A Dose-Response Study of the Effects of Prenatal and Lactational Exposure to TCDD on the Immune Response to Influenza A Virus

Abstract

The goal of the current study was to evaluate the immune response to a common respiratory pathogen, influenza A virus, in mice exposed to increasing doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during development. Additionally, the treatment paradigm was designed to provide exposure throughout fetal and neonatal development, beginning on d 1 of gestation. To accomplish this, impregnated C57Bl/6 mice were treated with 0.25 μg/kg TCDD on d 0 and 7 of pregnancy, followed by 2 additional doses of 0.25, 1, or 5 μg/kg given on d 14 and postpartum d 2. The adult offspring were infected with influenza virus, and components of the adaptive and innate immune responses were evaluated. Our results show that developmental exposure to TCDD dose-responsively suppressed both the cell-mediated and antibody responses to influenza virus in female but not males. In contrast, TCDD exposure enhanced the innate immune responses in offspring of both sexes; specifically, neutrophilia and interferon (IFN) γ levels in the lung were increased. These alterations in functional immunity did not result from overt toxicity to the immune organs, as developmental TCDD exposure did not alter the cellular composition of the thymus, spleen, or bone marrow. These findings extend our knowledge of the dose-responsive nature of immunological defects induced by developmental exposure to TCDD and offer insight regarding the dose required to alter the immune response to viral infection. Moreover, we demonstrate a clear dose at which no observable effects on immune function later in life were detected.

This research was supported by research grant 6-FY01-41 from the March of Dimes Birth Defects Foundation, and by a grant from the National Institutes of Environmental Health Sciences, National Institutes of Health (ES10619). The authors thank Sabine Teske, Haley Neff-LaFord, Julie Lopez, and Nicole Harrison for technical assistance.

Notes

This research was supported by research grant 6-FY01-41 from the March of Dimes Birth Defects Foundation, and by a grant from the National Institutes of Environmental Health Sciences, National Institutes of Health (ES10619). The authors thank Sabine Teske, Haley Neff-LaFord, Julie Lopez, and Nicole Harrison for technical assistance.