Toxicant Exposure Impacts Host-pathogen interactions within the Reproductive Tract

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Project Summary Exposure to persistent environmental toxicants (such as dioxin) is a global problem, but disproportionately affects Veterans who were exposed dioxin derived from burn pits or Agent Orange. Dioxin exposure has been linked to diminished fertility and an increased risk of preterm birth in both males and females, even when the exposure occurred in utero. Recent studies indicate that female Veterans have increased risk of preterm birth associated with recent deployment, underscoring the need for better diagnostics and interventions to eliminate the risk of preterm birth associated with the unique environmental stressors encountered by Veterans. However, little is known about the underlying molecular factors that contribute to this risk. We hypothesize that exposure to environmental toxicants leads to perturbations in the host immune system programme which lead to increased susceptibility to inflammatory insults (such as infection) that can lead to preterm birth. Streptococcus agalactiae or Group B Streptococcus (GBS) is a bacterium that can cause invasive reproductive tract infections that lead to preterm birth. We have new and exciting data indicating females exposed to toxicant have increased susceptibility to GBS infection leading to adverse pregnancy outcomes. We also have strong data showing that toxicant exposure alters placental macrophage antimicrobial activity such as reactive oxygen species production, and GBS survival within macrophages. We also have strong data which supports that macrophages are critical mediators of immune homeostasis during pregnancy that also play a role in invasive GBS infections. Placental macrophages elaborate extracellular traps in response to GBS infectious insult and these traps are decorated with matrix metalloproteinases which are involved in the degradation of cell-to-cell matrices in gestational tissues that are important for maintaining a stable pregnancy. This translational research seeks to understand how toxicant exposure alters host susceptibility to preterm birth (using invasive infection as a model) and contributes to disease progression by modulating the host immune system. This knowledge may lead to new approaches for the prevention and treatment of reproductive tract infections which often lead to preterm birth, neonatal sepsis, maternal bacteremia, and fetal demise as well as ameliorate fertility issues associated with toxicant exposure.