Insulin Levels, Diabetes, PCBs and Dioxin

Insulin levels may be impacted by PCB and dioxin exposures, leading to Diabetes.

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The Diabetes Studies --- 34 to 66
linking Diabetes with PCBs and Dioxins

This is not a complete list of all studies on insulin levels and exposure to PCBs and Dioxin. For more studies, visit the TOXNET database operated by the National Library of Medicine (the source of these abstracts).

Study #34

enzyme activity was increased by PCBs in certain strains of mice and rats
enzyme activity was decreased by PCBs in guinea pigs
enzyme induction involves the Ah receptor
study used PCBs 126 and 52

We examined the in vivo effect of a highly toxic coplanar polychlorinated biphenyl (PCB) on the hepatic activity of glucose 6-phosphate dehydrogenase (G6PDH) in aryl hydrocarbon (Ah)-responsive (C57/BL) and -less-responsive (DBA) strains of mice. The activity in the C57BL strain was moderately increased by 3,3',4,4',5-pentachlorobiphenyl (PCB 126) in a dose dependent manner. However, this was not observed in DBA mice although greater doses were injected. 2,2',5,5'-Tetrachlorobiphenyl (PCB 52) with a non-planar structure did not increase G6PDH activity. The increase in G6PDH activity with PCB 126 was also seen in rats, but not in guinea pigs. The activity in the latter species was decreased rather than increased. These results suggest that the induction of hepatic G6PDH by coplanar PCB is mediated by a mechanism involving the Ah receptor, and the response was highly species-specific. (Hori et al, 1997)

Study #35

PCBs may shift rats toward urea formation rather than glucose synthesis and nitrogen retention

The influence of Aroclor 1254 (ARO) treatment or pair-feeding (PF) on gluconeogenesis and urea synthesis and on isolated hepatic mitochondria was studied in rats of different ages. ARO (300 mg/kg, po on 4 consecutive days) induced variable weight loss in young (153 +/- 10 g (initial wt), -10.9%), intermediate-age (195 +/- 10 g, -17.0%), and old (232 +/- 23 g, -4.9%) rats. Isolated mitochondria contained equal amounts of cytochromes aa3, b, c1 and c with exception that c1 and c were lower in the young ARO rats than in the PF controls. Mitochondria from ARO rats, which lost more weight than ad libitum-fed (AF) rats, showed suppression of ADP-stimulated H+ and oxygen uptake and succinate plus valinomycin maximal swelling in a potassium acetate and sucrose medium. Mitochondria from young ARO rats absorbed less incident light than mitochondria from PF or AF rats. Maximally swollen mitochondria from intermediate-age ARO rats, contracted more rapidly with antimycin addition than those from PF or AF controls. These findings showed greater permeability of ARO mitochondria to impermeable and accumulated ions. In contrast, mitochondria from ARO rats without significant weight loss showed activation of ADP-stimulated H+ and oxygen uptake and maximal swelling in comparison to mitochondria from AF and PF rats, but contracted like these controls after the antimycin addition. Urea synthesis in ARO rats, which lost 9.9% of initial body wt (173 +/- 6 g) and experienced a nitrogen deficit (Ebner et al., 1986), was significantly increased 12 min postinjection of NH4 acetate, and was greater than the urea level in AF rats at this time point. In comparison, gluconeogenesis was significantly increased in AF rats 12 min postinjection of NH4 acetate and was greater than in ARO rats at this time point. These differences were also observed when the data were expressed as the rate of glucose or urea appearance in peripheral blood per 100 g body wt. In PF rats, blood glucose and urea concentrations were intermediate to and indistinguishable from the ARO and AF groups. These data demonstrate that hepatic mitochondria from ARO rats that experienced a significant loss of body weight were suppressed and more permeable to ions than AF and PF controls. These mitochondrial properties may have predisposed the ARO rats toward urea formation rather than glucose synthesis and nitrogen retention. (Ebner et al, 1987a)

Study #36

loss of nitrogen by the ARO group was attributed to increased excretion of urinary nitrogen, most likely as urea, in relation to the nitrogen intake

Nitrogen balance and the efficiency of retaining assimilated dietary nitrogen (biological value) were evaluated in Aroclor 1254-treated (ARO) rats and in vehicle-treated, pair-fed (PF) and ad libitum-fed (AF) rats (150-190 g). ARO-treated rats (300 mg/kg/day, po on 4 consecutive days) lost weight and consumed less chow than the AF group while the weight of the PF rats was not different from those of either the ARO or AF groups. The nitrogen balance and the biological value for the ARO rats were also significantly less than those of the AF rats whereas the PF controls were not different. The ingested calories (expressed in kcal/(kg body wt)0.73) by the ARO and PF rats were equal, but were less than those of the AF group. The ARO and PF groups excreted the same amounts of fecal nitrogen which were less than the fecal nitrogen excretion by the AF rats. The absorbed fraction of the ingested nitrogen was the same among all groups, which indicated that the digestibility and absorption of the dietary nitrogen were not changed. By contrast, the ARO group excreted the same amount of urinary nitrogen and urea as AF rats while the PF group excreted significantly less urinary nitrogen than the latter controls. Thus, the loss of nitrogen by the ARO group was attributed to increased excretion of urinary nitrogen, most likely as urea, in relation to the nitrogen intake. The nitrogen retention and balance in rats with ARO exposure are similar to the response in rats fed a diet of low biological value except that the influence of ARO on nitrogen metabolism occurred during the postabsorption phase. (Ebner et al, 1987b)

