Page 849 - The Toxicology of Fishes

Reproductive Impairment of Great Lakes Lake Trout by Dioxin-Like Chemicals 829

HSP90
zfAHR2 Cytoplasm
TCDD HSP90
AIP
Nucleus
HSP90
AIP
HSP90
zfAHRR1
TCDD
HSP90
HSP90 zfAHR2 HSP90 TCDD TCDD zfAHRR2
AIP HSP90 zfAHR2 zfAHR2 zfARNT1
AIP
AHRE TCDD-responsive genes
zfARNT1 Induced
zfCYP1A
mRNAs
zfAHR1
Unknown
zfARNT2
proteins
Downstream
cellular effects

Endpoints
of toxicity
FIGURE 21.4 Aryl hydrocarbon receptor (AhR) signaling pathway in zebrafish. The AhR and ARNT isoforms marked
with an “X” are not in the functional pathway of AhR-related toxicity in zebrafish, as is the case with zfCYP1A.

Endpoints of TCDD Developmental Toxicity in Fish
Like other fish species, zebrafish embryos exposed to TCDD at the blastula stage develop normally
through gastrulation and primary organogenesis. TCDD toxicity is not manifested until later stages of
development when morphogenesis of primary organ systems and embryo growth occur. For zebrafish,
the early-life-stage period when endpoints of developmental toxicity are first manifested occurs 48 to
120 hours post-fertilization (hpf). If developing zebrafish are exposed to TCDD, prior to or during this
time, TCDD toxicity is manifested 48 to 120 hpf by cardiovascular dysfunction culminating in heart
malformation, peripheral ischemia and eventually heart failure, impaired osmoregulation culminating in
edema, impaired erythropoiesis leading to anemia, hemorrhage, reduced jaw growth and jaw malforma-
tion, altered brain morphology, body growth retardation, uninflated swim bladder, and, beginning around
144 hpf, mortality associated with blue sac syndrome (Antkiewicz et al., 2005; Belair et al., 2001; Bello
et al., 2004; Carney et al., 2006b; Dong et al., 2002; Henry et al., 1997; Hill et al., 2003, 2004a,b;
Teraoka et al., 2002). The gross morphological manifestations of TCDD developmental toxicity in
zebrafish are edema, cardiovascular toxicity, anemia, impaired chondrogenesis, and neurotoxicity.

Edema
The hallmark response to TCDD in the zebrafish embryo is the accumulation of edema fluid in the
pericardium beginning at 72 hpf and in the yolk sac beginning at 96 hpf (Belair et al., 2001; Dong et
al., 2002; Henry et al., 1997; Hill et al., 2004a). The edema may be caused by TCDD-induced disruption
of osmoregulatory or circulatory function. In the zebrafish embryo, osmoregulation is carried out by the
pronephric kidney and skin (Drummond et al., 1998; Hagedorn et al., 1998; Rombough, 2002). Also,
due to the close association between osmoregulatory function of the skin and kidney and circulatory
function of the heart and vasculature, edema may be secondary to cardiovascular dysfunction. The gills
are less likely to be involved because their osmoregulatory function does not occur until later, after the
critical period for TCDD developmental toxicity has passed. Although glomerular filtration is largely
unaffected by TCDD prior to edema (Hill et al., 2004a), peripheral blood flow is reduced (Carney et al.,