Metabolome disruption of pregnant rats and their offspring resulting from repeated exposure to a pesticide mixture representative of environmental contamination in Brittany

Abstract

The use of pesticides exposes humans to numerous harmful molecules. Exposure in early-life may be responsible for adverse effects in later life. This study aimed to assess the metabolic modifications induced in pregnant rats and their offspring by a pesticide mixture representative of human exposure. Ten pregnant rats were exposed to a mixture of eight pesticides: acetochlor (246 μg/kg bw/d) + bromoxynil (12 μg/kg bw/d) + carbofuran (22.5 μg/kg bw/d) + chlormequat (35 μg/kg bw/d) + ethephon (22.5 μg/kg bw/d) + fenpropimorph (15.5 μg/kg bw/d) + glyphosate (12 μg/kg bw/d) + imidacloprid (12.5 μg/kg bw/d) representing the main environmental pesticide exposure in Brittany (France) in 2004. Another group of 10 pregnant rats served as controls. Females were fed ad libitum from early pregnancy, which is from gestational day (GD) 4 to GD 21. Urine samples were collected at GD 15. At the end of the exposure, mothers and pups were euthanized and blood, liver, and brain samples collected. 1H NMR-based metabolomics and GC-FID analyses were performed and PCA and PLS-DA used to discriminate between control and exposed groups. Metabolites for which the levels were significantly modified were then identified using the Kruskal-Wallis test, and p-values were adjusted for multiple testing correction using the False Discovery Rate. The metabolomics analysis revealed many differences between dams of the two groups, especially in the plasma, liver and brain. The modified metabolites are involved in TCA cycle, energy production and storage, lipid and carbohydrate metabolism, and amino-acid metabolism. These modifications suggest that the pesticide mixture may induce oxidative stress associated with mitochondrial dysfunction and the impairment of glucose and lipid metabolism. These observations may reflect liver dysfunction with increased relative liver weight and total lipid content. Similar findings were observed for glucose and energy metabolism in the liver of the offspring, and oxidative stress was also suggested in the brains of male offspring.

Inflammatory Effects of Subacute Exposure of Roundup in Rat Liver and Adipose Tissue

“…59,60 Metabolomics and proteomic studies reported signs of liver dysfunction and hepatic lipid accumulation in adult 61 and in pregnant rats. 62 Another group also suggested a fatty liver condition development in female rats with a long-term exposure of Roundup, 32 based on a multi-omics study. The present study adds to the current understanding of the adverse effects of herbicides on liver and adipose tissues by reporting an increase in inflammation and fibrosis of liver with a subacute exposure of Roundup.…”

Glyphosate and glyphosate‐based herbicide exposure during the peripartum period affects maternal brain plasticity, maternal behaviour and microbiome

“…Although it is hypothesised that the effects of glyphosate in the brain might be linked to glutamate excitotoxicity and oxidative stress, the molecular target(s) of glyphosate in the brain is/are not well defined. As introduced above, glyphosate is best known for its direct inhibitory effects on EPSPS.…”

“…This is important because a few studies suggest that some of the observed adverse effects of GBH are not triggered by glyphosate itself but by some adjuvants, or 'inert' molecules, found in the pesticide formulation, such as the polyethoxylated tallowamine. 41,42 Although it is hypothesised that the effects of glyphosate in the brain might be linked to glutamate excitotoxicity and oxidative stress, 21,26,38,43 the molecular target(s) of glyphosate in the brain is/are not well defined. As introduced above, glyphosate is best known for its direct inhibitory effects on EPSPS.…”

Discovery of treatment for nerve agents targeting a new metabolic pathway

“…Fatty acids, like arachidonic acid, oleic acid, docosahexaenoic acid, and linoleic acid, were downregulated from 24-h through 14-days. Several studies of long-term, low-dose exposures to OPs have shown similar metabolic results indicating a dysfunction in glycolysis/TCA cycle and a shift toward beta-oxidation of fatty acids as a response (Bonvallot 2018 ; Wang 2009 ; Zhang 2010 ). Studies performed by Wang et al investigating serum metabolic profiles of rats exposed to low doses of chlorpyrifos showed decreases in serum lactate levels, which was seen in our study, and a decrease in very low-density lipids (VLDL) (Wang 2009 ).…”