Study #37

lipids influence the action of PCBs

Epididymal adipocytes, isolated from rats pretreated with [14C]-2,4,5,2',4',5'-hexachlorobiphenyl (6-CB), were utilized to examine the relationship between the mobilization of lipid and 6-CB and to determine whether 6-CB was differentially associated with subcellular organelles over time as has been demonstrated for newly synthesized lipid. Lipolysis, induced by the presence of 8 X 10(-7) M isoproterenol (ISO) for 50 min, depleted approximately 1% of total cellular triacylglycerols (TG) regardless of time from treatment with 6-CB. The percentage of cellular 6-CB released from adipocytes to incubation buffer infranatants was not correlated with the magnitude of lipolysis produced over the 50-min incubation period; nor was the percentage of 6-CB released to the buffers correlated with the length of the incubation period, regardless of the presence of ISO. Although adipocytes responded similarly to lipolytic stimuli independent of time (days) since 6-CB treatment, significant decreases were found in the percentage of 6-CB released from adipocytes over time. The in vitro labeling of this newly synthesized TG in fat cells with [U-14C]glucose or [1-14C]palmitate demonstrated that TG was differentially distributed among adipocyte organelles. Newly synthesized TG was also the first to be mobilized under lipolytic stimulus. 6-CB was not released in a similar fashion, since radioactivity associated with the chemical levels of [14C]-6-CB and glucose-derived 14C in buffers were not correlated over time. 6-CB was found to redistribute to all available lipid pools during the subcellular fractionation procedure and thus did not resemble TG. However, it is possible that 6-CB may exist in equilibrium among organelle fractions and that it becomes sequestered within the nonsoluble lipid compartment with time, thus decreasing its appearance in the soluble buffer infranatants over the experimental time course. (Gallenberg et al, 1987)

Study #38

PCBs, which induce hepatic P-450, had no effect on salicylate-induced nephrotoxicity nor on the covalent binding of [14C]salicylate equivalents to renal mitochondria

A previous study in this laboratory demonstrated that greater nephrotoxicity was induced by 500 mg/kg [14C]salicylate in 12-month-old male Sprague-Dawley rats than in 3-month-old animals, and the increased nephrotoxicity was correlated with greatly increased binding of radioactivity to the renal mitochondria in the older rats. To determine the role of reactive intermediate generation in salicylate-induced nephrotoxicity, male Sprague-Dawley rats were pretreated with piperonyl butoxide, phenobarbital, or Aroclor prior to the administration of 500 mg/kg [14C]salicylate. In the kidneys of rats pretreated with only corn oil, mitochondrial macromolecules contained 57% of the total covalently bound radioactivity while in the livers of these same animals, microsomes contained most (52%) of the bound radioactivity. Pretreatment with piperonyl butoxide, an inhibitor of mixed function oxidase activity, decreased (a) salicylate-induced nephrotoxicity; (b) the covalent binding of [14C]salicylate equivalents to renal mitochondria; and (c) the formation of the 2,3- and 2,5-dihydroxybenoic acid metabolites of salicylate. Pretreatment with phenobarbital and Aroclor, inducers of hepatic P-450, on the other hand, had no effect on salicylate-induced nephrotoxicity nor on the covalent binding of [14C]salicylate equivalents to renal mitochondria. These data are consistent with the hypothesis that salicylate is metabolized to reactive intermediates that irreversibly bind to renal mitochondria and lead to salicylate-induced nephrotoxicity. (Kyle et al, 1986)

Study #39

PCBs increased inner membrane permeability and fragility of hepatic mitochondria
PCBs are correlated with hypoglycemia and suppressed glucogenesis
PCB exposure poises hepatic mitochondria toward the synthesis of urea intermediates
study used PCB commercial mixture Aroclor 1254

Previous studies have shown that the polychlorinated biphenyl mixture, Aroclor 1254 (ARO), -induced wasting in male rats is associated with increased permeability of hepatic mitochondria. This was correlated with hyperuremia and stimulated urea synthesis, hypoglycemia and suppressed glucogenesis after an ammonium acetate injection, and decreased retention of assimilated nitrogen and food intake. For ARO-toxic rats (100 mg/kg, ip, for 1, 2, and 4 days) versus Tween 80-treated, ad libitum-fed controls, mitochondrial carbamoyl phosphate (CP) formation (the initial step in urea synthesis from NH4+) was progressively stimulated for the duration of treatment from NH4+ and ATP but not from NH4+ and ADP. ARO maximal stimulation of CP formation also correlated with significant loss in body weight. Mitochondrial ornithine transcarbamoylase synthesis of citrulline from ornithine and carbamoyl phosphate was also stimulated. In comparison to fasted rats (24 hr), mitochondrial CP synthesis from NH4+ was enhanced with ADP but not with ATP. This ARO uncoupling of mitochondrial NH4+ metabolism and stimulation of CP formation with exogenous ATP and citrulline synthesis may have resulted from increased availability of substrates and cofactors in the matrix space, leakage of enzymes from the matrix, or a combination of these effects. These results are consistent with an increased inner membrane permeability and fragility during isolation and assays. In agreement with our previous studies, the data show that ARO exposure poises hepatic mitochondria toward the synthesis of urea intermediates.

