US EPA

2049093 

Journal Article 

Epigenetic Transgenerational Effects Of Endocrine Disruptors On Male Fertility And Other Diseases 

Skinner, M 

2006 

1 

Toxicological Sciences
ISSN: 1096-6080
EISSN: 1096-0929 

TOX/6002399 

90 

1-S 

381 

eng 

The molecular and cellular control of embryonic testis development was investigated to elucidate the regulation of male sex determination and testis morphogenesis. Changes in the embryonic testis transcriptome have identified potential new regulatory factors. Endocrine disruptors were used to potentially interfere with embryonic testis development and further investigate this biological process. The estrogenic pesticide methoxychlor and anti-androgenic fungicide vinclozolin were used. Previous studies have shown that methoxychlor and vinclozolin both interfere with embryonic testis cord formation and cause an increased spermatogenic cell apoptosis in the adult testis of the F1 generation. Interestingly, a transient in vivo exposure to endocrine disruptors of only the F0 gestating mother at the time of male sex determination caused a transgenerational phenotype (F1-F4) of spermatogenic cell apoptosis and sub-fertility. This appears to be mediated by an epigenetic mechanism involving altered DNA methylation and permanent re-programming of the male germ-line. A series of genes with altered DNA methylation and imprinting have been identified. Observations demonstrate that a transient embryonic in utero exposure to an endocrine disruptor influences the embryonic testis transcriptome and through epigenetic effects (e.g. DNA methylation) results in abnormal germ cell differentiation that subsequently influences adult spermatogenic capacity and male fertility, and that this phenotype is transgenerational through the male germline. In addition to effects on male fertility, other disease states are observed associated with premature aging, prostate disease, kidney disease and tumor development. The novel observations of transgenerational epigenetic endocrine disruptor actions on male reproduction and other diseases critically impact the potential hazards of these compounds as environmental toxicants. The ability of an environmental compound to induce an epigenetic transgenerational disease state has significant implications for disease etiology and for areas such as evolutionary biology. 

Pregnancy; Animals; Epigenesis, Genetic; Endocrine Disruptors/ TOXICITY; Prenatal Exposure Delayed Effects/CHEMICALLY INDUCED/GENETICS/PATHOLOGY; Infertility, Male/ CHEMICALLY INDUCED/GENETICS/PATHOLOGY; DNA Methylation; Spermatozoa/DRUG EFFECTS/PATHOLOGY; Apoptosis/DRUG EFFECTS