Organohalogen concentrations and a gross and histologic ...

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available, and hence the intake of 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD; 2378-T4D) in East Greenland polar bears during this period could
not be evaluated.
Metabolism
The mixed function oxidase (MFO) subenzyme cytochromes P-450 isozymes
(CYP1A, CYP2B, CYP3A, CYP2E) and epoxide hydrolase located in the
smooth endoplasmatic reticulum and microsomes is a ubiquitous group of
enzymes in mammals that plays a central role in the oxidative biotransformation
(Phase 1; hydroxylation) of organohalogens and other xenobiotics
in polar bears and other mammals (e.g. Boon et al. 1992, Goksøyr and
Förlin 1992, Stegeman and Hahn 1994, Goksøyr 1995, Letcher et al. 1996,
Parkinson 1996, Lewis et al. 1998, Lewis 2000, O’Hara et al. 2001). When organohalogens
are metabolised into even more toxic substances (e.g. PCBs to
HO-PCBs and MeSO 2 -PCBs; DDTs to DDE) these are retained in the body
through blood-protein binding and/or reaccumulated in adipose tissue (e.g.
Letcher et al. 2000, Guvenius et al. 2002) which is also the case for the East
Greenland polar bears investigated in the present thesis (e.g. Dietz et al. 2004,
Sandala et al. 2004). The microsome Phase 2 conjugation (e.g. glucuronidation
and sulfation) increases the water solubility and thereby facilitates elimination
via renal filtration or entero hepatic excretion (e.g. Parkinson 1996). As the
CYP-isozymes are upregulated through exposure to organohalogens, this
subcellular system has been used as a biomarker for organohalogens in several
species (e.g. Boon et al. 1992, Wong et al. 1992, de March et al. 1998, O’Hara
et al. 2001, AMAP 2004) and to date correlation studies of biomarkers in polar
bears have mainly been on thyroid hormones (T 3 /T 4 ), retinol (vitamin A) and
sex steroids (e.g. Sandau 2001, Skaare et al. 2001).
Toxicity
The physical and chemical properties of organohalogens are determined by
the number of halogen atoms and their positioning in the biphenyl ring, and
the individual characteristics determine the biological activity of the individual
congeners (de March et al. 1998). Common for the toxicity of organohalogens
are endocrine disruption through their xenobiotic activity in the
subcellular enzyme CYP-systems and through their steroid and peptide hormone
structures which is similar to several mammal steroid and peptide hormones
(e.g. de March et al. 1998, AMAP 2004). The subcellular organohalogen
endocrine disruption is mediated through the cytosolic Ah(arylhydrocarbon)receptor
inducing the subsequent gene (DNA) interaction that results in the
expression of CYP-related proteins and enzymes (e.g. Poland and Knutson
1982, Safe 1984, Safe 1986, Borlakoglu and Haegele 1991, Safe 1991, Colborn et
al. 1993, Safe 1994, de March et al. 1998, Damstra et al. 2002, AMAP 2004). The
CYP1A and CYP1B type enzymes can bioactivate endogenous compounds in
the body to toxic forms (e.g. 17β-estradiol and estrone into carcinogenic 4hydroxyestrogens)
which may be highly carcinogenic or disrupting the homeostasis
of estrogen hormones (e.g. van Duursen et al. 2003). The CYP1A and
CYP1B type enzymes can also bioactivate exogenous compounds (anthropogenic)
in the body to toxic forms (e.g. PCB congener substrates into OH-
PCB and other metabolites), which may be endocrine active, carcinogenic or
can themselves induce or influence other types of cellular gene expression
(Ibid.). These properties have the potential of inducing osteoporosis, histopathological
changes, immunosuppression, reduced reproductive success,
Cushing’s syndrome, skin lesions, promotion of carcinogenesis etc.