(Ebner et al, 1988)

Study #40

PCBs cause liver glycogen islets to disappear and dramatic local alterations of mitochondrial cristae

The cytotoxicity of a commercial PCB mixture, Aroclor 1254, was assessed on cultured foetal rat hepatocytes. Under control conditions, dexamethasone stimulates immature hepatocytes to differentiate into both hepatocytes and biliary epithelial cells. Consequently, foetal rat hepatocytes maintain, in vitro, a liver-like organization with spaces corresponding to the lumen of biliary canalicules, many mitochondria, and a well-developed rough endoplasmic reticulum (RER). This in vivo-like organization of cultured rat hepatocytes remains unchanged in medium supplemented with Aroclor 1254 at concentrations below 25 microM. In the 25-125 microM concentration range, however, PCBs severely alter some cellular organelles, notably causing important development of the RER and the appearance of cytoplasmic lacunae containing laminated concentric membrane arrays. In addition, the number of lipid droplets increases, the glycogen islets disappear, and dramatic local alterations of the mitochondrial cristae occur. In exposed and unexposed cells, the following biochemical parameters were measured: the DNA content, protein synthesis, lipid peroxidation, and urea formation. The results show that Aroclor 1254 at concentrations exceeding 25 microM (but not at lower concentrations) causes irreversible damage to cultured hepatocytes. The observed ultrastructural modifications are in good agreement with several in vivo studies on rat liver. Thus, isolated foetal rat hepatocytes have considerable potential as an alternative to whole animals for use in (eco)toxicological studies. (Thome et al, 1995)

Study #41

dioxin is associated with an increased prevalence of diabetes and hyperinsulinemia in non-diabetic subjects (certain PCBs are dioxin-like)
high blood dioxin levels may cause insulin resistance

High exposures of Vietnam veterans to 2,3,7, 8-Tetrachlorodibenzo-p-dioxin, a dioxin contained in the herbicide mixture Agent Orange, have previously been demonstrated to be associated with an increased prevalence of diabetes and hyperinsulinemia in non-diabetic subjects. Sixty-nine persons were identified who were in good health and had normal glucose levels during glucose tolerance testing. These subjects lived within 25 miles of the Vertac/Hercules Superfund site located in Jacksonville, Arkansas. The blood sera lipid concentrations of TCDD for the 69 subjects ranged between 2 and 94 ppt. When subjects with blood sera lipid TCDD levels in the top 10% (TCDD > 15 ppt, n = 7) were compared to subjects with lower levels (2-15 ppt, n = 62), there were no group differences in age, obesity, gender distribution, total lipids, or glucose levels. However, plasma insulin concentrations, at fasting and 30, 60, and 120 min following a 75 g glucose load, were significantly higher in the group with high blood TCDD levels. These finding could not be explained by other known risk factors for hyperinsulinemia. The finding of the TCDD-hyperinsulinemia relationship is consistent with studies of Vietnam veterans and suggests that high blood TCDD levels may cause insulin resistance. (Cranmer et al, 2000)

Study #42

dioxin is associated with increased diabetes incidence, at background levels of dioxin exposure

Data from several epidemiologic studies suggest that exposure to unusually high amounts of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) increases the risk of diabetes mellitus, and experimental data suggest that the mechanism for this is decreased cellular glucose uptake. To investigate the dose-response relation more closely, we examined the association of serum dioxin level with prevalence of diabetes mellitus and with levels of serum insulin and glucose among 1,197 veterans in the Air Force Health Study who never had contact with dioxin-contaminated herbicides and whose serum dioxin level was within the range of background exposure typically seen in the United States (< or =10 ng/kg lipid). Compared with those whose serum dioxin level was in the first quartile (<2.8 ng/kg lipid), the multivariate-adjusted odds of diabetes among those in the highest quartile (> or =5.2 ng/kg lipid) was 1.71 (95% confidence interval = 1.00-2.91). The association was slightly attenuated after adjustment for serum triglycerides. Whether adjustment for serum triglycerides was appropriate, however, cannot be determined with available data. The association of background-level dioxin exposure with the prevalence of diabetes in these data may well be due to reasons other than causality, although a causal contribution cannot be wholly dismissed. (Longnecker et al, 2000)

Study #43

diabetes was found in six of 10 (60%) workers with current serum dioxin concentrations > 1500 pg/g lipid
dioxin significantly increased adjusted mean serum glucose concentration
dioxin may affect glucose metabolism

Some studies suggest that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) may affect glucose metabolism and thyroid function. To further assess the relation between exposure to TCDD and endocrine function, data from the largest morbidity study of industrial workers exposed to TCDD were examined. A cross sectional study of workers employed > 15 years earlier in the manufacture of 2,4,5-trichlorophenol or one of its derivatives at two United States chemical plants was conducted. The referent group consisted of people with no occupational exposure to phenoxy herbicides and were recruited from the neighbourhoods where the workers lived. A total of 281 workers and 260 unexposed referents participated. The mean current serum lipid adjusted TCDD concentration among workers was 220 pg/g lipid, and among referents was 7 pg/g lipid (p < 0.05). The half life extrapolated TCDD concentrations (the estimated TCDD concentration when occupational exposure to TCDD stopped) among workers averaged 1900 pg/g lipid (range: not detected--30,000 pg/g lipid). Overall, the prevalence of diabetes mellitus was not significantly different between the workers and referents. Also, there was not a significant positive trend between prevalence of diabetes and increasing serum TCDD concentration. However, diabetes was found in six of 10 (60%) workers with current serum TCDD concentrations > 1500 pg/g lipid. After excluding subjects being treated for diabetes, workers in the group with the highest half life extrapolated TCDD concentrations had a significantly increased adjusted mean serum glucose concentration compared with referents (p = 0.03). Workers were also found to have a significantly higher adjusted mean free thyroxine index compared with referents (p = 0.02), especially among workers in the group with the highest half life extrapolated TCDD concentrations. However, no evidence was found that workers exposed to TCDD were at increased risk of thyroid disease. These findings provide modest evidence that exposure to TCDD may affect thyroid function and glucose metabolism. (Calvert et al, 1999)

