Abstract
BackgroundPermethrin and N,N-diethyl-meta-toluamide (DEET) are the pesticides and insect repellent most commonly used by humans. These pesticides have been shown to promote the epigenetic transgenerational inheritance of disease in rats. The current study was designed as an epigenome-wide association study (EWAS) to identify potential sperm DNA methylation epimutation biomarkers for specific transgenerational disease.MethodsOutbred Sprague Dawley gestating female rats (F0) were transiently exposed during fetal gonadal sex determination to the pesticide combination including Permethrin and DEET. The F3 generation great-grand offspring within the pesticide lineage were aged to 1 year. The transgenerational adult male rat sperm were collected from individuals with single and multiple diseases and compared to non-diseased animals to identify differential DNA methylation regions (DMRs) as biomarkers for specific transgenerational disease.ResultsThe exposure of gestating female rats to a permethrin and DEET pesticide combination promoted transgenerational testis disease, prostate disease, kidney disease, and the presence of multiple disease in the subsequent F3 generation great-grand offspring. The disease DMRs were found to be disease specific with negligible overlap between different diseases. The genomic features of CpG density, DMR length, and chromosomal locations of the disease specific DMRs were investigated. Interestingly, the majority of the disease specific sperm DMR associated genes have been previously found to be linked to relevant disease specific genes.ConclusionsObservations demonstrate the EWAS approach identified disease specific biomarkers that can be potentially used to assess transgenerational disease susceptibility and facilitate the clinical management of environmentally induced pathology.
Highlights
Permethrin and N,N-diethyl-meta-toluamide (DEET) are the pesticides and insect repellent most commonly used by humans
The no observable adverse effect level (NOAEL) for long-term exposure to permethrin in rats ranges from 100 to 500 mg/kg/day, while there has been no lowest observable adverse effect level established in humans [reviewed in [73]]
A control lineage was established that used F0 gestating rats exposed to the vehicle control dimethyl sulfoxide (DMSO)
Summary
Permethrin and N,N-diethyl-meta-toluamide (DEET) are the pesticides and insect repellent most commonly used by humans. These pesticides have been shown to promote the epigenetic transgenerational inheritance of disease in rats. The human population is nearly universally exposed to pesticides, and these chemicals are often toxic to human health [1]. Many commonly used pesticides, such as permethrin and the insect repellent N,N-diethyl-meta-toluamide, DEET, have been deemed safe and relatively benign by the United States Environmental Protection Agency [2, 3]. Recent research efforts have identified numerous toxicities and health effects resulting from exposure to these environmental chemicals [2, 4,5,6]. The benign status of commonly used pesticides is being challenged [7,8,9], but the regulatory agencies have not responded by updating guidelines and policies [2]
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