Effects of Sublethal Exposure to a Glyphosate-Based Herbicide Formulation on Metabolic Activities of Different Xenobiotic-Metabolizing Enzymes in Rats

Abstract

The activities of different xenobiotic-metabolizing enzymes in liver subcellular fractions from Wistar rats exposed to a glyphosate (GLP)-based herbicide (Roundup full II) were evaluated in this work. Exposure to the herbicide triggered protective mechanisms against oxidative stress (increased glutathione peroxidase activity and total glutathione levels). Liver microsomes from both male and female rats exposed to the herbicide had lower (45%-54%, P < 0.01) hepatic cytochrome P450 (CYP) levels compared to their respective control animals. In female rats, the hepatic 7-ethoxycoumarin O-deethylase (a general CYP-dependent enzyme activity) was 57% higher (P < 0.05) in herbicide-exposed compared to control animals. Conversely, this enzyme activity was 58% lower (P < 0.05) in male rats receiving the herbicide. Lower (P < 0.05) 7-ethoxyresorufin O-deethlyase (EROD, CYP1A1/2 dependent) and oleandomycin triacetate (TAO) N-demethylase (CYP3A dependent) enzyme activities were observed in liver microsomes from exposed male rats. Conversely, in females receiving the herbicide, EROD increased (123%-168%, P < 0.05), whereas TAO N-demethylase did not change. A higher (158%-179%, P < 0.01) benzyloxyresorufin O-debenzylase (a CYP2B-dependent enzyme activity) activity was only observed in herbicide-exposed female rats. In herbicide-exposed rats, the hepatic S-oxidation of methimazole (flavin monooxygenase dependent) was 49% to 62% lower (P < 0.001), whereas the carbonyl reduction of menadione (a cytosolic carbonyl reductase-dependent activity) was higher (P < 0.05). Exposure to the herbicide had no effects on enzymatic activities dependent on carboxylesterases, glutathione transferases, and uridinediphospho-glucuronosyltransferases. This research demonstrated certain biochemical modifications after exposure to a GLP-based herbicide. Such modifications may affect the metabolic fate of different endobiotic and xenobiotic substances. The pharmacotoxicological significance of these findings remains to be clarified.

Potential toxic effects of glyphosate and its commercial formulations below regulatory limits

“…As a consequence of liver intoxication, Roundup triggers the activation of xenobiotic-metabolizing enzymes. CYP1A1/2 and CYP3A dependent enzymes were inhibited in male rats from 0.7 ppm dissolved in water after a 90-day exposure (Larsen et al, 2014). Disruptions of CYP1A1/2 and CYP3A enzymes were observed at levels as low as 0.1 ppb in drinking water for a life-long exposure , and corroborated in hepatocyte cell lines (Gasnier et al, 2011).…”

“…Most of these studies were not chronic studies and were of short duration. Three studies even reported hepatorenal changes below the ADI at levels relevant for environmental exposures (Larsen et al, 2014;Larsen et al, 2012;Seralini et al, 2014a). However, their pharmacotoxicological relevance needs to be ascertained by replications.…”

Effects of contaminated natural soil by Glyphosan SL on biochemical responses of the earthworm Eisenia sp.

“…These findings may be due to significant toxicity of additives (adjuvants or co-formulates) present in the pesticide preparations such as alcohol ethoxylates and alkylamine ethoxylates that enhance glyphosate stability and penetration into cell (Ibrahim, 2016 , respectively. Herbicide formulations containing ethoxytaled surfactants were found more toxic than glyphosate itself in different mammalian cell lines (Larsen et al, 2014).…”

Human Health Risks of the Use of Glyphosate and Glyphosate-Based Herbicides: Review

“…53 Doksan günlük 0,07 ppm glifosat maruziyeti de erkek sıçanlarda CYP1A1/2 ve CYP3A inhibisyonuna neden olmuştur. 54 EFSA'nın değerlendirmesine göre, sıçanlarda yürütülen uzun süreli çalışmalardan elde edilen bilgiler doğrultusunda gözlemlenen ters etki seviyesi (NOAEL) 100 mg/kg/gün, ters etki gösteren en düşük seviye (LOAEL) ise 350 mg/kg/gün olarak bulunmuştur. 55 …”