PgmNr M5094: Susceptibility to diethylstilbestrol exposure in mice.

Authors:
D. L. Aylor; N. E. Allard; T. I. Konneker


Institutes
North Carolina State University, Raleigh, NC.


Abstract:

Diethylstilbestrol (DES) is a drug that caused infertility and cancer in some adults who were exposed prenatally before its use was ended in 1971. Some DES-exposed mouse strains also display reproductive defects (male and female) and cancer; yet other mouse strains are unaffected. This indicates a strong genetic component to susceptibility. Our goal is to identify the gene x environment interactions (GxE) associated with clinical traits and molecular profiles in DES-exposed inbred mouse strains. To accomplish this goal, we are screening a large panel of inbred mouse strains that includes 50 lines from the Collaborative Cross (CC) genetic reference panel. We observe novel strain-specific reproductive defects in DES-exposed males, including some that lead to azoospermia and infertility. In females, we have measured the acute effects of DES exposure on uterine gene expression for a known susceptible strain (FVB/NJ) and a known resistant strain (C57BL/6J). A substantial number of genes are differentially expressed between DES-exposed and control mice in both strains, but only 61% of these genes are shared. This illustrates the large effect genetic background can have on DES-induced changes in uterine gene expression. These strain-specific responses to DES involve coordinate regulation of hundreds of genes and can help narrow down sets of genes associated with disease susceptibility. We have identified gene modules that characterize strain-specific DES response and we relate these to clinical data derived from uterine histopathology. We conclude that the combination of genetic variation with functional genomics is a powerful tool for identifying genes involved in differential susceptibility to toxicants, and we propose that this approach is broadly relevant to other toxicological studies in rodents.