Environmental signaling, immune function, and cellular development
Environmental signals influence the behavior of cells throughout the body. In some cases this is part of normal physiology, but in other instances environmental signals cue cells to work aberrantly. When this occurs, pathology generally ensues, leading to poorer health. For many chemicals from our environment the mechanisms by which they perturb physiology are largely unknown, and determining these mechanisms forms the basis of most of our research. We have several interrelated projects currently underway.
The aryl hydrocarbon receptor (AhR)
The AhR is a ligand-activated transcription factor that mediates many environmental signals. Its normal function in the body is unknown, but numerous exogenous chemicals bind to AhR, affecting gene expression and cell function. A major focus of our research is to delineate the mechanisms by which the AhR regulates the development and function of the immune system. To accomplish this, we often use influenza viruses, as they are common human pathogens, and because humans exposed to pollutants that bind AhR often have more respiratory illness. We often use the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) because it binds the AhR with very high affinity and causes sustained activation. This makes it a powerful research tool, as we can probe AhR-regulated pathways by exploiting the knowledge gained when they are perturbed. Also, TCDD represents a large group of highly toxic chemicals found throughout the world, and daily low-level exposure to them has been linked to impairment of the immune, reproductive, and endocrine systems. Current projects seek to understand AhR's normal role in, and how pollutants impact, the immune system and developing organs, and include the following projects:
• The role of AhR in immune response to respiratory viral infection
• The role of AhR in programming the developing immune system
• The role of the AhR in mammary gland differentiation and lactogenesis
There is now compelling evidence that developmental exposures to chemicals from our environment lead to disease later in life, and our interest in how environmental signals alter the developing immune system extends beyond AhR and dioxin. We have two additional funded projects in this area.
Neonatal oxygen supplementation and respiratory viral infection
In collaboration with Dr. Michael O'Reilly, we are studying the effects of neonatal oxygen supplementation on pulmonary immune function. Premature infants are often given high oxygen supplementation, which has substantially reduced premature infant mortality. However, even as adolescents, these infants exhibit reduced lung function and are more likely to be re-hospitalized due to respiratory viral infection. Using a mouse model, we are currently determining how neonatal high oxygen treatment disrupts the response to respiratory viral infection. Moreover, we are integrating our research findings with studies of immune responses in infected children who were born prematurely, which we hope will help us identify novel therapeutic opportunities for improving the health of children born prematurely.
Developmental immunotoxicity of bisphenol A (BPA)
BPA is used in the manufacture of polycarbonate plastics and epoxy resins, and is one of the highest volume chemicals produced worldwide. Existing but very limited data indicate that maternal exposure adversely impacts the developing immune system, and this is a cause for concern. Yet, our current inadequate understanding of BPA's developmental immunotoxicity fetters progress toward comprehensive assessment of the human health effects of BPA. To address this we have started a new project in which we will conduct the most detailed analysis to-date of the impact of the BPA on immune system development and function in the context of animal models of human diseases, such as asthma, influenza, and inflammatory bowel disease.
Sifkarovski J, Grayfer L, De Jesús Andino F, Paige Lawrence B, Robert J. "Negative effects of low dose atrazine exposure on the development of effective immunity to FV3 in Xenopus laevis." Developmental and comparative immunology. 2014 Nov; 47(1):52-8. Epub 2014 Jun 28.
2014 Jul 22
Boule LA, Winans B, Lawrence BP. "Effects of Developmental Activation of the AhR on CD4(+) T-Cell Responses to Influenza Virus Infection in Adult Mice." Environmental health perspectives. 2014 Jul 22; Epub 2014 Jul 22.
Jin GB, Winans B, Martin KC, Lawrence BP. "New insights into the role of the aryl hydrocarbon receptor in the function of CD11c? cells during respiratory viral infection." European journal of immunology. 2014 Jun; 44(6):1685-98. Epub 2014 Mar 19.
2014 May 22
Maduekwe ET, Buczynski BW, Yee M, Rangasamy T, Stevens TP, Lawrence BP, O'Reilly MA. "Cumulative neonatal oxygen exposure predicts response of adult mice infected with influenza A virus." Pediatric pulmonology. 2014 May 22; Epub 2014 May 22.
Regal JF, Lawrence BP, Johnson AC, Lojovich SJ, O'Reilly MA. "Neonatal oxygen exposure alters airway hyper-responsiveness but not the response to allergen challenge in adult mice." Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2014 Mar; 25(2):180-6. Epub 2014 Feb 13.