Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Dec;34(4):708-19.
doi: 10.1016/j.reprotox.2012.08.010. Epub 2012 Sep 11.

Pesticide and insect repellent mixture (permethrin and DEET) induces epigenetic transgenerational inheritance of disease and sperm epimutations

Affiliations

Pesticide and insect repellent mixture (permethrin and DEET) induces epigenetic transgenerational inheritance of disease and sperm epimutations

Mohan Manikkam et al. Reprod Toxicol. 2012 Dec.

Abstract

Environmental compounds are known to promote epigenetic transgenerational inheritance of disease. The current study was designed to determine if a "pesticide mixture" (pesticide permethrin and insect repellent N,N-diethyl-meta-toluamide, DEET) promotes epigenetic transgenerational inheritance of disease and associated DNA methylation epimutations in sperm. Gestating F0 generation female rats were exposed during fetal gonadal sex determination and the incidence of disease evaluated in F1 and F3 generations. There were significant increases in the incidence of total diseases in animals from pesticide lineage F1 and F3 generation animals. Pubertal abnormalities, testis disease, and ovarian disease (primordial follicle loss and polycystic ovarian disease) were increased in F3 generation animals. Analysis of the pesticide lineage F3 generation sperm epigenome identified 363 differential DNA methylation regions (DMR) termed epimutations. Observations demonstrate that a pesticide mixture (permethrin and DEET) can promote epigenetic transgenerational inheritance of adult onset disease and potential sperm epigenetic biomarkers for ancestral environmental exposures.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Ancestral (F0 generation female) exposure to a commonly used pesticide-insect repellent mixture (Permethrin + DEET) promoted adult-onset transgenerational testis disease, but no significant prostate disease. Percentages of males with testis (panel A) or prostate disease (panel B) in F1 and F3 generations are presented. The actual number of diseased rats / total number of rats in each lineage are shown above the respective bar graphs (* P<0.05). Representative micrographs (Scale bar = 200 μm) showing histopathology images of adult-onset transgenerational testis and prostate disease in pesticide lineage (panels D and F) compared to F3 generation control lineage (panels C and E). Testis sections from pesticide lineage showed histopathology including azoospermic and atretic seminiferous tubules, (marked by asterisks in panel D), presence of vacuoles in basal regions of seminiferous tubules, sloughed spermatogenic cells in center of seminiferous tubule and lack of seminiferous tubule lumen. Prostate sections showed hyperplastic ductular epithelium (marked by arrows in panel F).
Figure 2
Figure 2
Ancestral (F0 generation female) exposure to a commonly used pesticide-insect repellent mixture (Permethrin + DEET) promoted no significant adult-onset transgenerational kidney disease in males or females. Percentages of females (panel A) and males (panel B) with kidney disease in F1 and F3 generations are presented. The actual number of diseased rats / total number of rats in each lineage are shown above the respective bar graphs (* P<0.05). Representative micrographs (Scale bar = 100 μm) showing histopathology images of adult-onset transgenerational kidney disease in pesticide lineage (panel D) compared to F3 control lineage (panel C). Kidney sections showed proteinaceous fluid filled cysts (marked by arrows in panel D).
Figure 3
Figure 3
Ancestral (F0 generation female) exposure to a commonly used pesticide-insect repellent mixture (Permethrin + DEET) promoted transgenerational pubertal abnormality in females and males, adult-onset transgenerational primordial follicle loss and polycystic ovary disease in females and no significant tumor development in males or females. Percentages of females (panel A) and males (panel B) with pubertal abnormality or those with primordial follicle loss (panel C) or polycystic ovary disease (panel D) in F1 and F3 generations are presented. The actual number of diseased rats / total number of rats in each lineage are shown above the respective bar graphs (* P<0.05; *** P<0.001).
Figure 4
Figure 4
Ancestral (F0 generation female) exposure to a commonly used pesticide-insect repellent mixture (Permethrin + DEET) promoted adult-onset transgenerational diseases in rats. Incidences of total female disease (panel A), total male disease (panel B), female multiple disease (panel C) and male multiple disease (panel D) in F1 and F3 generations are presented. The actual number of diseased rats / total number of rats in each lineage are shown above the respective bar graphs (* P<0.05; ** P<0.01; *** P<0.001).
Figure 5
Figure 5
Regions presenting pesticide-induced transgenerational change in F3 generation sperm DNA methylation. Chromosomal locations for regions detected with MeDIP-Chip with transgenerational change in DNA methylation are indicated with arrowheads. There were 363 differentially methylated regions in sperm DNA from pesticide lineage compared to control lineage.
Figure 6
Figure 6
Functional gene categories associated with the F3 generation rat genes with altered DNA methylation (DMR) due to ancestral exposure to pesticide.
Figure 7
Figure 7
Direct connection gene network for list of F3 generation rat genes with altered DNA methylation. Direct connection genes are shown according to their location in the cell, the rest of genes are not connected and not shown. Node shapes code: oval and circle – protein; diamond – ligand; circle/oval on tripod platform – transcription factor; ice cream cone – receptor; crescent – kinase or protein kinase; irregular polygon - phosphatase. Arrows with plus sign show positive regulation/activation, arrows with minus sign – negative regulation/inhibition; grey arrows represent regulation, lilac - expression, purple – binding, green – promoter binding, and yellow – protein modification.

Similar articles

Cited by

References

    1. Skinner MK, Manikkam M, Guerrero-Bosagna C. Epigenetic transgenerational actions of environmental factors in disease etiology. Trends Endocrinol Metab. 2010;21:214–222. - PMC - PubMed
    1. Anway MD, Cupp AS, Uzumcu M, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science. 2005;308:1466–1469. - PMC - PubMed
    1. Guerrero-Bosagna C, Settles M, Lucker B, Skinner M. Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome. PLoS ONE 2010. 5:e13100. - PMC - PubMed
    1. Jirtle RL, Skinner MK. Environmental epigenomics and disease susceptibility. Nat Rev Genet. 2007;8:253–262. - PMC - PubMed
    1. Kitchen LW, Lawrence KL, Coleman RE. The role of the United States military in the development of vector control products, including insect repellents, insecticides, and bed nets. J Vector Ecol. 2009;34:50–61. - PubMed

Publication types

MeSH terms