Question

The plasticizer di-(2-ethylhexyl) phthalate (DEHP) is used widely in synthesizing plastics. Due to its heavy use and its ability to leak out of plastic products, it is important to analyze its potential to be toxic in humans.

a. Mice exposed to DEHP develop liver tumors. It has been found that DEHP activates a nuclear receptor called Peroxisome Proliferator-Activated Recepter-a (PPARa). Activation of this receptor results in many changes, including a decrease in apoptosis and increase in cell proliferation. Does DEHP induce tumors through a genotoxic or non-genotoxic mechanism?

b. Scientists created a mouse that has both copies of the PPARa gene deleted. Will this mouse develop liver tumors due to exposure to DEHP? Explain.

c. Guinea pigs have very low levels of PPARa protein in their liver cells. They do not develop liver tumors upon exposure to DEHP. Is this difference due to a toxicokinetic or toxicodynamic effect? Explain.

d. Humans also have very low levels of PPARa in the liver. Imagine that you are charged with making recommendations on the safety guidelines for DEHP. What would you recommend? Why?

Answer 1

a. Genotoxic substances are those which cause tumors by interacting with the genetic material. Given that DEHP acts by activating PPARa receptors. Therefore, this is a non-genotoxic mechanism.

b. A mouse that has both copies of the PPARa gene deleted is not likely to develop liver tumors due to exposure to DEHP because PPARa, the target for the carcinogen, will not be produced in such animals.