Maternal glyphosate exposure causes autism-like behaviors in offspring through increased expression of soluble epoxide hydrolase

Pu, Yaoyu; Yang, Jun; Chang, Lijia; Qu, Youge; Wang, Siming; Zhang, Kai; Xiong, Zhili; Zhang, Jiancheng; Tan, Yunfei; Wang, Xingming; Fujita, Yūkō; Ishima, Tamaki; Wang, Debin; Hwang, Sung Hee; Hammock, Bruce D.; Hashimoto, Kenji

doi:10.1073/pnas.1922287117

Cited by 109 publications

(70 citation statements)

References 55 publications

(62 reference statements)

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“…The research around Roundup is highly contentious: some scientists have claimed that it causes pathologies ranging from cancer (e.g. [ 2 ]) to celiac disease [ 3 ] and autism [ 4 ], while industry-paid research reports that the herbicide has no untoward effects. Much of the controversial evidence on Roundup is rooted in outdated toxicity tests, called LC50 [ 5 ], from which safe use of chemicals in the environment is extrapolated.…”

Section: Introductionmentioning

confidence: 99%

Roundup causes embryonic development failure and alters metabolic pathways and gut microbiota functionality in non-target species

Suppa

Kvist

et al. 2020

Microbiome

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Background Research around the weedkiller Roundup is among the most contentious of the twenty-first century. Scientists have provided inconclusive evidence that the weedkiller causes cancer and other life-threatening diseases, while industry-paid research reports that the weedkiller has no adverse effect on humans or animals. Much of the controversial evidence on Roundup is rooted in the approach used to determine safe use of chemicals, defined by outdated toxicity tests. We apply a system biology approach to the biomedical and ecological model species Daphnia to quantify the impact of glyphosate and of its commercial formula, Roundup, on fitness, genome-wide transcription and gut microbiota, taking full advantage of clonal reproduction in Daphnia. We then apply machine learning-based statistical analysis to identify and prioritize correlations between genome-wide transcriptional and microbiota changes. Results We demonstrate that chronic exposure to ecologically relevant concentrations of glyphosate and Roundup at the approved regulatory threshold for drinking water in the US induce embryonic developmental failure, induce significant DNA damage (genotoxicity), and interfere with signaling. Furthermore, chronic exposure to the weedkiller alters the gut microbiota functionality and composition interfering with carbon and fat metabolism, as well as homeostasis. Using the “Reactome,” we identify conserved pathways across the Tree of Life, which are potential targets for Roundup in other species, including liver metabolism, inflammation pathways, and collagen degradation, responsible for the repair of wounds and tissue remodeling. Conclusions Our results show that chronic exposure to concentrations of Roundup and glyphosate at the approved regulatory threshold for drinking water causes embryonic development failure and alteration of key metabolic functions via direct effect on the host molecular processes and indirect effect on the gut microbiota. The ecological model species Daphnia occupies a central position in the food web of aquatic ecosystems, being the preferred food of small vertebrates and invertebrates as well as a grazer of algae and bacteria. The impact of the weedkiller on this keystone species has cascading effects on aquatic food webs, affecting their ability to deliver critical ecosystem services.

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Section: Introductionmentioning

confidence: 99%

Roundup causes embryonic development failure and alters metabolic pathways and gut microbiota functionality in non-target species

Suppa

Kvist

et al. 2020

Microbiome

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“…Whereas we observed an increase in both pyridoxal and serotonin in the caecum we found a decrease in the level of pyridoxal in serum suggesting that the pesticide mixture could lead to a deficiency in vitamin B6. In a recent study, administration of a high-dose of glyphosate caused autism-like behaviors in murine male offspring (Pu et al 2020). Chlorpyrifos has also been found to be associated with an increased risk for autism spectrum disorder with intellectual disability in human populations (von Ehrenstein et al 2019).…”

Section: Discussionmentioning

confidence: 99%

Multi-omics phenotyping of the gut-liver axis allows health risk predictability fromin vivosubchronic toxicity tests of a low-dose pesticide mixture

Mesnage

Teixeira

Mandrioli³

et al. 2020

Preprint

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Human health effects from chronic exposure to mixtures of pesticide residues are little investigated. We compared standard histopathology and serum biochemistry measures and multi-omics analyses in an in vivo subchronic toxicity test of a mixture of six pesticide active ingredients frequently detected in foodstuffs (azoxystrobin, boscalid, chlorpyrifos, glyphosate, imidacloprid and thiabendazole). Sprague-Dawley rats were administered with the pesticide mixture with each ingredient at its regulatory permitted acceptable daily intake. Analysis of water and feed consumption, body weight, histopathology and serum biochemistry showed little or no physiological effects from exposure to the pesticide mixture. In marked contrast, analysis of the host-gut microbiome axis using serum and caecum metabolomics revealed that nicotinamide and tryptophan metabolism were affected, which suggested the initiation of a cell danger response, including adaptation to oxidative stress. Only limited effects were detected on the caecum microbiota by shotgun metagenomics. Further analyses of in vitro bacterial cultures showed that growth of Lactobacillus rhamnosus and Escherichia coli strains was negatively impacted by the pesticide mixture at concentrations that were not inhibitory when exposure was to a single agent. Transcriptomics of the liver showed that 257 genes had their expression changed. Gene functions affected included those involved in the regulation of response to hormones and correlated with previously reported transcriptome changes following administration of nicotinamide. Genome-wide DNA methylation analysis of the same liver samples showed that 4255 CpG sites were differentially methylated (> 10% difference). Overall, we demonstrated that unlike standard blood biochemical and organ histological analysis, in-depth molecular profiling using a combination of high-throughput ‘-omics’ methods in laboratory animals exposed to low concentrations of pesticides reveals metabolic effects on the gut-liver axis, which can potentially be used as biomarkers for the prediction of future negative health outcomes. Our data suggest that adoption of multi-omics as part of regulatory risk assessment procedures will result in more accurate outcome measures, with positive public health implications.

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“…Pu et al ( 1 ) support their hypothesis with four citations, three of which ( 2 – 4 ) confuse correlation with causation by selectively citing or misinterpreting available literature. None of the disease associations conjectured by these three publications stems from empirical evidence, nor are they consistent with credible, reproducible toxicological data or observations in human populations.…”

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confidence: 93%

“…Pu et al ( 1 ) report that a soluble epoxide hydrolase (sEH) inhibitor mitigated the effects of maternal stress on F1 mice that exhibited atypical neurological symptoms. Research into the role of sEH in disease is valuable, and our comments do not cast doubt on the importance of sEH as a pharmaceutical target.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Additional observations regarding glyphosate-based herbicides and developmental toxicity

Reeves¹,

Dunn²

2020

Proc. Natl. Acad. Sci. U.S.A.

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Maternal glyphosate exposure causes autism-like behaviors in offspring through increased expression of soluble epoxide hydrolase

Cited by 109 publications

References 55 publications

Roundup causes embryonic development failure and alters metabolic pathways and gut microbiota functionality in non-target species

Roundup causes embryonic development failure and alters metabolic pathways and gut microbiota functionality in non-target species

Multi-omics phenotyping of the gut-liver axis allows health risk predictability fromin vivosubchronic toxicity tests of a low-dose pesticide mixture

Additional observations regarding glyphosate-based herbicides and developmental toxicity

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