Study #44

diabetes (any mention on the death certificate) showed a negative dioxin exposure-response trend

In 1997, the International Agency for Research on Cancer classified 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a group 1 human carcinogen, based largely on four highly exposed industrial cohorts that showed an excess of all cancers combined. In this study, we extended the follow-up period for the largest of these cohorts by 6 years and developed a job-exposure matrix. METHODS: We did cohort mortality analyses involving 5132 chemical workers at 12 U.S. plants by use of life table techniques (U.S. population referent) and Cox regression (internal referent). We conducted exposure-response analyses for 69% of the cohort with adequate work history data and adequate plant data on TCDD contamination. All P values are two-sided. RESULTS: The standardized mortality ratio (SMR) for all cancers combined was 1.13 (95% confidence interval = 1.02-1.25). We found statistically significant positive linear trends in SMRs with increasing exposure for all cancers combined and for lung cancer. The SMR for all cancers combined for the highest exposure group was 1.60 (95% confidence interval = 1.15-1.82). SMRs for heart disease showed a weak increasing trend with higher exposure (P = .14). Diabetes (any mention on the death certificate) showed a negative exposure-response trend. Internal analyses with Cox regression found statistically significant trends for cancer (15-year lag time) and heart disease (no lag). CONCLUSIONS: Our analyses suggest that high TCDD exposure results in an excess of all cancers combined, without any marked specificity. However, excess cancer was limited to the highest exposed workers, with exposures that were likely to have been 100-1000 times higher than those experienced by the general population and similar to the TCDD levels used in animal studies. (Steenland et al, 1999)

Study #45

dioxin and insulin regulation have a compensatory metabolic relationship

We studied insulin, fasting glucose, and sex hormone-binding globulin (SHBG) in Air Force veterans exposed to Agent Orange and its contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), during the Vietnam War. The index subjects were veterans of Operation Ranch Hand, the unit responsible for aerial herbicide spraying in Vietnam from 1962-1971. Other Air Force veterans who served in Southeast Asia during the same period but were not involved with spraying herbicides served as comparisons. We assigned each Ranch Hand veteran based on his dioxin level to one of three exposure categories, named background, low, and high. Among nondiabetic veterans, we found the mean of the logarithm of insulin significantly increased in the high dioxin category. Additionally, in nondiabetic veterans the relation between SHBG and insulin interacted significantly with dioxin category on the log scale within strata defined by age and percent body fat. Among young (age, < or = 53 yr), lean (percent body fat, < or = 25%) nondiabetic veterans in the high category, the slope relating the logarithm of SHBG and the logarithm of insulin was significantly decreased. These findings suggest a compensatory metabolic relationship between dioxin and insulin regulation. (Michalek et al, 1999)

Study #46

dioxin is associated with significant increases in diabetes in women

To investigate, in a population heavily exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the possible unusual occurrence of diseases other than cancer. Five year extension of the follow up of the cohort involved in the Seveso accident. Soil measurements identified three exposure zones: (A) highest contamination, (B) substantial, and (R) low but higher than background contamination. Blood TCDD measurements, although limited in number, confirmed zone exposure ranking. The 15 year mortality in the exposed cohort was compared with that of a large population in the surrounding non-contaminated territory. Relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated with Poisson regression techniques. The already noted increased occurrence of cardiovascular deaths was confirmed, in particular in zone A, among males for chronic ischaemic heart disease (five deaths, RR 3.0, 95% CI 1.2 to 7.3), and among females for hypertensive disease (three deaths, RR 3.6, 95% CI 1.2 to 11.4) and chronic rheumatic heart disease. Novel findings were the increase of chronic obstructive pulmonary disease, most notably among males in zone A (four deaths, RR 3.7, 95% CI 1.4 to 9.9) and females in zone B (seven deaths, RR 2.4, 95% CI 1.1 to 5.1); and from diabetes, which was significantly increased in females in zone B (13 deaths, RR 1.9, 95% CI 1.1 to 3.2). In zone R, chronic ischaemic heart disease (males and females), hypertension (females), and diabetes (females) showed less pronounced, although significant excesses. As well as high TCDD exposure, the accident caused a severe burden of strain in the population. Both these factors might have contributed to the noted increased risks (in particular, circulatory and respiratory). The cardiovascular and immune toxicity of TCDD, as well as its complex interaction with the endocrine system, might be relevant to the explanations of these findings. These results, although not conclusive, concur with previous data in suggesting cardiopulmonary and endocrine effects in humans highly exposed to TCDD. (Pesatori et al, 1998)

Study #47

dioxin may be associated with diabetes

The authors studied noncancer mortality among phenoxyacid herbicide and chlorophenol production workers and sprayers included in an international study comprising 36 cohorts from 12 countries followed from 1939 to 1992. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin or higher chlorinated dioxins (TCDD/HCD) was discerned from job records and company questionnaires with validation by biologic and environmental measures. Standard mortality ratio analyses suggested a moderate healthy worker effect for all circulatory diseases, especially ischemic heart disease, among both those exposed and those not exposed to TCDD/HCD. In Poisson regression analyses, exposure to TCDD/HCD was not associated with increased mortality from cerebrovascular disease. However, an increased risk for circulatory disease, especially ischemic heart disease (rate ratio [RR] 1.67, 95% confidence interval [Cl] 1.23-2.26) and possibly diabetes (RR 2.25, 95% Cl 0.53-9.50), was present among TCDD/HCD-exposed workers. Risks tended to be higher 10 to 19 years after first exposure and for those exposed for a duration of 10 to 19 years. Mortality from suicide was comparable to that for the general population for all workers exposed to herbicides or chlorophenols and was associated with short latency and duration of exposure. More refined investigations of the ischemic heart disease and TCDD/HCD exposure association are warranted. (Vena et al, 1998)

