(350) Di(2-ethylhexyl) Phthalate and Diisononyl Phthalate Exposures Alter Expression of Hox Genes in the Mouse Ovary.

Phthalates are a type of plasticizer commonly used in consumer products including plastic food containers, personal care products, and medical tubing. Humans are continuously exposed to phthalates due to their tendency to leach from plastics and enter the body. Di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) are two of the most commonly used phthalates. Exposure to phthalates negatively affects the female reproductive system; however, effects of DEHP and DiNP on the ovary are not well understood. Previous experiments demonstrated that short-term exposure to DEHP and DiNP aberrantly regulates ovarian expression of several Hox genes (Hoxb3, Hoxc10, and Hoxd10) compared to the control. Hox genes are a class of homeobox transcription factors that regulate animal development. Because the previous study only investigated the short-term effects of phthalate exposure on ovarian expression of Hox genes, the current study tested the hypothesis that long-term exposure to DEHP and DiNP alters Hox gene expression in the mouse ovary. Adult CD-1 female mice were exposed to vehicle control (corn oil), DEHP (0.15 ppm, 1.5 ppm, and 1500 ppm), or DiNP (0.15 ppm, 1.5 ppm, and 1500 ppm) for 6 months through chow consumption ad libitum. The 0.15 ppm dose represents daily human exposure, the 1.5 ppm dose is similar to occupational exposure, and the 1500 ppm is a toxicological dose. After 6 months of exposure, ovaries were collected from the mice and subjected to quantitative polymerase chain reaction (qPCR) to measure expression of Hoxa1, Hoxa5, Hoxa7, Hoxa10, Hoxb2, Hoxb3, Hoxb3os, Hoxb4, Hoxb7, Hoxb9, Hoxc9, Hoxc10, Hoxd9, Hoxd10, Hoxd11, Pbx1, and Pbx2. Expression levels of Hoxb3 and Hoxb4 were below the limit of detection. The results indicate that long-term DiNP exposure differentially regulates the expression of Hoxd9 and Hoxa1 in ovary compared to control. Specifically, DiNP at 1.5 ppm and 1500 ppm decreases Hoxd9 expression compared to control, whereas DiNP at 0.15 ppm increases Hoxa1 expression compared to control. DiNP exposure did not affect the ovarian expression of Hoxa5, Hoxa7, Hoxa10, Hoxb2, Hoxb3os, Hoxb7, Hoxb9, Hoxc9, Hoxc10, Hoxd10, Hoxd11, Pbx1, or Pbx2. DEHP exposure did not differentially regulate expression of the selected Hox genes. Collectively, these data indicate that long-term phthalate exposure abnormally regulates expression of some Hox genes in the mouse ovary. Supported by NIH R01 ES034112, T32 ES007326, and T32 HD108075.