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. 2013 Apr:36:104-16.
doi: 10.1016/j.reprotox.2012.11.011. Epub 2013 Jan 25.

Hydrocarbons (jet fuel JP-8) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations

Rebecca Tracey  1 , Mohan Manikkam, Carlos Guerrero-Bosagna, Michael K Skinner
Affiliations

Hydrocarbons (jet fuel JP-8) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations

Rebecca Tracey et al. Reprod Toxicol. 2013 Apr.

Abstract

Environmental compounds have been shown to promote epigenetic transgenerational inheritance of disease. The current study was designed to determine if a hydrocarbon mixture involving jet fuel (JP-8) promotes epigenetic transgenerational inheritance of disease. Gestating F0 generation female rats were transiently exposed during the fetal gonadal development period. The direct exposure F1 generation had an increased incidence of kidney abnormalities in both females and males, prostate and pubertal abnormalities in males, and primordial follicle loss and polycystic ovarian disease in females. The first transgenerational generation is the F3 generation, and the jet fuel lineage had an increased incidence of primordial follicle loss and polycystic ovarian disease in females, and obesity in both females and males. Analysis of the jet fuel lineage F3 generation sperm epigenome identified 33 differential DNA methylation regions, termed epimutations. Observations demonstrate hydrocarbons can promote epigenetic transgenerational inheritance of disease and sperm epimutations, potential biomarkers for ancestral exposures.

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Figures

Figure 1
Figure 1
Ancestral (F0 generation female) exposure to jet fuel (hydrocarbon mixture JP8) and testes or prostate disease in F1 and F3 generation males. Percentages of males with testis (panel A) or prostate (panel B) disease in F1 and F3 generations are presented. The number of diseased rats / total number of rats in each group is shown above the respective bar graphs (* P<0.05). Representative micrographs (Scale bar = 200 µm) showing histopathology images of adult-onset transgenerational testis (panel D) and prostate disease (panel F) in jet fuel exposure lineage compared to F3 generation control lineage testis and prostate (panels C and E). Testis sections showed histopathologies including azoospermic and abnormal seminiferous tubules. Prostate sections (insets) show atrophic ductular epithelium. Arrows indicate the lack of normal spermatogenesis in the testis and prostate epithelial cell atrophy.
Figure 2
Figure 2
Ancestral (F0 generation female) exposure to jet fuel (hydrocarbon mixture JP8) and kidney disease in F1 and F3 generation females and males. Percentages of females (panel A) and males (panel B) with kidney disease in F1 and F3 generations are presented. The number of diseased rats / total number of rats in each group is shown above the respective bar graphs (** P<0.01). Representative micrographs (Scale bar = 200 µm) showing histopathology images of adult-onset transgenerational kidney disease in jet fuel exposure lineage (panel D) compared to F3 generation control lineage (panel C). Kidney sections showed proteinaceous fluid filled cysts. Arrows indicate cystic structures and abnormal Bowman’s capsules.
Figure 3
Figure 3
Ancestral (F0 generation female) exposure to jet fuel (hydrocarbon mixture JP8) and pubertal abnormalities in females and males, and primordial follicle loss and polycystic ovary disease in 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. Small follicular cysts (panel E) and luteal cysts (panels F and G) were present in ovaries of jet fuel lineage (Scale bar = 100 µm; 25 µm for inset in panel E). The number of diseased rats / total number of rats in each group is shown above the respective bar graphs (* P<0.05; ** P<0.01; *** P<0.001). Arrows identify ovarian cysts.
Figure 4
Figure 4
Ancestral (F0 generation Female) exposure to jet fuel (hydrocarbon mixture JP8) and obesity in females and males. Percentage of females (panel A) and males (panel B) with obesity in F1 and F3 generations are presented. The number of diseased rats / total number of rats in each group is shown above the respective bar graphs (* P<0.05; ** P<0.01). Abdominal fat deposition in (C) obese F3 generation jet fuel lineage male compared to (D) non-obese F3 generation control lineage male. The pink fat deposition (adiposity) indicated by arrows is observed in panel C on most organs compared to lack of fat deposit in panel D.
Figure 5
Figure 5
Ancestral (F0 generation female) exposure to jet fuel (hydrocarbon mixture JP8) and tumor development or disease incidence in rats. Percentages of females (panel A) and males (panel B) with tumor development. Incidences of total disease in females (panel C), total disease in males (panel D), multiple disease in females (panel E) and multiple disease in males (panel F) in F1 and F3 generations are presented. The number of diseased rats / total number of rats in each group is shown above the respective bar graphs (* P<0.05; ** P<0.01; *** P<0.001).
Figure 6
Figure 6
Serum estradiol concentrations in proestrus-estrus stage in F3 generation control (n=35) and jet fuel (n=21) lineage females (panel A). Serum estradiol concentrations in diestrus stage in F3 generation control (n=36) and jet fuel (n=13) lineage females (panel B). Serum testosterone concentrations in F3 generation control (n=66) and jet fuel (n=40) lineage males (panel C). The mean ± SEM are presented (* P<0.05; *** P<0.001).
Figure 7
Figure 7
Chromosome plot (number and size) of differential DNA methylation regions (DMR) in F3 generation jet fuel lineage sperm. Chromosomal locations for DMR are indicated with arrowheads. There were 33 DMR in F3 generation jet fuel lineage sperm DNA compared to control lineage sperm DNA.
Figure 8
Figure 8
F3 generation sperm functional gene categories for DMR associated genes. The number of genes per category is indicated.
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