Page 862 - The Toxicology of Fishes

842 The Toxicology of Fishes

• Necrosis of the retina, brain, liver, and spinal cord
• Domed skulls and foreshortened maxillae
• Arrested development of skeletal and soft tissues

Most importantly, the above signs of TCDD toxicity are probably secondary to circulatory failure
(Spitsbergen et al., 1991). Cardiovascular toxicity is first detected in TCDD-exposed lake trout sac fry
as a reduction in perfusion of certain vascular beds and progresses gradually over a period of several
days to complete cessation of blood flow. Accordingly, necrotic lesions in the retina, brain, liver, and
spinal cord are probably secondary to the ischemia/anemia and hypoxia associated with this develop-
mental cardiovascular toxicity (Spitsbergen et al., 1991). The insidious TCDD-induced circulatory failure
is also considered responsible for the lethargy and arrested soft tissue and skeletal development in half-
hatched embryos and sac fry and is the most probable cause of death. Decreased access to yolk sac
nutrients, secondary to reduced perfusion of the vitelline vasculature, contributes to reduced growth of
the sac fry and to mortality (Heming and Buddington, 1988). These findings of cardiovascular toxicity
as a primary manifestation of TCDD toxicity in salmonines have been confirmed in subsequent mech-
anistic toxicological studies with zebrafish.
These gross and histopathologic signs of TCDD toxicity in lake trout sac fry are strikingly similar to
blue sac disease in hatchery-reared salmonines (Spitsbergen et al., 1991). Both are expressed between
hatching and swim-up culminating in mortality (Wolf, 1954); however, the etiology of blue sac disease
is poorly understood. Physical or chemical stressors such as elevated ammonia, temperature shock, or
hypoxia may trigger it (Ayles, 1974; Balon, 1980; Burkhalter and Kaya, 1977; Lasee, 1995; Wolf, 1969,
as cited in Spitsbergen, 1991). Because the symptomology of blue sac disease (Wolf, 1954) is essentially
identical to that produced by TCDD-like PCBs, PCDDs, and PCDFs in lake trout and other fish species
the term blue sac syndrome has been coined to describe it (Walker and Peterson, 1994).
Spitsbergen et al. (1991) showed in lake trout embryos and larvae exposed to a LD dose of TCDD
100
that mortality was greatest during the sac fry stage (~44%) followed by the hatching stage (~30%).
Mortality of half-hatched TCDD-exposed embryos was apparently caused by their inability to effectively
distribute hatching enzyme throughout the chorion which resulted in their dying only partially removed
from the chorion (Spitsbergen et al., 1991). Some mortality was also detected during the egg stage
(~9%), but it was substantially less than that observed during hatching or at the sac fry stage. Subsequent
studies, conducted at lower egg concentrations of TCDD, have confirmed that mortality during the egg
stage is exceedingly low compared to the sac fry stage (Walker et al., 1991).

Impaired Swim Bladder Inflation
Rainbow trout fry, exposed to TCDD as newly fertilized eggs that developed only mild yolk sac edema
as sac fry, continually swam to remain off the bottom of the tank. This suggested an inability to maintain
swim bladder inflation. A lack of swim bladder inflation is also a sign of TCDD toxicity in early life
stages of Japanese medaka (Oryzias latipes) (Harris et al., 1994) and zebrafish (Danio rerio) (Henry et
al., 1997). This was observed in lake trout embryos from Lake Michigan in the mid- to late-1970s, but
has not been a consistent observation since that time in salmonine fry from Lake Michigan (Mac and
Edsall 1991).

Impaired Cardiovascular Function
The cardiovascular system is a key site of action for TCDD (Cantrell et al., 1996, 1998; Guiney et al.,
1997; Henry et al., 1997; Mizell et al., 1996; Spitsbergen et al., 1991). In TCDD-exposed lake trout,
endothelial cells of yolk sac vessels, dorsal venule, dorsal arteriole, and sinusoidal endothelium of the
liver displayed positive staining for CYP1A1 protein one week prior to hatch (Guiney et al., 1997).
Endothelial cells showed the earliest positive staining for CYP1A1 of any tissue or cell type observed.
A positive correlation between CYP1A induction in vascular endothelial cells and mortality of TCDD-
exposed lake trout sac fry suggests that persistent stimulation of the AhR signaling pathway in the