Page 568 - The Toxicology of Fishes

548 The Toxicology of Fishes

cell growth, in the vulva and cervix, which can progress to cancer. These tumors often have viral oncogene
sequences integrated into the cellular DNA. Examples include the viral E6 and E7 proteins from HPV
that bind to and inactivate the p53 gene and Rb genes, respectively, leading to various tumor types
(Orjuela et al., 2000); the hepatitis B virus, which alters the ras gene and ultimately leads to hepatocellular
carcinoma (Kim et al., 2001); and the Epstein–Barr virus, which alters the expression of p53 and can
lead to papilloma formation (Katori et al., 2006). DNA tumor viruses, similarly to certain classes of
chemical contaminants, can therefore act as initiating agents of certain cancer types as well as act in the
progression of others, although no specific DNA tumor virus action in fish has been investigated to date.
Among fishes, the research effort to date has primarily focused on understanding the retroviral
etiologies of various types of cancers and has not addressed the interplay between viral and chemical
interactions leading to carcinogenesis. Examples include lymphomas in northern pike (Esox lucius)
(Sonstegard, 1976), plasmacytoid leukemia in Chinook salmon (Oncorhynchus tshawytscha) (Eaton and
Kent, 1992), dermal sarcoma in walleye (Stizostedion vitreum) (Bowser et al., 1988), probable viral-
induced papillomas in brown bullheads (Ictalurus nebulosus) and white suckers (Catostomus commer-
soni) (Baumann et al., 1996), viral-induced neurofibromatosis in bicolor damselfish (Stegastes partitus)
(Rahn et al., 2004), retroviral-induced swim bladder sarcomas in Atlantic salmon (Paul et al., 2006),
and retroviral-induced dermal sarcoma in moray eel (Gymnothorax funebris) (Buck et al., 2001). Addi-
tional studies have strongly suspected, though failed to isolate, a viral infectious agent in the development
of fish tumors. Occasionally, a viral etiology is suspected and ruled out using reverse transcriptase activity
as an indication of viral involvement. An example is the pigmented subcutaneous spindle cell tumors
that affect up to 25% of selected gizzard shad (Dorosoma cepedianum) sampled from the Lake of the
Arbuckles (Jacobs and Ostrander, 1995; Geter et al., 1998; Ostrander et al., 1995).
Combined, such studies demonstrate that fish are susceptible to retrovirally induced events, although
the action of DNA tumor viruses has yet to be investigated. This action may contribute to the multistep
progression of the carcinogenesis process in a manner similar to mammalian models. In terms of the
mechanism of DNA tumor virus-induced cancers, one might again consider the fish protooncogene and
tumor suppressor genes as likely targets. High conservation of the ras, p53, and Rb gene sequences in
fish suggests that they may be similarly susceptible to viral activation and inactivation. Indeed, the Rb
E1A viral binding domain is one of many structurally conserved domains observed in the medaka Rb
gene (Rotchell et al., 2001a).

Epigenetic Carcinogens

In addition to genotoxic impacts via direct interaction with DNA structure, it is also now well established
that multistage chemical carcinogenesis in mammals includes processes under the control of a variety
of epigenetic events. Precise mechanisms are still under investigation and have yet to be explored in any
depth using fish models. Epigenetic events include those where early changes are induced by carcinogens
in target cells and are often tied closely with cell cycle growth: proliferation or programmed cell death,
or both (Schneider and Kulesz-Martin, 2004). Several mechanisms have been investigated in mammals.
One is the inhibition of apoptosis which helps altered cells escape cell death and adopt a tumorigenic
phenotype (Nguyen-Ba and Vasseur, 2006). Tumor suppressor p53, for example, is often altered by
methylation (as well as by mutation) in certain kinds of human cancers (Agirre et al., 2003). Upregulation
of oncoproteins by epigenetic events is another possibility, as is carcinogens binding to and disabling
the proofreading enzyme involved in generating new DNA strands (Bignold, 2003). These are all
examples of epigenetic mechanisms.
Investigations into epigenetic mechanisms in fish are few. The roles of DNA and histone methylation
and transposable element excision have been examined in aquaria-held zebrafish and medaka fish
developmental studies (Iida et al., 2006; Rai et al., 2006), although not as yet in any carcinogenesis
application. In an environmental application, methylation status in the CYP1A gene promoter of fish
sampled from the creosote-contaminated Elizabeth River in Virginia has also been investigated by Timme-
Laragy et al. (2005), who postulated that methylation status might account for apparent CYP1A unin-
ducibility but found no such evidence to confirm this. In another study of liver toxicity and carcinogenicity
of flounder from the German Wadden Sea coast, investigators failed to find gene mutations and instead