CORRELATION OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN INDUCTION OF CYTOCHROME P4501A IN VASCULAR ENDOTHELIUM WITH TOXICITY IN EARLY-LIFE STAGES OF LAKE TROUT
Pd. Guiney et al., CORRELATION OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN INDUCTION OF CYTOCHROME P4501A IN VASCULAR ENDOTHELIUM WITH TOXICITY IN EARLY-LIFE STAGES OF LAKE TROUT, Toxicology and applied pharmacology, 143(2), 1997, pp. 256-273
Edema and cardiovascular dysfunction occur in vertebrates exposed to 2
,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during early development. Th
is study examined cytochrome P4501A (CYP1A) induction in endothelium a
nd its possible association with mortality due to the edema and vascul
ar effects of TCDD in lake trout early life stages. Lake trout (Salvel
inus namaycush) eggs were injected at 24-50 hr postfertilization with
0.2 mu l of 50 mM phosphatidylcholine liposomes or liposomes containin
g TCDD to give seven doses ranging from 11 to 176 pg TCDD/g egg. Doses
of TCDD greater than 44 pg/g egg elicited hemorrhages; yolk sac, peri
cardial, and meningial edema; craniofacial malformations; regional isc
hemia; growth retardation; and mortality at the sac fry stage of devel
opment. Expression of CYP1A was assessed at four developmental stages,
by immunohistochemical analysis of serial sections of individual fish
with monoclonal antibody 1-12-3 to teleost CYP1A. CYP1A staining occu
rred in endothelial cells of many organs of TCDD-exposed but not vehic
le-exposed embryos at 1 week prehatch and sac fry at 2 weeks posthatch
. Earlier developmental stages examined were negative for CYP1A expres
sion at any dose of TCDD. The strongest response occurred in sac fry a
t TCDD doses greater than sg pg TCDD/g egg but was detected at doses a
s low as 22 pg TCDD/g egg. CYP1A staining in endothelium appeared at l
ower doses and was stronger than that in other cell types, in both pre
hatch embryos and posthatch sac fry. Thus, the vascular system is a ma
jor initial site affected by TCDD in lake trout early life stages, and
the vascular endothelium is a cell type uniquely sensitive to inducti
on of CYP1A in these developing animals. Based on an index of immunohi
stochemical staining of CYP1A, endothelial CYP1A induction in sac fry
by TCDD occurred with an ED50 of 64-69 pg TCDD/g egg, similar to the d
ose-response for mortality occurring during the sac fry stage of devel
opment (LD50 = 47 pg TCDD/g egg). The correlations seen here suggest t
hat CYP1A or aryl hydrocarbon receptor (AhR) in the endothelium may be
linked to early lesions that result in TCDD-induced vascular derangem
ents leading to yolk sac, pericardial, and meningial edema that is ass
ociated with lake trout sac fry mortality, but the precise mechanism r
emains to be determined. (C) 1997 Academic Press.