Monster Seminar JAM - Epigenetic Transgenerational Actions of Endocrine Disruptors on Reproduction and Disease: New Paradigm for Disease Etiology and Evolution
Dr. Michael K. Skinner, Department of Molecular Biosciences, Washington State University
Transgenerational effects of environmental toxicants, such as endocrine disruptors, significantly amplify the impact and health hazards of these compounds. The transgenerational nature of the actions of these compounds suggests a permanent imprinted epigenetic effect on the germ-line. One of the most sensitive periods to endocrine disruptor exposure is during embryonic gonadal sex determination when the germ line is undergoing a re-methylation process. The objective of the research was to investigate the mechanism of action of model endocrine disruptors on male reproduction with a focus on testis development. A rodent model system is used and the model endocrine disruptors tested were vinclozolin, which acts as an anti-androgenic compound, and methoxychlor, that have metabolites that are both weak estrogenic and anti-androgenic compounds. The hypothesis tested was that transient embryonic in utero exposure to an endocrine disruptor influences the embryonic testis development 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 germ-line. Previous studies have shown that methoxychlor and vinclozolin can effect embryonic testis development at the time of testis morphogenesis and that this causes an increase in germ cell apoptosis in the adult (Cupp, et al. 2003, Uzumcu, et al. 2004). Interestingly, observations demonstrate that this spermatogenic defect is transgenerational (F1, F2, F3 and F4 generations) and appears to be due to a permanent altered DNA methylation of the germ-line through an epigenetic action of the endocrine disruptor (Anway, et al. 2005). Recently we have identified a set of genes and DNA sequences with altered methylation states that become imprinted-like genes and transgenerationally transfer the altered DNA methylaion pattern. Abnormal testis development and germ cell differentiation caused by endocrine disruptors was found to be in part due to inappropriate control of the testis transcriptome. The expression of over 300 genes were found to be altered in the embryonic testis and surprisingly this altered transcriptome was the same for all vinclozolin generation (F1-F3) males. In addition to detection of the reproductive disorder, transgenerational effects on numerous disease states were observed including tumor development, prostate disease and kidney disease. Therefore, the transgenerational epigenetic mechanism involves the actions of an environmental compound at the time of sex determination to alter the epigenetic (i.e DNA methylation) programming of the germ line that induced the presence of new imprinted-like genes that then alter the transcriptomes of developing organs to induce disease development transgenerationally in a heritable manner. An epigenetic re-programming of the germ line to promote a disease state in a transgenerational (F1-F4) manner has significant evolutionary biology and disease etiology implications. The suggestion that environmental factors can reprogram the germ line to induce epigenetic transgenerational disease states is a new paradigm in disease etiology not previously considered.
Seattle Yacht Club
1807 East Hamlin Street
Date and Time:
October 12, 2006,
11:00 am - 12:30 pm