04/23/2019
Assessment of Glyphosate Induced Epigenetic Transgenerational Inheritance of Pathologies and Sperm Epimutations: Generational Toxicology
https://www.nature.com/articles/s41598-019-42860-0
http://archive.is/JLMkA
Abstract
Ancestral environmental exposures to a variety of factors and toxicants have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. One of the most widely used agricultural pesticides worldwide is the herbicide glyphosate (N-(phosphonomethyl)glycine), commonly known as Roundup. There are an increasing number of conflicting reports regarding the direct exposure toxicity (risk) of glyphosate, but no rigorous investigations on the generational actions. The current study using a transient exposure of gestating F0 generation female rats found negligible impacts of glyphosate on the directly exposed F0 generation, or F1 generation offspring pathology. In contrast, dramatic increases in pathologies in the F2 generation grand-offspring, and F3 transgenerational great-grand-offspring were observed. The transgenerational pathologies observed include prostate disease, obesity, kidney disease, ovarian disease, and parturition (birth) abnormalities. Epigenetic analysis of the F1, F2 and F3 generation sperm identified differential DNA methylation regions (DMRs). A number of DMR associated genes were identified and previously shown to be involved in pathologies. Therefore, we propose glyphosate can induce the transgenerational inheritance of disease and germline (e.g. sperm) epimutations. Observations suggest the generational toxicology of glyphosate needs to be considered in the disease etiology of future generations.
Results
Analysis of the transgenerational actions of glyphosate used outbred Sprague Dawley female rats (F0 generation) transiently exposed (25 mg/kg body weight glyphosate daily) during days 8 to 14 of gestation. This is half the NOAEL exposure of 50 mg/kg/day10, and due to rapid metabolism turnover would lead to a decreased (5–10 mg/kg) dose during the transient exposure period. The F1 generation animals (direct fetal exposure) were bred within the lineage to generate the F2 generation (direct germline exposure), which were bred to generate the F3 generation (transgenerational, no direct exposure). A control lineage used F0 generation gestating females administered vehicle control dimethyl sulfoxide (DMSO) or phosphate buffered saline (PBS). The control and glyphosate lineages were aged to 1 year and euthanized for pathology and sperm epigenetic analysis. No sibling or cousin breeding (crosses) was used in order to avoid any inbreeding artifacts in either the control or glyphosate lineages. Generally, 6–8 founder gestating females from different litters were bred, and 5 animals of each sex from each litter used to generate 25–50 individuals of each sex for each generation for analysis, as previously described. Therefore, litter bias was negligible, and the full spectrum of pathology within the generation and lineage was assessed.
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Conclusions
In summary, glyphosate was found to promote the epigenetic transgenerational inheritance of disease and pathology through germline (i.e. sperm) epimutations. Negligible pathology was observed in the F0 and F1 generations, while a significant increase in pathology and disease was observed in the F2 generation grand-offspring and F3 generation great-grand-offspring. Therefore, glyphosate appears to have a low or negligible toxic risk for direct exposure, but promotes generational toxicology in future generations. Observations suggest generational toxicology needs to be incorporated into the risk assessment of glyphosate and all other potential toxicants, as previously described. The ability of glyphosate and other environmental toxicants to impact our future generations needs to be considered, and is potentially as important as the direct exposure toxicology done today for risk assessment.