Toxic Time Bomb
How someone is 'raised' before birth may mark that person for disease after birth. Thomas Knudsen's team studies the links between early toxic exposure and adult development of cancer, diabetes and more.
The links between toxic chemical exposure and birth defects are known.
But what happens to a person exposed in utero to toxic chemicals 40 years later as they enter middle-age?
It's a question being explored by Thomas Knudsen, a professor in the molecular, cellular and craniofacial department in U of L's School of Dentistry.
For 20 years, Knudsen has studied the body's genetic and cellular workings to better understand how the developing fetus reacts to chemicals taken in by mothers through breath, by food, drink or other exposures.
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Lead investigator and School of Dentistry professor Thomas Knudsen studies how fetal exposure to toxic chemicals can lead to later adult disease.
"Three basic factors influence the risk of disease for a fetus," Knudsen explains. "One is genetics, what's passed on from parents to child. Environmental exposures are another and the third is lifestyle. The latter might include access to good prenatal care, dietary habits, or women who chose to smoke or drink during pregnancy."
Knudsen says all of these diverse factors coming into play can make evaluating toxic effects on embryos challenging, at least in humans.
"It becomes difficult to establish cause and effect for disease risk with so many competing factors at work," he says. "A condition might be just as attributable to poor diet as to exposure to an airborne chemical, for instance."
Knudsen uses animal models, lab mice in particular, for his studies because their embryos look and develop just like humans in their early stages.
"We can also see changes quickly in the animal model because the mouse embryo develops in one day what it takes the human embryo to develop in a week," he says. "This makes the mouse an attractive genetic model for human development. But it may also mean that 30 to 55 weeks after birth we can use the mouse to already see how disease such as breast cancer might develop in a middle-aged woman exposed to poor diet or toxins as a fetus."
"One of the concepts we're now exploring is called the Fetal Basics of Adult Disease, or FBAD," he says. "There is emerging evidence that maternal lifestyles as well as genetics and environment can put the fetus at risk for diseases or conditions that show up much later in life, such as diabetes, obesity, breast cancer or coronary disease.
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Knudsen's research team includes (from left to right): Reetu Singh, Amar Singh, Ben Hardin, Ken Knudsen, Maia Green (seated), Knudsen and Yihzi Zhang.
"It's pretty well established that women who were exposed to diethylstilbestrol (DES) during pregnancy may give birth to so-called 'DES babies'--daughters who are at risk for cervical cancer as young adults," he says. DES was prescribed to millions of women up to 1971 as a way of preventing miscarriage or premature birth.
Embryos are especially sensitive to two of the most common toxins: alcohol and methyl mercury.
"Alcohol abuse during pregnancy is a leading cause of mental retardation," Knudsen says. "Mercury, which comes from sources as diverse as volcanoes and industrial discharges, often comes to humans via the food chain, accumulating in the fatty tissues of fish. In some states, pregnant women are close to the margin of safety in the amount of environmental mercury exposure they receive, so eating just a few tainted fish during pregnancy can be very hazardous to the embryo."
Knudsen is especially interested in how mitochondria--the central organelle in cellular metabolism--respond to the stresses of alcohol or mercury exposure.
"When mitochondria sense something is wrong, they may send signals to the cell nucleus that contradict signals controlling development or that may slow growth and development," Knudsen says. "It's possible that mitochondria are waging a great struggle with the environment to try to bring things back into normal balance."
In its studies, Knudsen's research team uses many molecular and cellular tools including gene expression arrays, computational biology and comparative bioinformatics and animal models.
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Graduate student Maia Green and chemist Reetu Singh observe high-performance liquid chromatography to study patterns of metabolic reprogramming in embryonic cells which occurs when a fetus is exposed to toxins such as alcohol.
A major lab project is the creation of a computer-based model that can synthesize research data collected from around the world and simulate the complex factors--genetic, lifestyle, etc--that can affect a developing embryo.
"This could help us predict when certain changes might lead to abnormal development and would have the side benefit of helping use fewer animals in our work," Knudsen says.
In recently published papers, Knudsen's team demonstrated that they could prevent birth defects from appearing in mice exposed to methyl mercury or other environmental agents by using experimental drugs that bind a unique receptor on the mitochondria.
"We don't understand the details of this pathway just yet," Knudsen said. "But if we can figure out how these drugs prevent birth defects from occurring in the mouse, then we can begin to think about how this pathway might be used, perhaps medically in women, to lower the risk of birth defects in susceptible populations."
Knudsen has major research grants worth more than $3.4 million from the National Institutes of Health.
