Evaluating impacts of the trichloroethylene metabolite S-(1,2-dichlorovyinyl)-L-cysteine on transcriptomic responses and cytokine release in a macrophage model: implications for pregnancy outcomes.

Abstract

Trichloroethylene (TCE) is a volatile synthetic chemical used in various industrial processes like metal degreasing. Large amounts of TCE have been released into the environment. Exposure to TCE can occur through routes, such as inhalation for workers using TCE or ingestion of drinking water in contaminated areas. Macrophages are key immune cells in virtually all tissues in the human body, including the fetal membranes, making them a plausible target for DCVC-induced immunotoxicity. Macrophages are critical for maintaining anti-microbial defenses during pregnancy, but little data exists on TCE immunotoxicity during pregnancy. We previously showed that the TCE metabolite, S-(1,2-dichlorovinyl)-L-cysteine (DCVC), down-regulates immune functions in fetal membranes. To gain insight into immune functions impacted by DCVC, we treated a macrophage cell model (THP-1 cells) with DCVC followed by stimulation with bacterial or fungal toxins relevant for intrauterine infections: lipopolysaccharide (LPS), lipoteichoic acid (LTA), or zymosan. DCVC inhibited toxin-stimulated release of cytokines (e.g. TNFα and IL-1β) for all three microbial toxins. We then conducted benchmark dose modeling and compared benchmark doses for DCVC cytotoxicity vs. cytokine suppression and determined that inhibition of cytokine release was the more potent endpoint compared to cytotoxicity. Finally, we analyzed a previously generated transcriptomic dataset from THP-1 cells stimulated with LPS, with or without DCVC treatment. We identified transcription factors that were enriched with DCVC and/or LPS treatment, including NF-kB and Vitamin D receptor (VDR). Our findings show that DCVC potently alters cellular and molecular macrophage immune responses involved in defense against intrauterine pathogens.