Doctor of Philosophy (PhD)
Our genetic inheritance begins with one genome copy from each parent. The presence of one or more errors in either the maternal or the paternal genome can lead to genetic disease or disruption of the embryonic program and potential loss of the offspring. Numerous chemical and physical toxicants are known to produce germ line mutagenesis based on their ability to produce DNA sequence mutations. Exposures to these cytotoxic and mutagenic agents pose a risk for human offspring. However, very little is known regarding the sensitivity of the epigenetic patterns involved in reproductive functions to adverse effects of chemical agents. The present study was undertaken to address the potential for ethylene dichloride (EDC) to disrupt the epigenetic programming of the paternal genome in mammalian (mouse) sperm. Unfortunately, it is very difficult to study developing germ cells such as spermatogonia and their precursor spermatogonial stem cells within the in vivo mouse testis model. Thus, an in vitro mouse spermatogonial stem cell model was developed that enabled the triggering of a spermatogenesis differentiation pathway in these stem cell cultures. Since the epigenetic imprint patterns are reported to be established in the spermatogonial stem cell of prior to meiosis, this in vitro model enabled the treatment and study of the effects of EDC on DNA, 5-methlcytosine and histone modifications in the paternal gamete. Paternally imprinted genes, such as H19, Gtl2, and Rasgrf1, showed changes in histone methylation modifications in ethylene dichloride treated spermatogonia. These data demonstrate that ethylene dichloride can disrupt the genomic imprint in developing sperm, and thus perturb the embryonic programming of potential offspring in the mouse model. This work suggests that EDC may have the potential to cause genetic diseases in offspring from exposed males.
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Daigle, Harold J., "Testicular toxicity and the potential for 1, 2 -ethlyene dichloride (EDC) to initiate epigenetic disruption of the paternal genome" (2009). LSU Doctoral Dissertations. 2284.