Study #48

an excess of diabetes cases were associated with dioxin exposure

The industrial accident that occurred in the town of Seveso, Italy, in 1976 exposed a large population to substantial amounts of relatively pure 2,3,7,8-tetrachlorodibenzo-p-dioxin. Extensive monitoring of soil levels and measurements of a limited number of human blood samples allowed classification of the exposed population into three categories, A (highest exposure), B (median exposure), and R (lowest exposure). Early health investigations including liver function, immune function, neurologic impairment, and reproductive effects yielded inconclusive results. Chloracne (nearly 200 cases with a definite exposure dependence) was the only effect established with certainty. Long-term studies were conducted using the large population living in the surrounding noncontaminated territory as reference. An excess mortality from cardiovascular and respiratory diseases was uncovered, possibly related to the psychosocial consequences of the accident in addition to the chemical contamination. An excess of diabetes cases was also found. Results of cancer incidence and mortality follow-up showed an increased occurrence of cancer of the gastrointestinal sites and of the lymphatic and hematopoietic tissue. Experimental and epidemiologic data as well as mechanistic knowledge support the hypothesis that the observed cancer excesses are associated with dioxin exposure. Results cannot be viewed as conclusive. The study is continuing in an attempt to overcome the existing limitations (few individual exposure data, short latency period, and small population size for certain cancer types) and to explore new research paths (e.g., differences in individual susceptibility). (Bertazzi et al, 1998)

Study #49

dioxin increased glucose abnormalities, diabetes prevalence and use of diabetes medications
dioxin decreased time-to-diabetes-onset
dioxin increased serum insulin abnormalities
dioxin has an adverse relation to diabetes mellitus, glucose metabolism, and insulin production

We studied diabetes mellitus and glucose and insulin levels in Air Force veterans exposed to Agent Orange and its contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), during the Vietnam War. The index subjects of the Air Force's ongoing 20-year prospective epidemiologic study are veterans of Operation Ranch Hand (N = 989), the unit responsible for aerial herbicide spraying in Vietnam from 1962 to 1971. Other Air Force veterans who served in Southeast Asia during the same period but were not involved with spraying herbicides serve as Comparisons (N = 1,276). The median serum dioxin level in the Ranch Hand group was 12.2 parts per trillion (ppt) (range = 0-617.8 ppt), and the median dioxin level in the Comparison group was 4.0 ppt (range = 0-10 ppt). We found that glucose abnormalities [relative risk = 1.4; 95% confidence limits (CL) = 1.1, 1.8], diabetes prevalence (relative risk = 1.5; 95% CL = 1.2, 2.0), and the use of oral medications to control diabetes (relative risk = 2.3; 95% CL = 1.3, 3.9) increased, whereas time-to-diabetes-onset decreased with dioxin exposure. Serum insulin abnormalities (relative risk = 3.4; 95% CL = 1.9, 6.1) increased with dioxin exposure in nondiabetics. These results indicate an adverse relation between dioxin exposure and diabetes mellitus, glucose metabolism, and insulin production. (Henrikson et al, 1997)

Study #50

dioxin exposure symptoms can be confused with diabetes symptoms [or dioxins cause diabetes?]

The clinical recognition of dioxin-associated illness can be extremely difficult for the physician. After analyzing the relative sensitivity and specificity of reported manifestations of exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), we suggest criteria for the diagnosis of dioxin toxicity. Exposure to higher doses of 2,3,7,8-TCDD may lead to the appearance of chloracne and the increased excretion of porphyrins and porphyria cutanea tarda. Liver function abnormalities, peripheral neuropathy, hyperlipidemia, and evidence of weakness and depression may occur following exposure; however, these findings are less specific since diseases such as diabetes or alcoholism could cause several of these problems. The long-term effects of exposure to low-dose TCDD are currently uncertain. (Webb et al, 1986)

Study #51

diabetics may be predisposed to more toxic effects (peripheral neuropathy) as a result of dioxin exposure

In this study the prevalence rate of peripheral neuropathy in a population living in an area polluted with 2,3,7,8-tetrachlorodibenzo-dioxin (dioxin-TCDD) was determined. Of the 723 subjects invited to the first screening in 1977, 470 (65%) attended. At the second screening in 1978, of the 710 invited subjects, 319 (45%) attended. Prevalence rate ratios for peripheral neuropathy and the associated 95% confidence limits were calculated for subgroups determined by the presence of (i) predisposing factors to neuropathy (alcoholism, diabetes, occupational exposure to neurotoxic agents, etc) or (ii) conditions thought to result from exposure to dioxin-TCDD such as chloracne or abnormal serum hepatic enzyme levels. The prevalence rate of peripheral neuropathy among those subjects with predisposing factors and among those with chloracne or abnormal serum hepatic enzyme levels was nearly three times greater than among those without these manifestations. The results derived from this study may be useful qualitative pointers for identifying subjects at risk in the neurological follow-up. (Filippini et al, 1981)

Study #52

dioxin is associated with disorders of the metabolism of porphyrins, fats, carbohydrates, plasmaproteins

