PgmNr M5077: Population Variability and The Teratogenic Effects of Exposure to 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin During Pregnancy.

Authors:
M. R. Warren 1,2 ; D. Threadgill 1,2


Institutes
1) Texas A&M Health Science Center, College Station, TX; 2) Texas A&M College of Veterinary Medicine and Biomedical Sciences, College Station, TX.


Abstract:

Dioxin, formally known as 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), is a well-known toxin that exhibits carcinogenic and deleterious effects on various tissues and organs. People are exposed to small amounts of this persistent environmental pollutant through everyday products (i.e. styrofoam cups) and common foods. Dioxin exposure during pregnancy is a particular concern as it heightens the risk of fetal malformations. While toxin susceptibility often varies among individuals due to genetic differences, current studies of the teratogenic effects of dioxin do not account for inter-individual variability when evaluating exposure risks.  Our study aims to evaluate the effects of dioxin exposure on pregnant females and their embryos in genetically diverse mice to determine how genetic background impacts susceptibility.

According to the National Research Council (NRC), dose-response will linearize with non-cancerous endpoints even when accounting for genetic variability among the population. To test this prediction, we developed an in vivo study with a panel of mice that collectively mimic the amount of genetic variability present in human populations. In this study, 36 strains of pregnant female mice are being exposed to increasing doses of TCDD (0.001, 0.01, 0.1, 1, 10, 50, 100 ng/kg/day) for a period of 10 days following mating. At day (D)10.5 post mating the mice are euthanized and organs (kidney, liver, spleen, brain, uterus, lungs) and embryos collected.

Initial data identified several strains, such as 129S1/SvlmJ and CC019, as “resistant” to all levels of exposure. These strains showed no significant differences in implantation trends or the stage of embryonic development in comparison to untreated controls. High dose exposure led to a significant decrease in implantation rate in non-resistant strains, such as C57BL/6J and CBA/J. High dose exposure of TCDD (50 ng/kg and 100 ng/kg, per day) in these mice caused a trend toward a decrease in the number of viable embryos and delayed development within certain strains.

The data has shown interstrain differences greatly impacts the level of response and the overall outcome of pregnancy during exposure to TCDD. Ultimately the study will determine whether dose responses are linear when analyzed on individual genetic backgrounds, as they are when performed on a combined, genetically mixed population.