Science rarely follows a straight line, and so it’s not surprising that Jennifer Schlezinger’s path of scientific pursuit has been a meandering one. When she was an undergraduate and graduate student, her research interests ranged from the synthesis of organic catalysts to the use of mussels as sentinels (indicators) for exposure to heavy metals to the ecological effects of nutrient pollution in coastal ecosystems. Finally, Dr. Schlezinger settled on the toxicology of environmental pollutants, and she earned her PhD at the Woods Hole Oceanographic Institution studying the molecular mechanisms of PCB toxicity in a marine fish model. Following her PhD work, she began collaborating with Dr. David Sherr in 1998, studying the mechanisms by which environmental contaminants impair immune function. As an Assistant Professor of Environmental Health in BU’s School of Public Health, Dr. Schlezinger investigates how aromatic hydrocarbons (by-products of combustion) and phthalate esters (plasticizers used in manufacturing polyvinyl chloride) cause death in antibody-producing cells within the bone marrow microenvironment.
Jennifer Schlezinger has been a part of the Boston University SRP throughout her scientific training, from graduate student to principal investigator. During this time she has also become the mother of three children. Certainly being a mother has underscored the importance of understanding how environmental toxicants may adversely affect human health!
The studies in Dr. Schlezinger’s lab focus on how environmental chemicals impair the function of the immune system, in particular how these chemicals kill developing B lymphocytes, those cells that help to fight infections by making antibodies. The lab studies two types of chemicals: aromatic hydrocarbons and phthalate esters. Aromatic hydrocarbons, which are formed as by-products of the incomplete burning of organic materials, are found in car exhaust, cigarette smoke, and the char on a barbequed steak. Phthalate esters are ubiquitous environmental contaminants. Worldwide, more than 18 billion pounds of phthalates are produced yearly, mainly for use as plasticizers in polyvinyl chloride products, including car seats, toys, blood bags and other medical devices. Phthalates also are used as fixatives, detergents, lubricating oils, adhesives, defoaming agents, and solvents and can be found in other products as diverse as cosmetics, wood finishes, and pesticides. Because of the widespread industrial and commercial use, humans receive significant ambient daily exposures to phthalate esters as well as substantial acute exposures during some medical procedures, and the substances are priority chemicals designated by the Agency for Toxic Substances and Disease Registry (ATSDR).
Aromatic hydrocarbons and phthalates are toxic to multiple organ systems. In particular, exposure to these substances can result in developmental and reproductive toxicity. In addition, our lab has shown that aromatic hydrocarbons and phthalates have the potential to impair the immune system. What we want to know now is how these synthetic chemicals override naturally occurring cellular processes to induce cell death. Triggering the death of cells in the immune system would be one way that these environmental contaminants could potentially impair the body’s ability to respond to infections.
Once these toxic chemicals enter the body, one of the first steps in the path of their biological effect is to combine with a special type of protein, called a receptor protein. In general, receptors are designed to deliver signals from outside the cell to the nucleus, the “brain” of the cell, so that the cell can respond to changing conditions. Typically, receptors bind to chemicals that occur naturally within the body. However, when foreign chemicals, such as environmental pollutants, bind to a receptor, it may be hijacked from its normal function. The pollutant may thereby induce inappropriate cell responses, with potentially serious negative effects. The receptor protein that binds to aromatic hydrocarbons is called the aryl hydrocarbon receptor (AhR), and those that bind to phthalates are called the peroxisome proliferator-activated receptors (PPAR). In general, chemicals that bind to receptors such as AhR and PPAR are called agonists.
Binding to a receptor is not the only mechanism by which contaminants can alter cellular physiology. We have shown that the exposure of B lymphocytes to phthalates and other substances that bind with the PPAR causes changes in multiple groups of proteins, such as signaling proteins (called kinases) and death proteins (called caspases). Kinases are activated in a series of reactions—a cascade—thereby propagating a death signal in that cell. Caspases are the proteins responsible for initiating the reactions that actually break down dead cells.
Our results indicate that the bone marrow microenvironment in which antibody-forming B lymphocytes develop is exquisitely sensitive to environmental chemicals. Defining the mechanisms of how chemicals that can bind to AhR and PPAR induce death may suggest strategies that could be developed to avoid the immunosuppressive effects of these agonists, which are so widespread in the human environment. Indeed, considering that PPAR agonists are being investigated as potential chemotherapeutic agents, these studies also will aid in defining a therapeutic window that minimizes immunotoxicity.
Q. What are the most important routes of exposure for phthalates for humans?
A. Phthalates are ubiquitous in the environment, meaning that they are everywhere. They contaminate food, air and water. Essentially all humans carry a measurable burden of phthalates. Specifically, humans are exposed to phthalates on a daily basis by contact with soft plastics and eating food packaged in soft plastics. Phthalates are used as a plasticizing agent that is not permanently attached to the plastic, thus the phthalate leaches out of the plastic over time. In addition, humans are exposed by using cosmetics and other personal care items such as soaps and detergents. Phthalates are used to hold color or scent in these products. There is some concern that women are exposed to these compounds to a greater extent than men because of cosmetic use. More extreme exposure to phthalates occurs when people undergo medical treatments that require blood transfusions. Blood is stored in plastic bags that contain phthalates. The phthalates leach into the blood and thus the patient receiving the transfusion is exposed.