In 80 industrial workers producing herbicides (2,4,5-trichlorphenoxyaceticacidsodium and sodiumpentachlorphenolate) in Czechoslovakia the following signs of intoxication caused by 2,3,6,7-tetrachlordibenzodioxin were found: Dermatological: Chloracne and Porphyria cutanea tarda. Internal: Disorders of the metabolism of porphyrins, fats, carbohydrates, plasmaproteins. Neurological: Mainly lesions of the peripheral neurone. Psychiatric: Neurasthenic syndrome and organic lesions. Differences from the usual course of chloracne were observed. Porphyria cutanea tarda acquisita was most obvious, one patient suffered and died from severe atherosclerosis, hypertension and diabetes. Many patients developed polyneuropathy, as verified both by EMG and autopsy. Two patients died from bronchogenic carcinoma. (Jirasek et al, 1976)

Study #53

most, if not all, toxic effects of dioxin are mediated more or less through the binding affinity to the Ah receptor (certain PCBs also bind to the Ah receptor)
total fat (lipid) body content influences sensitivity or resistance to dioxin

The marked species differences in short-term toxicity (30-day LD50) of ca. 10,000 (LD50: guinea pigs ca. 1 microgram/kg body wt and Han/Wistar Kuopio rats more than 9600 micrograms/kg body wt) of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is one of the central issues of the controversies that have developed on the validity of risk assessment strategies for TCDD and related compounds. One of the most challenging issues that toxicologists face today is the identification of genes that contribute to or are responsible for increased resistance or sensitivity to TCDD and related compounds. It is assumed that most, if not all, toxic effects of TCDD are mediated more or less through the binding affinity to the Ah receptor. This hypothesis was extended and tries to explain the differences in sensitivity/resistance of animals including humans to TCDD by their total fat (lipid) content. In this respect the gene or genes which is or are responsible for obesity of mammals including humans are of great interest. An obvious linear positive logarithmic relationship between the oral 30-day LD50 (microgram/kg) of TCDD in different species and strains of mammals and their total body fat content (TBF%) was found: log LD50 = 5.30 x log (TBF)-3.22, or LD50 = 0.000603 x (TBF)5.30. By means of this regression the toxicity of TCDD in mammals including humans of different age and/or body weight can be predicted if their total body fat content is known. Examples of single-gene and polygenic disease models in different mammals, such as nonobese diabetic, diabetic, viable yellow, obese, and fat mice, as well as transgenic mice, and other suitable animal models, such as fatty Zucker rats, Han/Wistar (Kuopio) rats, and minipigs, are discussed, and predicted LD50 values of TCDD in these animals and humans are presented. (Geyer et al, 1997)

Study #54

chronic dietary PCB exposure significantly lowers intestinal levels of stored cholecystokinin (CCK) peptide

The ubiquitous and persistent nature of polychlorinated aromatic hydrocarbons (PCAHs) in our environment and the risk of exposure to PCAHs have provoked concern over their potential toxicity. In humans, exposure to PCAHs is aimed chiefly at epithelial cells residing in the intestinal mucosa, because oral intake of contaminated food is a major source of PCAHs. The purpose of this study, therefore, was to examine the effects of chronic exposure to various PCAHs [i.e. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB-126), and 2,2'4,4'5,5'-hexachlorobiphenyl (PCB-153)], given alone or as mixtures, on intestinal cholecystokinin (CCK) peptide and messenger RNA levels. We show that chronic PCAH treatment significantly lowers intestinal levels of stored CCK peptide. Intestinal CCK messenger RNA levels are not affected. In addition, 3,3',4,4',5-pentachlorobiphenyl treatment increased intestinal insulin-like growth factor-binding protein-3 levels in a dose-related manner. Acute 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment of intestinal CCK cells lowered levels of CCK-processing enzymes (i.e. prohormone convertase-1 and -2). Together, these data indicate that PCAHs may decrease intestinal levels of stored CCK peptide by affecting the intestinal insulin-like growth factor system and CCK processing. (Lee et al, 2000)

Study #55

dioxin is associated with changed insulin levels

The article presents studies of hormonal state in rats under daily or 20-day peroral administration of variable doses of 2,4-D herbicide containing dioxin. Changed levels of thyroid hormones, insulin, cortisol, testosterone and estradiol appeared to be divergent and dose-dependent, proving direct toxic effects of the herbicide in endocrine organs, altered hormonal effects in target organs and disorders of peripheral hormonal metabolism. (Gilmanov et al, 1997)

Study #56

significant decrease in fasting blood glucose and basal insulin level.
dioxin-induced wasting syndrome might relate to disturbed glucose metabolism of the main organ through insufficiency of caloric intake, thyroxine (T4) and insulin

In order to examine a relevance of glucose metabolism and thyroid function in TCDD-induced wasting syndrome, an insulin sensitivity assessment with chemical analysis of blood plasma were carried out in male Wistar rats exposed orally to TCDD. Laboratory findings in plasma showed elevation of glutamic-oxalacetic transaminase (GOT) and lipid peroxide value, decrease in thyroxine (T4) with increase in triiodothyronine (T3) value, and slight but significant decrease in fasting blood glucose and basal insulin level. The glucose disposal rate in euglycemic insulin clamp test was significantly elevated. These data suggest that TCDD-induced wasting syndrome might relate to the disturbance of glucose metabolism of the main organ through insufficiency of caloric intake, T4 and insulin. (Nichizumi et al, 1997)

