UC Toxics News: Summer 2002
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"Nearly 70% of human birth defects are unexplained", says Anthony F. Machado, a postdoctoral researcher at UC Los Angeles. "A growing number of scientists believe these are caused by environmental chemicals."

Machado is a former TSR&TP trainee who spearheaded the effort to form a group of researchers at UCLA that received a TSR&TP team award to investigate interactions between cadmium and arsenic in the production of birth defects. The project combines the biochemical expertise of Jon Fukuto and Nobel-laureate Louis Ignarro with developmental toxicologist Michael Collins and engineer and biomathematician James Liao. Machado is a teratologist (studies birth defects) by training who performed his doctoral research on reactive oxygen and nitrogen species in teratology in Michael Collins' lab.

"In 1979, reactive oxygen species was first proposed as a pathway", explains Machado. "This pathway is potentially responsible as the mechanism for some unexplained birth defects such as fetal alcohol syndrome and the structural malformations caused by thalidomide. But no one's looked at this with respect to metals."

Many toxicologists have already established that cadmium and arsenic both induce oxidative stress in the human body. Studies that investigated the effects of combining chemicals to produce birth defects in the past found that combinations of chemicals at doses below a teratogenic threshold could not combine to produce structural malformations. But they didn't take mechanism into account.

Machado's group is hypothesizing that due to the common pathway of oxidative-stress induction, exposure to low levels of cadium and arsenic at a sensitive time in development can cause human birth defects such as spina bifida.

Cadmium and arsenic are ubiquitous environmental contaminants - they are naturally occurring and are common industrial pollutants. Routine exposure comes from sources in food, water, and the air, particularly from cigarette smoke. These metals are acutely toxic and have been shown to cause birth defects in mice. "Because of our general ignorance of specific teratogenic mechanisms and the lack of previous research on chemicals combining in the same pathway", says Machado, "cadmium and arsenic are currently not considered to be human teratogens."

For the UCLA group, receiving the TSR&TP team award was critical to considering the problem. "It's rare that funding sources have a separate category just for collaborative work. We never would have combined toxicology and teratology without the TSR&TP urging us on", says Jon Fukuto. "This grant allows us to look at intractable problems that one lab couldn't do on its own", Machado adds. "Now multiple labs can look at this from multiple angles. For environmental problems, that's absolutely essential."