Q. Are these agents also causing environmental exposures for other animals and if so can any impacts be estimated?
A. This is an interesting question and I had to look up the answer, as I hadn’t thought of phthalate exposure in wildlife before. There are no studies that have estimated phthalate exposure in wildlife, that I found. However, I can tell you that a measurable amount of DEHP is found in effluent from sewage treatment plants, suggesting that humans are contributing a significant amount of these compounds to the environment by daily usage of phthalate containing products, along with the industrial sources.
Q. What is apoptosis (aka. Cell suicide)?
A. Apoptosis is one of the main types of programmed cell death, and it is essential in the developmental process. Necrosis, on the other hand, is a form of traumatic cell death caused by acute cellular injury that essentially causes the cell to explode. In contrast, apoptosis is carried out in an orderly process that is controlled by the activation of a series of specific proteins within the cell. For example, when hands and feet are initially formed in a developing human embryo, the digits are connected by webbing. The process of apoptosis eliminates those cells between the digits, allowing individual fingers and toes to form.
Why spend all this time and energy with programmed cell death? In the process of the cell shrinking and breaking apart, signals on the surface of the dying cell trigger other “custodial” cells called phagocytes to come and remove the dying cell. If the cell explodes and the contents leak into the surrounding area, as happens in necrosis, this triggers an inflammatory process that may damage the cells around it.
Q. Why (or how) would a toxic chemical be able to trigger a cell to die prematurely?
A. There is no simple answer to this question, as there are any number of ways by which a chemical might trigger a cell to die. My laboratory is particularly interested in how interactions of toxic chemicals with receptors within cells trigger a death mechanism. I’ll give a few definitions to help with this explanation, starting with receptor. A receptor is a protein that recognizes a particular type of chemical structure, and there are many of these receptors in cells that recognize foreign chemicals as well as chemicals, hormones and proteins made in the body. When a chemical binds to the receptor, it turns the receptor on, allowing it to go to work adjusting the cell’s molecular programming. In the case of aromatic hydrocarbons, these chemicals bind to a receptor called the aryl hydrocarbon receptor (AhR). Once the AhR is turned on, it then turns on the production of proteins that metabolize the aromatic hydrocarbons. What does “metabolize” mean? It means the process by which the proteins change the chemical structure of the aromatic hydrocarbons so that they can more easily leave the cell and be removed from the body. However, the change in chemical structure also allows these aromatic hydrocarbons to attack DNA.
Cells have mechanisms by which they can detect these attacks, and one way they can respond to the attack is to die. It is better for the organism as a whole to have that cell die than to have it replicate with damaged DNA. In the case of the B lymphocytes that we study, it is not the B cells themselves that have the AhR and produce the toxic metabolites, it is their “nurse” cells in the bone marrow that make the metabolite and then this metabolite is passed to the B cell where it causes death.
My laboratory also studies death mechanisms triggered by another class of chemicals, those that interact with the peroxisome proliferator activated receptors (PPARs). Once we observed that a variety of chemicals that interact with the PPARs, including phthalates, all caused death in B cells, we hypothesized that PPARs are involved in triggering death. However, our research has shown that, in fact, the receptor may not be involved; instead, these chemicals interfere with different organelles in the cells to trigger death. For instance, one of the chemicals causes the endoplasmic reticulum (the protein-building machinery in the cell) to release all of its calcium, and then the cell dies from calcium overload. Another chemical appears to interact with the mitochondria (the energy-producing center of the cell), causing the membranes to lose their integrity and release a death molecule. Finally, another chemical causes the cell to make reactive oxygen species. Cells have the ability to detect the presence of reactive oxygen species, and if the cell is unable to detoxify the reactive oxygen, it will initiate a death program.
Q. What roles do B lymphocytes play in our body?A. B cells are continually developing in the bone marrow. They go through a series of stages in which they construct a unique B cell receptor, a protein that sits on the surface of the cell and is capable of recognizing “intruders,” such as bacteria. However, because the receptors are constructed in a completely random fashion, some of them will recognize “self.” Since we do not want our immune system to be attacking ourself, the B cells are tested for “self” recognition, and those that recognize “self” undergo apoptosis. Once the B cell has constructed its receptor and the receptor passes the “self” test, the B cell leaves the bone marrow and begins to circulate in the blood and lymph, performing the role of immune surveillance.
Once the B cell recognizes an intruder with its receptor, and with help from other cells in the immune system, it will begin to produce antibodies. Antibodies can work in several ways. First, they can neutralize an intruder by sticking to the intruder’s surface, preventing it from interacting with cells in the body. Second, binding of antibodies on the surface of an intruder signals other cells to engulf or attack the intruder. Third, antibodies bound to the surface of an intruder attract other proteins that form a membrane attack complex with the antibodies, allowing the action of the antibody alone to kill the intruder.