Study #57

dioxin may stimulate or mimic insulin, and influence cell growth

Previous studies have demonstrated that 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) increases cell recovery in the human mammary epithelial cell line MCF-10A grown under growth factor-restricted conditions. TCDD was also found to mimic growth factor signaling pathways by stimulating the tyrosine phosphorylation of numerous effector molecules, and increased phosphatidylinositol 3-kinase (PI3K) activity in the absence of exogenously added growth factors. In the present studies, we have expanded on these initial results to show that TCDD (3-30 nM) increases cell recovery on days 2-6 by as much as 80% when insulin or epidermal growth factor (EGF) was removed from the media. The mechanism for this effect appears to be complex as TCDD inhibited apoptosis stimulated by EGF, or EGF and insulin, withdrawal by almost 80% as determined by Annexin V binding. However, withdrawal of insulin alone did not induce apoptosis even though TCDD did increase cell number in its absence. These results were corroborated by immunoblot analysis of poly(ADP-ribose) polymerase cleavage. Since TCDD stimulates PI3K activity, the phosphorylation status of Akt, a serine/threonine kinase that mediates PI3K-dependent inhibition of apoptosis, was examined. Immunoblot analysis revealed that TCDD causes a transient increase in the phosphorylated form of Akt that peaks at 6 h and disappears by 12 h. It appears that EGF stimulates an anti-apoptotic pathway, while insulin signals a pro-mitogenic pathway. By stimulating or mimicking one or both of these pathways TCDD may alter tightly regulated growth pathways in the MCF-10A cell line. (Davis et al, 2000)

Study #58

dioxin reduces insulin
dioxin reduces hepatic gluconeogenesis
dioxin reduces the activity of PEPCK, the rate limiting enzyme of gluconeogenesis, most likely through decreased expression of the PEPCK gene
dioxin derails glucose metabolism

We have previously shown that the rate of hepatic gluconeogenesis is reduced in TCDD-treated rats and that this decrease in carbohydrate production is associated with a dose-dependent reduction of the activity of PEPCK, the rate limiting enzyme of gluconeogenesis. This derailment of glucose metabolism has been suggested to be the critical lesion in acute TCDD toxicity. To further elucidate the mechanism of decreased PEPCK activity we performed Northern blot analyses using a cDNA probe complementary to a portion of the mRNA coding for PEPCK. We have demonstrated that 4 and 8 days after TCDD treatment (125 micrograms/kg, p.o.) liver PEPCK mRNA in Sprague-Dawley rats was decreased to very low levels as compared to vehicle-treated and pair-fed control animals. This decline of PEPCK mRNA was paralleled by decreased levels of PEPCK protein, as revealed by Western blot analyses and was accompanied by a reduction in the enzymatic activity of PEPCK. These results indicate that the decrease of PEPCK activity by TCDD is most likely the result of decreased expression of the PEPCK gene. These together with previous results also suggest that many of the physiological responses occurring in TCDD-treated animals (reduced feed intake, decreased insulin, increased corticosterone, increased glucagon and cAMP levels) which would normally stimulate PEPCK gene expression, are ineffective. Furthermore tryptophan 2,3-dioxygenase (TdO) activity, which is regulated in a very similar fashion to PEPCK activity, is also reduced after TCDD treatment, suggesting a common mechanism by which TCDD alters the regulation of these enzymes. P-450 1A1 mRNA and related EROD activity were maximally induced under the conditions of these experiments and represent a positive control for TCDD-related alterations of gene expression. However, because of differences in the dose-response characteristics of TCDD-induced reduction of PEPCK activity and induction of EROD activity an involvement of the Ah receptor in the reduction of PEPCK activity cannot be postulated. (Stahl et al, 1993)

Study #59

dioxin causes hypoinsulinemia
higher overall protein phosphorylation activities
dioxin causes a rise in protein-tyrosine kinases in pancreas at early stages of poisoning

To understand the basic mechanisms of TCDD's action to cause hypoinsulinemia in several experimental animals, we have studied TCDD-induced changes in various protein kinase activities in membrane preparations of guinea pig pancreas. For this purpose, young male guinea pigs were treated through a single intraperitoneal injection with 1 or 3 micrograms/kg of TCDD in vivo, and, after given time periods, pancreas samples were obtained and membranes were isolated through homogenization and centrifugation procedures. Several sets of incubation conditions were selected for protein kinase activity assay, each favoring a specific type of protein kinase. It was found that overall protein phosphorylation activities were higher in the preparation from TCDD-treated animals as compared to those found in pair-fed controls and that this trend was more pronounced when the assay medium contained Mn2+ in place of Mg2+ and EGTA. These are the conditions that are known to favor protein tyrosine kinases. Other types of protein kinases from the treated animals did not show any significant differences from the pair-fed control animals, though that of protein kinase C in the treated preparation showed a modest increase. To establish that the type of protein kinases stimulated by TCDD are protein tyrosine kinases, we have carried out phosphoamino acid analyses, KOH digestion, and western blot analyses using an antibody to phosphotyrosine. All the results were consistent in supporting the idea that TCDD causes a rise in protein-tyrosine kinases in pancreas at early stages of poisoning. (Ebner et al, 1993)

Study #60

dioxin causes hyperlipidemia, body weight loss (particularly body fat loss), anorexia, changes in carbohydrate metabolism, and lipid peroxidation
biochemical changes occur at very low doses, and some effects can last for long time periods
biochemical systems particularly affected are lipoprotein lipases, low-density-lipoprotein receptors, glucose transporter proteins (GLUTs), vitamin C uptake, and insulin secretion

The most consistent toxic effects of dioxin-type chemicals are hyperlipidemia, body weight loss (particularly body fat loss), anorexia, changes in carbohydrate metabolism, and lipid peroxidation. The biochemical systems particularly affected are lipoprotein lipases, low-density-lipoprotein receptors, glucose transporter proteins (GLUTs), vitamin C uptake, and insulin secretion. Some of these biochemical changes occur at very low doses, and some effects can last for long time periods. To provide a mechanistic explanation for such actions of dioxins, available experimental evidence has been reviewed. The most recent discovery indicates that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) directly acts with isolated cytosolic aryl-hydrocarbon (Ah) receptor under cell-free conditions even without the presence of the nucleus and is capable of activating key protein kinases that are involved in the growth factor signal-transduction pathway. The resulting activation of primary-response transcription factors in the nucleus appears to play a key role in coordinating vital cell program shifts, including lipid metabolism. (Matsumura et al, 1995)

