Many environmental pollutants can cause cells in the body to work differently than normal. The mechanisms by which this occurs are largely unknown, but a ligand activated transcription factor known as the aryl hydrocarbon receptor (AhR) plays an important role in some toxic effects of environmental pollutants. AhR’s normal function in the body is unknown, but many pollutants can bind to the receptor, which then turns on genes in the body. In addition to pollutants, many natural compounds bind to AhR. Therefore, we are exposed to molecules that activate AhR daily through ingestion and inhalation. A major focus of our research is to characterize molecular mechanisms by which pollutants change the immune system's ability to respond to respiratory infections. We focus on the pollutant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD or Dioxin) and how its interaction with AhR changes immune function.

Short-term exposure of humans to high levels of dioxins results in skin lesions, patchy darkening of the skin, and altered liver function. However, most exposures are to daily low levels, which has been linked to possible impairment of the immune system, the developing nervous system, the endocrine system and reproductive functions.  Researchers are still seeking to understand how dioxin causes these health effects.  Our laboratory uses dioxin to activate the AhR, which will help us to understand AhR's normal role in, and how pollutants impact, the immune system and developing organs.

Dioxins enter the cell membrane and can bind to the the Ah Receptor.

This binding triggers AhR to modify the activation of currently unknown genes.

PROJECTS IN THE LAB

Our laboratory has shown that by binding AhR, dioxin negatively affects the ability combat viral infection. One way dioxin affects the immune system is to reduce the response of virus specific CD8+ T cells. Fighting a viral infection is kind of like a race between the virus' ability to multiply and the host's ability to create an army of immune cells that kill the virus and virus-infected cells. Our data from mouse studies suggests that activation of AhR results in effects upon dendritic cells that then lead to decreased T cell function. Another way that dioxin affects immune function is to increase inflammation in the infected lung. Inflammation is an important part of fighting infection, but too much inflammation is detrimental—and our data suggest that when AhR is activated by dioxin, inflammation goes overboard.  A future line of study will be to determine the molecular pathways involved, with the aim of correlating our findings to AhR activation in humans.

Dendritic cells in the lung are involved in breaking up viruses and presenting parts of those viruses to naive T cells. An activated T cell goes on to develop into Cytotoxic T cells. These cytotoxic T cells can kill off infected cells, thus reducing the number of viruses in the body

When AhR is inappropriately activated in dendritic cells, our hypothesis is that naive T-cells can not be activated because there are cellular changes broght on by AhR activation that prevent the dendritic cell from activating naive CD8+ T cells

The role of dioxin and AhR in programming the fetal immune system

In our studies, maternal exposure to dioxins have been found to be toxic to function of her offspring's immune system. These pollutants essentially “reprogram” the fetal immune system, which then develops differently than it would have without exposure to the chemical. Current research aims to determine how the inappropriate activation of AhR during development changes the normal programming of the immune system by changing the expression of genes, with the potential of correlating these findings to human development.

We are currently testing whether or not AhR reprograms the immune system through an epigenetic mechanism.

Epigenetics refers to heritable changes in phenotype or gene expression that are caused by mechanisms that do not change the DNA sequence

These non-genetic changes are inherited during cell divisions for multiple generations.

The role of dioxin and AhR in lactogenesis

Every year, 3 to 6 million mothers of infants are unable to produce milk or have difficulty breast-feeding. Our laboratory has discovered a new toxic effect of AhR activation by dioxin in mice, that exposure during pregnancy affects the development of mammary glands and impairs milk production. The goals of this study are to further characterize this finding and to identify the milk-production pathways which are affected by exposure to dioxin. Not only may these findings in mice be relevant to human lactogenesis, but because the mechanisms that control milk production are similar to those that regulate the development of other cells in the body, our findings also have broad applications to understanding how dioxins affect development of other organs.

Selected reading (For more publications, see below):
Vorderstrasse BA, Fenton SE, Bohn AA, Cundiff JA, Lawrence BP. (2004) A novel effect of dioxin: exposure during pregnancy severely impairs mammary gland differentiation. Toxicol Sci. Apr;78(2):248-257.

Treatment of neonates with supplemental oxygen and effects on the immune system

The laboratory's studies in mice infected with influenza virus have allowed us to form a collaboration with Dr. Michael O'Reilly to study the effects of neonatal oxygen supplementation on long term lung function. Premature infants are often given oxygen supplementation after birth, a treatment that has reduced premature infant mortality. However, these infants exhibit reduced lung function even as adolescents, and are more likely to develop asthma, and be re-hospitalized when infected with respiratory viruses.  Using a mouse model to study this, we have discovered that neonatal high oxygen treatment disrupts the response to respiratory viral infection. By integrating our research findings with studies of immune responses in infected children who were born prematurely, we hope to identify novel therapeutic opportunities for improving the health of children born prematurely.

Selected reading (For more publications, see below):
O’Reilly MA, Marr SH, Yee M, McGrath-Morrow SA, Lawrence BP. Neonatal Hyperoxia Enhances the Inflammatory Response in Adult Mice Infected With Influenza A Virus. Am J Respir Crit Care Med. 2008. May 15;177(10):1103-10.

