Epigenome-wide association study for glyphosate induced transgenerational sperm DNA methylation and histone retention epigenetic biomarkers for disease

Abstract

The herbicide glyphosate has been shown to promote the epigenetic transgenerational inheritance of pathology and disease in subsequent great-grand offspring (F3 generation). This generational toxicology suggests the impacts of environmental exposures need to assess subsequent generations. The current study was designed to identify epigenetic biomarkers for glyphosate-induced transgenerational diseases using an epigenome-wide association study (EWAS). Following transient glyphosate exposure of gestating female rats (F0 generation), during the developmental period of gonadal sex determination, the subsequent transgenerational F3 generation, with no direct exposure, were aged to 1 year and animals with specific pathologies identified. The pathologies investigated included prostate disease, kidney disease, obesity, and presence of multiple disease. The sperm were collected from the glyphosate lineage males with only an individual disease and used to identify specific differential DNA methylation regions (DMRs) and the differential histone retention sites (DHRs) associated with that pathology. Unique signatures of DMRs and DHRs for each pathology were identified for the specific diseases. Interestingly, at a lower statistical threshold overlapping sets of DMRs and DHRs were identified that were common for all the pathologies. This is one of the first observations that sperm histone retention can potentially act as a biomarker for specific diseases. The DMR and DHR associated genes were identified and correlated with known pathology specific-associated genes. Observations indicate transgenerational epigenetic biomarkers of disease pathology can be identified in the sperm that appear to assess disease susceptibility. These biomarkers suggest epigenetic diagnostics could potentially be used to facilitate preventative medicine.

Epigenetic Changes Associated With Exposure to Glyphosate-Based Herbicides in Mammals

“…These results support previous works that found adverse effects related to fetal parameters and structural congenital anomalies after perinatal exposure of GBH (F0) in secondgeneration of rats (F2) (76,82,83). However, Deepika Kubsad et al (41) and Maamar et al (42) reported for the first time that transgenerational inheritance of disease in rodents could be produced by DMRs and DHRs in the male germline, and these sites could potentially act as a biomarkers for specific diseases. Based on these findings, further studies are needed to deepen on the generational toxicology of glyphosate, in the disease etiology of the future generations.…”

Exposure to glyphosate and tetrachlorvinphos induces cytotoxicity and global DNA methylation in human cells

“…Until now, numerous studies have been performed to investigate the genotoxicity, mutagenicity, and cell viability of glyphosate in different types of human cells (Mañas et al, 2009; Nagy et al, 2019). As we know, only a few studies have investigated global and gene-specific methylation alteration in response to glyphosate (Ben Maamar et al, 2020; Kwiatkowska et al, 2017; Woźniak et al, 2020). In the study, 0.25 mM concentration of glyphosate was reported to cause a decrease in the total amount of m 5 C. In addition, the levels of m 5 C in p16 and p53 genes significantly increased compared to the negative control.…”

Review: Mechanisms of Glyphosate and Glyphosate-Based Herbicides Action in Female and Male Fertility in Humans and Animal Models

“…In humans, adverse pregnancy outcomes were reviewed but no significant link was reported between an increase in hypospadias, anencephaly, preterm delivery, birth weight, and exposure to G or R. However, exposure to G during the pre-conception period was related to late abortion. G has been detected in farmers' urine in the µg/L range as well as in farmers' children's urine, but at lower concentrations [95].…”

“…Researchers have evaluated the adverse pregnancy outcomes due to exposure to G. De Araujo et al [95] reported a non-significant association between G or GBH parental exposure and an increase in hypospadias, anencephaly, gastroschisis, preterm deliveries, congenital anomalies, and birth weight. There was a possible link between G exposure during preconception and the risk of late abortion [91].…”