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Article Excerpt
The Lower North Shore region of the St. Lawrence River is home to a fish-eating population that displays an unusually high body burden of several organochlorines, including polychlorinated biphenyls (PCBs) and dioxin-like compounds (DLCs). We measured biomarkers indicative of liver enzyme induction and investigated the relationship with organochlorine body burden in adult volunteers from this population. We determined plasma concentrations of PCBs and chlorinated pesticides by high-resolution gas chromatography (HRGC) with electron capture detection. DLC concentrations were measured by the dioxin-receptor chemically activated luciferase expression (DR-CALUX) assay and in a subset of participants, by HRGC/high-resolution mass spectrometry. We measured cotinine, D-glucaric acid, and porphyrins in morning urine samples and determined liver CYP1A2 activity in vivo using the caffeine breath test. Neither DLC concentrations as measured by the DR-CALUX nor PCB-153 concentrations, the latter representing total PCB exposure, were correlated with biomarkers of effects. Smoking (morning urinary cotinine concentration) was positively related to CYP1A2 activity as measured by the caffeine breath test (p < 0.01). Liver CYP1A2 activity was in turn negatively correlated with PCB-105:PCB-153 and PCB-118:PCB-153 congener ratios (p < 0.05). Hence, despite the relatively high body burden of PCBs and DLCs in this population, only smoking had a significant correlation with biomarkers of hepatic enzyme induction. Our data are consistent with smoking-induced liver CYP1A2 activity altering heme metabolism and increasing the biotransformation of mono-ortho PCB congeners. Key words: cytochrome P450 CYP1A2, D-glucaric acid, dioxins, enzyme induction, food chain, organochlorine insecticides, polychlorinated biphenyls, porphyrins, smoking.
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Organochlorines (OCs) constitute a family of persistent, lipid-soluble compounds that includes industrial chemicals [e.g., polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB)], pesticides (e.g., DDT, methoxychlor, mirex), and by-products of combustion and various industrial processes [e.g., polychlorodibenzo-p-dioxins (PCDDs) and polychlorodibenzofurans (PCDFs)]. These compounds are released into the environment at southern latitudes and transported to northern regions by long-range oceanic and atmospheric transport processes (Barrie et al. 1992; Macdonald et al. 2000). OCs bioaccumulate in adipose tissues of various species from northern aquatic ecosystems. Biomagnification occurs in food webs, leading to relatively elevated concentrations in species located at the highest trophic levels, including human populations that consume large amounts of sea products (Dewailly et al. 1993; Kiviranta et al. 2002; Sjodin et al. 2000).
The Lower North Shore of the St. Lawrence River, a remote coastal region of Quebec, consists of 15 communities spread over a 400-km shoreline extending from Kegaska to Blanc Sablon (Figure 1). A large proportion of the 6,000 residents relies on fishing for subsistence and consequently consumes large amounts of seafood (Dewailly et al. 1992). Results from surveys conducted since 1990 have indicated that this population is highly exposed to PCBs and to dioxin-like compounds (DLCs) such as 2,3,7,8-substituted PCDDs and PCDFs as well as nonsubstituted and mono-ortho-substituted PCBs, compared to the southern Quebec population (Dewailly et al. 1992; Muckle et al. 1998; Ryan et al. 1997). Food items that contribute the most to this exposure are sea-bird eggs and possibly cod and seal liver (Dewailly et al. 1992; Ryan et al. 1997).
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Exposure to DLCs produces a wide variety of biologic and toxic effects such as teratogenesis, immunosuppression, and tumor promotion, most of them dependent on the activation of the aryl hydrocarbon receptor (AhR) (Mimura and Fujii-Kuriyama 2003; Poland and Knutson 1982; Safe 1990; Van den Berg et al. 1998). We previously reported on a group of 25 individuals from the Lower North Shore of the St. Lawrence River that had a mean total DLC concentration of 250 ng of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxic equivalents (TEQ)/kg plasma lipids, including PCDDs, PCDFs, and nonsubstituted and mono-ortho PCBs (Ryan et al. 1997). Assuming a 20% body fat content in humans, the corresponding body burden would be 50 ng TEQ/kg body weight. In laboratory animals exposed to TCDD, adverse effects (hormonal, reproductive, and developmental) have been observed at body burdens in the range of 28-73 ng TCDD/kg body weight (van Leeuwen et al. 2000), hence suggesting that DLC exposure in this fish-eating population might induce adverse health effects.
To refine the assessment of the health risks possibly related to the body burden of DLCs and other OCs in this fish-eating population, investigators can measure early biologic events such as the induction of drug-metabolizing enzyme activities. Activation of genes coding for biotransformation enzymes such as cytochrome P4501A1 (CYP1A1) and CYP1A2 is a well-known consequence of TCDD binding to the AhR (Walker et al. 1999; Whitlock 1999). Liver CYP1A2 activity in humans can be measured in vivo by a noninvasive method, the caffeine breath test (CBT; Kotake et al. 1982). In this test, CYP1A2 activity is monitored by following the appearance of [sup.13]C[O.sub.2] in exhaled breath resulting from the oxidative demethylation of [3-[sup.13]C-methyl]caffeine (Abraham et al. 2002; Brambilla et al. 1995; Kotake et al. 1982; Lambert et al. 1990). The concentration of D-glucaric acid in urine has also been proposed as a biomarker of exposure to xenobiotics (Brewster 1988; Hogue and Brewster 1991; Pooh et al. 1993). Glucuronidation is a major biotransformation pathway for a wide variety of xenobiotics and drugs, and its induction results in increased excretion of D-glucaric acid (Brewster 1988). Urinary D-glucaric acid excretion has also been shown to increase in humans exposed to OC pesticides (Hunter et al. 1972; Notten and Henderson 1977), PCBs (Maroni et al. 1984), and TCDD (Ideo et al. 1982). Urinary porphyrin excretion can also be altered by exposure to xenobiotics such has PCBs (Colombi et al. 1982), polybrominated biphenyls (Strik et al. 1979), and TCDD (Hoffman et al. 1986; Jung et al. 1994). Provided sufficient exposure dose, all these chemicals induce chronic disturbances in hepatic synthesis of porphyrins and thus lead to excess total porphyrin excretion and skin symptoms in the final stage (Hogue and Brewster 1991). Presumably, these chemicals would also alter urinary porphyrin profile at early stages before overt toxicity, and therefore, the later constitutes a much more sensitive biomarker than total porphyrin determination (Johnson et al. 1988).
In the present study, we measured concentrations of porphyrins and D-glucaric acid in urine samples and performed the CBT in volunteers from two communities located on the Lower North Shore of the St. Lawrence River. We measured plasma lipid concentrations of PCBs and chlorinated pesticides by high-resolution gas chromatography (HRGC) with electron capture detection (ECD) and DLCs by the dioxin-receptor chemical-activated luciferase gene expression (DR-CALUX) bioassay. Finally, because tobacco smoking can induce liver enzyme activities, smoking status was assessed by questionnaire and validated using urinary cotinine measurements.
Materials and Methods
Study population and measurements. We recruited participants in this study from two Lower North Shore settlements: Tete-a-la-Baleine and La Tabatiere (Figure 1). Potential subjects were selected from the list of those who participated in a previous survey (Dewailly et al. 1992), and therefore, their concentration of OCs in plasma lipids was already known. We tried to recruit individuals with both high and low exposure to PCBs. Our research nurse contacted potential subjects by telephone and asked interested individuals to visit their local health center the week after for an information meeting. After a brief medical examination, subjects with cardiac arrhythmia, uncontrolled hypertension, or with...
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