My (First) 30 Years in Neurotoxicology

By Lucio G. Costa, DEOHS

EDITOR'S NOTE: Dr. Lucio Costa will deliver the School’s Winter Quarter 2010 Distinguished Faculty Lecture on Feb. 10 at 3:30 p.m. in T-739 Health Sciences. A reception will follow.

Lucio G. Costa

After a degree in Pharmacology at the University of Milan, and the then-mandatory year in the Italian army, I chose a post-doctoral offer from the University of Texas in Houston over a lucrative one from a multinational pharmaceutical industry. I have never regretted it, as it was the start of my career in neurotoxicology. In Houston, I was asked to understand why animals may become tolerant to the neurotoxic effects of organophosphorus insecticides. We¹ discovered that this was due, to a great extent, to a decrease in the number of cholinergic muscarinic receptors (the proteins that bind the neurotransmitter acetylcholine) in brain and peripheral tissues. This project started my interest in the nervous system and how it may be adversely affected by chemicals.

Neurotoxicology—the study of substances that harm nerve cells and the underlying mechanisms—has a primary role in toxicology: most chemicals known to be toxic to humans are neurotoxic; the standards for exposure (both occupational and environmental) to several chemicals are often driven by neurotoxic effects; and neurotoxic chemicals may contribute to neurodevelopmental disorders (lead and methylmercury are the two most famous examples), as well as to neurodegenerative disorders, such as Parkinson’s disease. Neurotoxicity issues are also associated with substances of abuse (alcohol, drugs), side effects of pharmaceuticals, global pesticide poisonings, and exposure to natural neurotoxin or environmental contaminants. Neurotoxicology thus offers a myriad of possible avenues of research projects of great scientific interest and relevance for public health.

Since my arrival at the University of Washington, in 1983, I have been involved in a number of projects in the field of neurotoxicology. A central focus of my research has been the mechanisms involved in neurotoxic effects on both the mature and the developing nervous system, such as our studies with ethanol. It is well known that exposure to alcohol in utero may be associated with the Fetal Alcohol Syndrome (FAS), initially described by several UW investigators. My work on cholinergic muscarinic receptors led to investigations of signal transduction pathways activated by these receptors, and their modulation by chemicals. The serendipitous discovery of an enhanced signaling during the so-called brain growth spurt, a period of brain development which is particularly sensitive to the toxic effects of ethanol, spurred the hypothesis that interactions of alcohol with the cholinergic system may underlie at least some of its developmental neurotoxicity.

We found strong correlations between the ethanol’s ability to cause microencephaly, or a small brain, which is a hallmark of FAS, and inhibition of muscarinic receptor signaling. We have subsequently shown that this biochemical effect of alcohol is particularly pronounced in astrocytes, characteristic star-shaped cells in the brain and spinal cord; by inhibiting the action of acetylcholine at muscarinic receptors in astrocytes, ethanol impairs their proliferation and their ability to foster neuronal differentiation, thus providing some mechanistic basis for some of the effects of alcohol seen in in vivo exposure. 

Other projects over the years have involved figuring out the mechanisms behind the neurotoxicity of formamidines (a family of insecticides/acaricides), the marine toxin domoic acid, and polybrominated diphenyl ether flame retardants, an emerging class of widespread environmental pollutants.  

A second area of my research has been the development and validation of biomarkers, or indicators of exposure and susceptibility to toxicants. An example of these studies is our work with acrylamide, a chemical whose polymers are used in the treatment of drinking water and waste water, in the manufacture of glues, paper, and cosmetics, as well as in research laboratories. Acrylamide is also produced in some foods prepared at high temperatures. Acrylamide is known to induce peripheral neuropathy, a form of neurotoxicity that involves damage to the vast communications network that transmits information from the central nervous system to the rest of the body.

In our research, we identified adducts (or combinations) of acrylamide to hemoglobin and discovered a metabolite of acrylamide (glycidamide) that is most likely involved in its carcinogenic effects. We then validated these measurements in animals and, later, in a group of workers in an acrylamide-producing factory in China. Our findings indicated that hemoglobin adducts of acrylamide are an excellent indicator of cumulative exposure to this chemical and can identify, as well as predict, potential neurotoxicity.

Years later, some observations that we did not follow up at that time—the presence of hemoglobin adducts of acrylamide in unexposed animals and humans—opened the field to studies on acrylamide formation in food and its possible risks for humans.

Biomarkers of susceptibility, which often reflect genetic polymorphism, i.e. genetic variations in certain individuals, are an additional area of my research. One project is focusing on paraoxonase (PON1), a polymorphic enzyme that is involved in the metabolism of certain organophosphates (a class of insecticide that was originally synthesized during World War II). PON1 also plays an important role in lipid metabolism and hence, in cardiovascular diseases. Individuals with a "low activity" PON1 enzyme would be expected to be more sensitive to the neurotoxicity of certain insecticides. Our more than 25 years of collaborative work with Clem Furlong (Research Professor in Medical Genetics) have led to the molecular characterization of PON1 and demonstrated its role in modulating the neurotoxicity of certain organophosphorus insecticides.

1. I once heard that there are three types of “we”: the normal we (= us), the royal we (= I), and the scientist’s we (= they). None of the work summarized in this article would have been possible without the hard work of students and research scientists in my laboratory and the precious and indispensable collaboration of many colleagues. Space limitations are the only reason they are not mentioned.

Further reading:
Costa LG, Manzo L. Occupational Neurotoxicology. CRC Press, 1998.
Costa LG, Furlong CE. Paraoxonase (PON1) in Health and Disease: Basic and Clinical Aspects. Kluwer Academic Publisher, 2002.
Aschner M, Costa LG. The Role of Glia in Neurotoxicity. CRC Press, 2004.
Costa LG, Eaton DL. Gene-Environment Interactions: Fundamentals of Ecogenetics. Wiley, 2006.
Costa LG, Giordano G, Guizzetti M. Neurotoxicology in Vitro: Methods and Protocols. Springer (in press).