Role of Aryl Hydrocarbon Receptor in Mesencephalic Circulation Failure and Apoptosis in Zebrafish Embryos Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent and potent developmental toxicant in various animals, with developing fish being the most sensitive organisms. Although the expression of aryl hydrocarbon receptor (AHR) as well as the partner molecule, AHR nuclear translocator (ARNT) in the brain has been reported, the effect of TCDD on the brain remains to be clarified in detail. Previously, we reported local circulation failure and apoptosis in dorsal midbrain caused by TCDD in developing zebrafish. In the present experiments, we investigated the effects of morpholino antisense oligos against aryl hydrocarbon receptor 2 (zfAHR2) (AHR2-MO) on toxicological endpoints caused by TCDD in developing zebrafish. AHR2-MO but not its negative homologue (4mis-AHR2-MO) improved TCDD-evoked circulation failure in mesencephalic vein and reduced the occurrence of apoptosis in dorsal midbrain, with concomitant inhibition of CYP1A induction in vascular endothelium. Injection of bovine serum albumin (BSA) into the general circulation, followed by immunohistochemistry with anti-BSA, showed that TCDD raised vascular permeability to albumin in dorsal midbrain, which was blocked by AHR2-MO and N-acetlycystein. In the absence of TCDD, development of embryos injected with AHR2-MO appeared normal at least until 60 h after fertilization. It is concluded that AHR2 activation in the vascular endothelium of the zebrafish embryo midbrain is involved in the mesencephalic circulation failure and apoptosis elicited by TCDD. This is the further evidence that vascular endothelium is the target of TCDD in relation to local circulation failure and apoptosis in dorsal midbrain.

When evolution is the solution to pollution: Key principles, and lessons from rapid repeated adaptation of killifish (Fundulus heteroclitus) populations

“…Fish typically have four AHR genes, products of a tandem gene duplication ( AHR1 and AHR2 ) and paralogs of each of these (designated “a” and “b”), the result of a whole‐genome duplication at the base of the teleost lineage, after its divergence from the lineage leading to tetrapods (Hahn et al., 2006, 2017). The relative roles of each AHR are not yet fully understood, but the AHR2 paralogs appear to mediate many of the toxic and adaptive responses to DLCs and some PAHs (Antkiewicz, Peterson, & Heideman, 2006; Billiard et al., 2006; Clark et al., 2010; Dong, Teraoka, Tsujimoto, Stegeman, & Hiraga, 2004; Goodale et al., 2012; Incardona et al., 2006; Jönsson et al., 2007; Lanham, Prasch, Weina, Peterson, & Heideman, 2011; Prasch et al., 2003; Waits & Nebert, 2011). For some chemicals, however, responses may be mediated by AHR1 (Goodale et al., 2012; Incardona et al., 2006).…”

Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

“…In separate experiments, fish have provided evidence that the vascular endothelium is also a sensitive target for TCDD toxicity, and this may prove important with regards to the human health effects of TCDD. In fish TCDD elicits increased vascular permeability, which in lake trout manifests as yolk sac edema, and in zebrafish as extravascular accumulation of serum proteins in mesencephalic brain tis-sues (Guiney et al, 2000;Dong et al, 2004). Although the precise nature of this microvascular leakage remains to be determined, decreased cardiac output, increased endothelial vacuolation (Guiney et al, 2000), disruption of peripheral vascular beds (Henry et al, 1997) and/or disruption of angiogenic signaling (Bello et al, 2004) have been suggested.…”

Basal and 3,3′,4,4′,5-pentachlorobiphenyl-induced expression of cytochrome P450 1A, 1B and 1C genes in zebrafish

“…Knockout studies show that ligand-activated aryl hydrocarbon receptor (AHR) largely determines the induction of mammalian CYP1As and CYP1B1 (e.g., Shimada et al, 2002). AHR also regulates CYP1As in non-mammalian vertebrates; knock-down of AHR2 in zebrafish (Danio rerio) embryos abolishes induction of the single CYP1A by the potent AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Prasch et al, 2003;Dong et al, 2004). TCDD also induces zebrafish CYP1B1 (Handley-Goldstone et al 2005), presumably via the AHR.…”

“…TCDD also induces zebrafish CYP1B1 (Handley-Goldstone et al 2005), presumably via the AHR. Knockout and knockdown studies show that AHRs mediate TCDD toxicity in mammals and fish (Fernandez-Salguero et al, 1996;Prasch et al, 2003;Dong et al, 2004).…”