Page 387 - The Toxicology of Fishes

Liver Toxicity 367

(A) 100 µm (B) 100 µm

(C) 100 µm (D) 100 µm

FIGURE 7.16 (See color insert following page 492.) In vivo imaging of tumor formation in STII medaka (brightfield
microscopy). Neoplastic response following early life stage exposure of STII medaka to the reference hepatocarcinogen
diethylnitrosamine (DEN). Aqueous bath exposure was of 24-hour duration at 100 ppm DEN. Fish were exposed as 14-
day-old hatchlings and followed serially in a noninvasive manner for 10 months. At 10 months after exposure, a subset of
cohorts developed hepatic tumors (green arrowhead). (A, C) In vivo imaging (brightfield) of hepatic tumor formation (green
arrowheads) in DEN-exposed medaka; shown is an enlargement of the total liver mass, approximately 18% of the total
body length. After anesthesia, the liver was removed and processed for histopathology. Hepatic neoplasm showed mixed
hepatocellular (B) and cholangiocellular (D) carcinomas. Focus of biliary hyperplasia was seen in the same liver; here, a
single layer of biliary epithelium lines large cystic spaces in the liver (D). The opaque white tissue in the brightfield images
(A and B) is ovary; the gut occupies caudal most region of the abdominal cavity.

to bromodichloromethane or chloroform induced bile duct dilatation and cystic enlargement of extrahe-
patic bile passageways (Toussaint et al., 2001a,b). Studies of hepatic carcinogenesis in trout (Hendricks
et al., 1984) and in medaka (Okihiro and Hinton, 1999) have also shown that the intrahepatic biliary
epithelial cells are involved in chronic toxicity. Cholangiomas, cholangiocellular carcinomas, and mixed
hepato- and cholangiocellular carcinomas have been reported (Hinton, 1993b) (Figure 7.16). From this
brief review, it is apparent that the biliary system is a target of xenobiotic-induced toxicity in fishes and
that better understanding of the involved mechanisms is urgently needed.

Factors Influencing Xenobiotic-Induced Liver Injury
Because of its central location in the circulatory system of vertebrates, the liver is a target for many
toxicants, and it receives toxic substances both from intestinal and branchial routes. Further, due to the
large exchange surface at the sinusoidal pole of the hepatic parenchymal cells, together with an array of
uptake systems and transporters at the hepatocyte membrane, the liver is able to efficiently extract
toxicants from the circulation. The toxic chemicals can directly impair liver structures and functions; for
example, by inducing cytotoxic damage and necrosis they can induce toxic effects after being metabolized
into reactive molecules, or they can act indirectly through affecting interactions and signaling between
the various liver cell types. Toxicant action may also impact seemingly unrelated hepatic functions. An
example is provided by the antiestrogenic activity of AhR-binding xenobiotics. Induction of the AhR
pathway by these compounds is associated with a reduced synthesis of hepatic vitellogenin, which is
under the control of estrogen (Anderson, 1996; Navas and Segner, 2000, 2001). This antiestrogenic effect
of AhR-binding xenobiotics is mediated through a cross-talk between the AhR and the ER (Cheshenko
et al., 2007; Ohtake et al., 2003), thereby resulting in a toxicant effect on an unexpected target.