agency for Research on Cancer classified glyphosate as a probable human carcinogen in 2015. AimsTo further study the health effects of glyphosate and GBHs, the Ramazzini Institute, in collaboration with an international network of institutes and universities, has launched the Global Glyphosate Study (GGS), the most comprehensive toxicological study ever performed on these compounds. The GGS is an integrated study designed to test a wide range of toxicological outcomes including carcinogenicity, neurotoxicity, multi-generational effects, organ toxicity, endocrine disruption and prenatal developmental toxicity. The present study reports the first definitive results on leukemia incidence and mortality from the carcinogenicity arm of the GGS. MethodGlyphosate and two GBHs, Roundup Bioflow (MON 52276) used in the European Union (EU) and RangerPro (EPA 524-517) used in the U.S., were administered long-term to Sprague-Dawley (SD) rats beginning in prenatal life until 104 weeks of age via drinking water at doses of 0.5, 5, and 50 mg/kg body weight/day. This dose range encompasses both the EU Acceptable Daily Intake (ADI) and the EU No Observed Adverse Effect Level (NOAEL) for glyphosate. Each experimental group was composed of 51 males and 51 females, the total number animals were 1020 (510 males and 510 females). ResultsIn the animals exposed to glyphosate, a significantly increased trend in incidence of lymphoblastic leukemia was observed in males. In the Roundup Bioflow-treated animals, significantly increased trends were observed in incidence of lymphoblastic leukemia (males and females), monocytic leukemia (males), total myeloid leukemia (males), and all leukemias combined (males and females). In the RangerPro-treated animals, significantly increased trends were observed in incidence of lymphoblastic leukemia (males and females), monocytic leukemia (males) and all leukemias combined (males). 43% of leukemias deaths in the glyphosate and GBHs treated groups occurred before the first year of age (52 weeks). ConclusionsGlyphosate and GBHs at exposure levels corresponding to the EU ADI and the EU NOAEL caused significant, dose-related increased trends in incidence of leukemia, a very rare malignancy, in SD rats. Notably, about half of the leukemia deaths seen in the glyphosate and GBH groups occurred at less than one year of age, comparable to less than 35-40 years of age in humans.

pharmacology and toxicology↗

bioRxiv2021

TRAP1 and cyclophilin D compete at OSCP subunit to regulate enzymatic activity and permeability transition pore opening by F-ATP synthase

Binding of the mitochondrial chaperone TRAP1 to client proteins shapes cell bioenergetic and proteostatic adaptations, but the panel of TRAP1 clients is only partially defined. Here we show that TRAP1 interacts with F-ATP synthase, the protein complex that provides most cellular ATP. TRAP1 competes with the peptidyl-prolyl cis-trans isomerase cyclophilin D (CyPD) for binding to the oligomycin sensitivity-conferring protein (OSCP) subunit of F-ATP synthase, increasing its catalytic activity and counteracting the inhibitory effect of CyPD. Moreover, TRAP1 inhibits opening of the permeability transition pore (PTP) formed by F-ATP synthase and effectively antagonizes the PTP-inducing effect of CyPD, which elicits mitochondrial depolarization and cell death. Consistently, electrophysiological measurements indicate that TRAP1 and CyPD compete in the modulation of channel activity of purified F-ATP synthase, resulting in PTP inhibition and activation, respectively, and outcompeting each other effect on the channel. Moreover, TRAP1 counteracts PTP induction by CyPD, whereas CyPD reverses TRAP1-mediated PTP inhibition. Our data identify TRAP1 as a F-ATP synthase regulator that can influence cell bioenergetics and survival and can be targeted in pathological conditions where these processes are dysregulated, such as cancer.

cell biology↗