Abstract
Atrazine is a common agricultural herbicide previously shown to promote epigenetic transgenerational inheritance of disease to subsequent generations. The current study was designed as an epigenome-wide association study (EWAS) to identify transgenerational sperm disease associated differential DNA methylation regions (DMRs) and differential histone retention regions (DHRs). Gestating female F0 generation rats were transiently exposed to atrazine during the period of embryonic gonadal sex determination, and then subsequent F1, F2, and F3 generations obtained in the absence of any continued exposure. The transgenerational F3 generation males were assessed for disease and sperm collected for epigenetic analysis. Pathology was observed in pubertal onset and for testis disease, prostate disease, kidney disease, lean pathology, and multiple disease. For these pathologies, sufficient numbers of individual males with only a single specific disease were identified. The sperm DNA and chromatin were isolated from adult one-year animals with the specific diseases and analyzed for DMRs with methylated DNA immunoprecipitation (MeDIP) sequencing and DHRs with histone chromatin immunoprecipitation (ChIP) sequencing. Transgenerational F3 generation males with or without disease were compared to identify the disease specific epimutation biomarkers. All pathologies were found to have disease specific DMRs and DHRs which were found to predominantly be distinct for each disease. No common DMRs or DHRs were found among all the pathologies. Epimutation gene associations were identified and found to correlate to previously known disease linked genes. This is one of the first observations of potential sperm disease biomarkers for histone retention sites. Although further studies with expanded animal numbers are required, the current study provides evidence the EWAS analysis is effective for the identification of potential pathology epimutation biomarkers for disease susceptibility.
Highlights
Chronic exposure to ecological toxicants can be highly detrimental to health outcomes of animal and human populations
The current study focused on atrazine impacts, but observations will need to be compared to other endocrine disruptor actions in the future
A control lineage was established that used F0 gestating rats exposed to the vehicle control dimethyl sulfoxide (DMSO)
Summary
Chronic exposure to ecological toxicants can be highly detrimental to health outcomes of animal and human populations. Environmental exposures such as endocrine disrupting chemicals are a major source of concern for overall wildlife and human health [1, 2]. Atrazine is found in many ground water sources in North America where the aquatic ecological effects are a source of concern, as well as impacts on human health [4]. Low doses of atrazine exposures have been shown to have negative effects in a wild rodent species (Caolmys laucha), including reduction of motility in sperm and an increase in damage to sperm DNA in males [9]. Maternal exposure to atrazine resulted in the offspring having impaired spatial learning and memory, damage to the hippocampal morphology, and a reduction in expression of genes related to memory formation in the hippocampus [10]
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