BackgroundAncestral environmental exposures to a variety of environmental factors and toxicants have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. The present work examined the potential transgenerational actions of the insecticide dichlorodiphenyltrichloroethane (DDT) on obesity and associated disease.MethodsOutbred gestating female rats were transiently exposed to a vehicle control or DDT and the F1 generation offspring bred to generate the F2 generation and F2 generation bred to generate the F3 generation. The F1 and F3 generation control and DDT lineage rats were aged and various pathologies investigated. The F3 generation male sperm were collected to investigate methylation between the control and DDT lineage male sperm.ResultsThe F1 generation offspring (directly exposed as a fetus) derived from the F0 generation exposed gestating female rats were not found to develop obesity. The F1 generation DDT lineage animals did develop kidney disease, prostate disease, ovary disease and tumor development as adults. Interestingly, the F3 generation (great grand-offspring) had over 50% of males and females develop obesity. Several transgenerational diseases previously shown to be associated with metabolic syndrome and obesity were observed in the testis, ovary and kidney. The transgenerational transmission of disease was through both female (egg) and male (sperm) germlines. F3 generation sperm epimutations, differential DNA methylation regions (DMR), induced by DDT were identified. A number of the genes associated with the DMR have previously been shown to be associated with obesity.ConclusionsObservations indicate ancestral exposure to DDT can promote obesity and associated disease transgenerationally. The etiology of disease such as obesity may be in part due to environmentally induced epigenetic transgenerational inheritance.

Ancestral environmental exposures such as toxicants, abnormal nutrition or stress can promote the epigenetic transgenerational inheritance of disease and phenotypic variation. These environmental factors induce the epigenetic reprogramming of the germline (sperm and egg). The germline epimutations can in turn increase disease susceptibility of subsequent generations of the exposed ancestors. A variety of environmental factors, species and exposure specificity of this induced epigenetic transgenerational inheritance of disease is discussed with a consideration of generational toxicology. The molecular mechanisms and processes involved in the ability of these inherited epimutations to increase disease susceptibility are discussed. In addition to altered disease susceptibility, the potential impact of the epigenetic inheritance on phenotypic variation and evolution is considered. Observations suggest environmentally induced epigenetic transgenerational inheritance of disease is a critical aspect of disease etiology, toxicology and evolution that needs to be considered.

The actions of environmental toxicants and relevant mixtures in promoting the epigenetic transgenerational inheritance of ovarian disease was investigated with the use of a fungicide, a pesticide mixture, a plastic mixture, dioxin and a hydrocarbon mixture. After transient exposure of an F0 gestating female rat during embryonic gonadal sex determination, the F1 and F3 generation progeny adult onset ovarian disease was assessed. Transgenerational disease phenotypes observed included an increase in cysts resembling human polycystic ovarian disease (PCO) and a decrease in the ovarian primordial follicle pool size resembling primary ovarian insufficiency (POI). The F3 generation granulosa cells were isolated and found to have a transgenerational effect on the transcriptome and epigenome (differential DNA methylation). Epigenetic biomarkers for environmental exposure and associated gene networks were identified. Epigenetic transgenerational inheritance of ovarian disease states was induced by all the different classes of environmental compounds, suggesting a role of environmental epigenetics in ovarian disease etiology.

The Drosophila fruitless (fru) gene product Fru has been postulated to be a neural sex-determination factor that directs the development of at least two male-specific characteristics, namely courtship behaviour and formation of the muscle of Lawrence (MOL). The fru gene encodes a putative transcription factor with a BTB domain and two zinc-finger motifs, and with consensus Tra-binding sequences. The binding of Tra to these sequences results in sex-specific alternative splicing of the fru mRNA, leading to production of the 'male-type' or 'female-type' Fru protein. We show here that the Fru protein is not detected in the female central nervous system (CNS), despite the similar level of expression of fru mRNA in both male and female CNS. As ectopic expression of both the 'male-type' (with the sequence for the amino-terminal extension) and 'female-type' (without the sequence for the amino-terminal extension) fru cDNA can induce formation of the MOL in females, the presence or absence of the Fru protein, and not its sex-specific structure, seems to be responsible for the sexually dimorphic actions of the fru gene.