POTENTIAL FOR COLLABORATION

Epidemiologists and Clinicians, Biochemists and Chemists:

         It is very difficult to determine how much toxin an individual or group has been exposed to, or to assess the significance of outcomes in large groups of people. Also, when we study people, we often only have access to their medical records and maybe blood samples. However, when our body fights an infection, the relevant place to look at what is going on is usually not the blood, but the place where the infection has taken hold. These complications make it difficult to measure changes to immune function in people, and lead to gaps in our understanding of the effects of these toxins. Partnership between epidemiologists, clinicians, biochemists and immunologists would help scientists resolve these unknowns and make advancements toward better understanding the AhR and effects of environmental toxins.

SELECTED PUBLICATIONS

Lawrence BP, Denison MS, Novak H, Vorderstrasse BA, Harrer N, Neruda W, Reichel C, Woisetschlager M. Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low molecular weight compound. Blood. 2008 Feb 12. [Epub ahead of print]

O’Reilly MA, Marr SH, Yee M, McGrath-Morrow SA, Lawrence BP. Neonatal Hyperoxia Enhances the Inflammatory Response in Adult Mice Infected With Influenza A Virus. Am J Respir Crit Care Med. 2008. May 15;177(10):1103-10.

Hogaboam JP, Moore AJ, Lawrence BP. 2007. The aryl hydrocarbon receptor affects distinct tissue compartments during ontogeny of the immune system. Toxicol Sci. Mar;102(1):160-170.

Teske S, Bohn AA, Hogaboam JP, Lawrence BP. 2007. Aryl hydrocarbon receptor targets pathways extrinsic to bone marrow cells to enhance neutrophil recruitment during influenza virus infection. Toxicol Sci. Mar;102(1):89-99

Lawrence BP. 2007. Environmental toxins as modulators of antiviral immune responses. Viral Immunol. Summer;20(2):231-242. Review

Lawrence BP. 2007. Environmental toxins as modulators of antiviral immune responses. Viral Immunol. Summer;20(2):231-242.

Neff-LaFord H, Teske S, Bushnell TP, Lawrence BP. 2007. Aryl hydrocarbon receptor activation during influenza virus infection unveils a novel pathway of IFN-gamma production by phagocytic cells. J Immunol. Jul 1;179(1):247-255.

Lawrence BP, Roberts AD, Neumiller JJ, Cundiff JA, Woodland DL. 2006. Aryl hydrocarbon receptor activation impairs the priming but not the recall of influenza virus-specific CD8+ T cells in the lung. J Immunol. Nov 1;177(9):5819-5828.

Vorderstrasse BA, Lawrence BP. 2006. Protection against lethal challenge with Streptococcus pneumoniae is conferred by aryl hydrocarbon receptor activation but is not associated with an enhanced inflammatory response. Infect Immun. Oct;74(10):5679-5686.

Vorderstrasse BA, Cundiff JA, Lawrence BP. (2006) A dose-response study of the effects of prenatal and lactational exposure to TCDD on the immune response to influenza a virus. J Toxicol Environ Health A. Mar;69(6):445-463.

Bohn AA, Harrod KS, Teske S, Lawrence BP. (2005) Increased mortality associated with TCDD exposure in mice infected with influenza A virus is not due to severity of lung injury or alterations in Clara cell protein content. Chem Biol Interact. Aug 15;155(3):181-190.

Schmittgen TD, Gissel KA, Zakrajsek BA, Lawrence BP, Liu Q, Jupe ER, Lerner MR, Do SV, Brackett DJ. (2005) Diverse gene expression pattern during 5-fluorouridine-induced apoptosis. Int J Oncol. Aug;27(2):297-306

Teske S, Bohn AA, Regal JF, Neumiller JJ, Lawrence BP. (2005) Activation of the aryl hydrocarbon receptor increases pulmonary neutrophilia and diminishes host resistance to influenza A virus. Am J Physiol Lung Cell Mol Physiol. Jul;289(1):L111-124.

Lawrence BP, Vorderstrasse BA. (2004) Activation of the aryl hydrocarbon receptor diminishes the memory response to homotypic influenza virus infection but does not impair host resistance. Toxicol Sci. Jun;79(2):304-314.

Vorderstrasse BA, Fenton SE, Bohn AA, Cundiff JA, Lawrence BP. (2004) A novel effect of dioxin: exposure during pregnancy severely impairs mammary gland differentiation. Toxicol Sci. Apr;78(2):248-257.

Neff-LaFord HD, Vorderstrasse BA, Lawrence BP. 2003. Fewer CTL, not enhanced NK cells, are sufficient for viral clearance from the lungs of immunocompromised mice. Cell Immunol. Nov;226(1):54-64.

Mitchell KA, Lawrence BP. (2003) T cell receptor transgenic mice provide novel insights into understanding cellular targets of TCDD: suppression of antibody production, but not the response of CD8+ T cells, during infection with influenza virus. Toxicol Appl Pharmacol. Nov 1;192(3):275-286.

Mitchell KA, Lawrence BP. (2003) Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) renders influenza virus-specific CD8+ T cells hyporesponsive to antigen. Toxicol Sci. Jul;74(1):74-84.

Warren TK, Mitchell KA, Lawrence BP. (2000) Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses the humoral and cell-mediated immune responses to influenza A virus without affecting cytolytic activity in the lung. Toxicol Sci. Jul;56(1):114-123.