2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) enhances placental inflammation

Abstract

Preterm birth is a leading cause of perinatal morbidity and mortality that is often associated with ascending infections from the lower genital tract. Recent studies with animal models have suggested that developmental exposure to the environmental toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can increase the risk of preterm birth in the offspring. How TCDD may modify placental immunity to ascending infections is unclear. Therefore, we studied the effects of TCDD treatment on basal and Escherichia coli-stimulated cytokine production by placental explants. Cultures of second-trimester placentas were treated with up to 40 nM TCDD for 72 h and then stimulated with 107 CFU/ml E. coli for an additional 24 h. Concentrations of cytokines and PGE2 were measured in conditioned medium by immunoassay. TCDD exposure increased mRNA levels of IL-1β by unstimulated cultures, but no effects on protein levels of this cytokine were detected. TNF-α production was unaffected by TCDD for unstimulated cultures, but pre-treatment with 40 nM TCDD significantly increased E. coli-stimulated TNF-α production. Both basal and bacteria-stimulated PGE2 and COX-2 gene expression were enhanced by TCDD pretreatment. In contrast, production of the anti-inflammatory cytokine, IL-10, was reduced by TCDD pretreatment for both unstimulated and E. coli-stimulated cultures. No effect of TCDD on the viability of the cultures was detected. These results suggest that TCDD exposure may shift immunity to enhance a proinflammatory phenotype at the maternal–fetal interface that could increase the risk of infection-mediated preterm birth.

Metatranscriptomic Analysis of the Mouse Gut Microbiome Response to the Persistent Organic Pollutant 2,3,7,8-Tetrachlorodibenzofuran

“…Circulating LPS in mice treated with 24 µg/kg BW TCDF was significantly higher than the control after a pairwise t test with a Bonferroni correction to account for multiple comparisons (p = 0.031). An increase in LPS levels after TCDF exposure has been previously described [9], and additional increases in inflammatory factors like Tnf-α, IL-1β, and IL-10 have been reported [9,[35][36][37]. In Figure 6B, cecal LPS was investigated and surprisingly there was a significant decrease in cecal LPS (1.61 times lower, p = 0.038) after 24 µg/kg BW TCDF as compared to the control.…”

“…LPS is primarily created by gram-negative bacteria, so the increase of LPS production after TCDF treatment is further supported by a significant increase in the gram-negative genus Parasutterella (Figure 2). Previous studies by our group and others noted that dietary TCDF (at 24 µg/kg body weight TCDF) and TCDD caused increases of inflammatory markers, like IL-1β, IL-10, TNF-α, LCN-2, and IgA [9,[35][36][37]. Additionally, it has been reported that increased levels of circulating LPS can increase gut inflammation and contributes to obesity in rodents [19,38].…”

Instrumenting a Fetal Membrane on a Chip as Emerging Technology for Preterm Birth Research

“…We and others have observed that environmental toxicants may cause disruptions of immune-endocrine pathways during infection-related processes which may contribute to disease pathogenesis, although, human epidemiological data has been less conclusive (76)(77)(78). Animals models have shown that environmental toxicant exposures, such as endocrine disputing chemicals such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD or dioxin) enhance the inflammatory response of pregnant dams resulting in a high incidence of spontaneous preterm birth in response to low level lipopolysaccharide (LPS) stimuli compared to vehicle treated controls (79,80).…”

Toxicant Disruption of Immune Defenses: Potential Implications for Fetal Membranes and Pregnancy

“…For example, some PBDEs increased E. coli-stimulated IL-1β and IL-6 secretion and COX-2 expression, as well as reduced E. coli-stimulated IL-10 release in human placental explants (Peltier et al, 2012;Arita et al, 2018c). Similarly, TCDD increased bacteriastimulated PGE 2 and COX-2 gene expression and decreased IL-10 secretion (Peltier et al, 2013). Notably, the PBDE and TCDD effects were observed in the absence of impacts on explant viability and in placenta tissue obtained from both term (Arita et al, 2018c) and preterm (Peltier et al, 2012(Peltier et al, , 2013 stages of pregnancy, suggesting that immunomodulatory effects can occur throughout gestation.…”