Principal Investigator

B. Paige Lawrence, Ph.D. University of Rochester work Box 850 601 Elmwood Ave Rochester NY 14642 office: MRBX 3-11108 p 585-275-1974 f 585-276-0239

Transgenerational Exposures as Modifiers of Host Defense Against Infection

The objective of this project is to define key parameters involved in transgenerational inheritance of alterations in the function of the mammalian immune system that occur as a result of environmental exposure. Specifically, to determine how exposure of pregnant mothers affects no only their offspring’s immune system, but the immune system of subsequent generations (i.e., not just the F1 and F2 progeny, but also the F3 generation); a phenomenon called transgenerational inheritance. The immune system is fundamentally important to public and individual health, and even slight modifications in its function can have a profoundly negative impact on health and disease. For instance, influenza virus infections pose significant global health threats, infecting over 1 billion people annually. Evidence points to prenatal and early life exposure to pollutants as overlooked contributors to poorer clinical outcomes following influenza and other respiratory infections. However, few studies have examined whether and how environmental exposures that occur in the womb affect the immune system of subsequent generations.

One family of environmental agents for which there is evidence that developmental exposure affects the function of the immune system in humans and animal models is aryl hydrocarbon receptor (AHR) ligands. Early life exposure to the prototype AHR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) profoundly disrupts the response of specific lymphocyte subsets to infection in the F1 generation, and exciting pilot data from our laboratory reveal that lymphocyte function is affected in F2 offspring. Other data support the idea that these changes are due, at least in part, to alterations in DNA methylation. Moreover, TCDD causes transgenerational (F3) effects and altered DNA methylation in other organ systems. Using contemporary, sensitive assays that directly relate to disease outcome, we are characterizing an integrated set of disease-specific T cell responses in the F3 generation, and directly comparing these changes to the modified anti-viral immune response observed in F2 and F1 offspring. This comprehensive analysis includes defining the dose-dependent nature of transgenerational effects on T cell functions, and establishing the ligand-specific nature of immune function changes across generations. We are also defining the developmental window of susceptibility, basis of sex differences, and role of parental origin in transgenerational inheritance of altered immunity to viral infection. In other studies, we are investigating the mechanisms by which AHR ligand exposures transmit aberrant immune function from one generation to the next. This is accomplished in part by identifying genes and gene networks that are altered in a transgenerational manner using genetic, pathway-specific, and genome-wide approaches, and linking these changes to alterations in DNA methylation and other epigenetic regulatory mechanisms.

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