Dioxin activates HIV-1 gene expression by an oxidative stress pathway requiring a functional cytochrome P450 CYP1A1 enzyme.

Abstract

We have studied the effect of several environmental chemicals on the transient expression of a chloramphenicol acetyltransferase (cat) reporter gene linked to the promoter sequences in the long terminal repeat (LTR) of the human immunodeficiency virus type 1 (HIV-1). Aflatoxin B1, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) and benzo[a]pyrene cause a significant increases in CAT expression in mouse hepatoma Hepa-1 cells. The induction of CAT after TCDD treatment is abolished by administration of N-acetyl-L-cysteine or 2-mercaptoethanol and does not take place in a mutant cell line that lacks CYP1A1 enzymatic activity. Linker-scanning mutational analysis of transcription factor binding sites in the promoter revealed that both the NF kappa B and an adjacent aromatic hydrocarbon response element (AhRE) are required for TCDD-dependent CAT expression. In addition, mutation of the NFAT/AP-1 binding sites in the negative regulatory region of the promoter increases the magnitude of the TCDD effect. We conclude that induction of a functional CYP1A1 monooxygenase by TCDD stimulates a pathway that generates thiol-sensitive reactive oxygen intermediates which, in turn, are responsible for the TCDD-dependent activation of genes linked to the LTR. These data might provide an explanation for findings that TCDD increases infectious HIV-1 titers in experimental systems and for epidemiologic reports suggesting that exposure to aromatic hydrocarbons, such as found in cigarette smoke, is associated with an acceleration in AIDS progression.Imagesp366-aFigure 2.Figure 3.Figure 4.Figure 5.

2,3,7,8-Tetrachlorodibenzo-p-dioxin induces apoptotic cell death and cytochrome P4501A expression in developing Fundulus heteroclitus embryos

“…Stimulation of CYP1A and other enzymes can lead to cellular and physiological signs of oxidative stress (Stegeman and Hahn, 1994;Yao et al, 1995) and may contribute to cellular damage and cell death (Kurl et al, 1993;Sakamoto et al, 1995).…”

EZR1: A Novel Family of Highly Expressed Retroelements Induced by TCDD and Regulated by a NF-κB-Like Factor in Embryos of Zebrafish (Danio rerio)

“…45,46 Moreover, TCDD-induced activation of binding of NF-jB in the LTR of HIV occurs through an AHR-and CYP1A1-dependent oxidative signal. 15 Thus, TCDD-induced, AHR-dependent ROS production, whether via a CYP1, COX2, or some other path, is a potential mechanism for both EZR1 activation and cardiovascular toxicity, although not directly investigated here. 47 This is particularly intriguing in light of findings that induction of a novel LINE-1retrotransposon (L1Md-A2) in mouse vascular smooth muscle cells by benzo[a]pyrene also involves a redoxsensitive mechanism.…”

“…[11][12][13][14] Intriguingly, TCDD has been implicated in stimulating retroviral expression, involving both the AHR and NF-jB. 15 Thus, we investigated the regulation of EZR1, examining the promoter region of EZR1 for possible regulatory elements, including those possibly involved in the induction by TCDD and those that could be involved in retrotransposon regulation. Analysis of the promoter region of the EZR1 retroelement failed to disclose any AHR response elements; however, a putative NF-jB binding site is present.…”

Risks and Management of Dioxins and Dioxin-like Compounds in Baltic Sea Fish: An Integrated Assessment

“…in monkeys (Riecke et al 2003). Yao et al (1995) found that TCDD can activate expression of human HIV-1 gene expression in vitro by various mechanisms, stressing the importance such compounds may have in the progression of AIDS, and provided data suggesting two different signal transduction pathways.…”