Study #61

dioxin causes hypophagia and body weight loss
dioxin seems to affect the same regulation chain that is involved in the lesioning of the ventromedial hypothalamus

Long-term regulation of body weight and food intake were studied after rats were subjected to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which causes hypophagia and body weight loss, and to ventromedial hypothalamic lesion, which causes hyperphagia, metabolic changes and obesity. These two factors appeared to have an interaction, as ventromedial hypothalamic lesion initially aggravated the effects of TCDD on body weight and food intake. This was seen in both TCDD-resistant and TCDD-susceptible rat strains. In contrast, if TCDD was given several weeks before the lesion and body weight had stabilized to a low level, no aggravation was seen, but TCDD completely blocked the effects of ventromedial hypothalamic lesion. Thus, TCDD seems to affect the same regulation chain that is involved in the lesioning of the ventromedial hypothalamus. TCDD might serve as a tool in studying different mechanisms of long-term food intake and body weight regulation. (Tuomisto et al, 1995)

Study #62

dioxin causes a time- and dose-dependent decrease in cellular glucose uptake
glucose transporters and enzymes are altered by dioxin

This study examined the changes in cellular glucose uptake, cAMP-dependent protein kinase (PKA), and progesterone production induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in human luteinizing granulosa cells (LGCs) in culture. The role of Ah receptor on TCDD-mediated toxicity in human LGCs was investigated. Treatment of human LGCs with TCDD produced a time- and dose-dependent decrease in the cellular uptake of glucose. The Vmax and the K(m) of glucose transport were decreased by TCDD treatment. Furthermore, cytochalasin B, a specific inhibitor of facilitative glucose transporter proteins, totally abolished the portion of glucose transport activity that is sensitive to TCDD. Pretreatment of the cells with the Ah receptor blockers 4,7-phenanthroline and alpha-naphthoflavone antagonised the effect of TCDD on 3H-Me-glucose uptake. Structure-activity relationship studies with TCDD and three dioxin congeners revealed a rank order for their potency in the inhibition of glucose transport as follows: TCDD > 1,2,3,7,8-PCDD > 1,2,4,7,8-PCDD > 2,7-DCDD. Such a rank order is consistent with the previously determined biological activity of TCDD and the other dioxin congeners. Treatment of cells for 48 h with 10 nM TCDD substantially reduced PKA and progesterone production. The inhibitory effect of TCDD on progesterone production was more pronounced in the presence of insulin (10 micrograms/mL) and D-glucose (13.3 mM). However, cytochalasin B abolished the effect of TCDD on progesterone production. Forskolin (adenylate cyclase activator) abolished the effect of TCDD on glucose uptake and progesterone production but it did not affect the action of TCDD on PKA activity. A relationship between glucose transporting activity and progesterone production in human LGCs treated with TCDD is indicated by several lines of evidence: a) cytochalasin B downregulated glucose transporting activity and progesterone production, b) insulin plus D-glucose downregulated glucose uptake and amplified the negative effect of TCDD on progesterone production, and c) forskolin abolished the negative effect of TCDD on glucose transporting activity and on progesterone production. From the present data we conclude that glucose transporting activity can be used as a sensitive biomarker to detect the very early response to TCDD in human steroid-producing cells and that effect of TCDD on steroid production is mediated through the cAMP-dependent protein kinase. (Enan et al, 1996)

Study #63

dioxin inhibited breast cancer cell growth stimulated by insulin, through binding to the Ah receptor

Insulin stimulated proliferation of MCF-7 human breast cancer cells in serum-free medium, whereas 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,7,8-tetrachlorodibenzofuran (TCDF) did not affect cell growth. In cells cotreated with insulin plus TCDD or TCDF, insulin-induced cell proliferation and [3H]thymidine incorporation were inhibited. In contrast, alpha-naphthoflavone, a partial aryl hydrocarbon (Ah) receptor antagonist, blocked the inhibitory effects of TCDD, suggesting that the Ah receptor was involved in TCDD-induced responses in MCF-7 cells. TCDD alone did not affect Kd and Bmax values for binding of [125I]insulin to the insulin receptor (IR); however, in MCF-7 cells cotreated with insulin plus TCDD, the insulin-induced Kd value for IR-ligand binding was decreased and the Bmax value was increased. TCDD induced IR mRNA levels and inhibited several other insulin-induced responses including c-fos protooncogene expression, phosphorylation of the insulin receptor, and a 185-kDa protein in MCF-7 cells. (Liu et al, 1996)

Study #64

dioxin reduced estradiol in human luteinized granulosa cells through blockage of the mitotic signal directly or indirectly through the interaction of PTK/MAP2K and PKA signaling.
dioxin and insulin sometimes have synergistic effects on enzyme levels

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) caused a significant decrease in estradiol (E2) production when it was administered to human luteinized granulosa cells (hLGCs) in culture. We investigated the involvement of the epidermal growth factor receptor (EGFR) and protein tyrosine kinase (PTK) in this TCDD-induced toxicity. Upregulation in 125I-EGF binding to EGFR was measured after 24 h of TCDD treatment, while downregulation in EGFR binding was measured after 72 h of TCDD treatment. Upregulation of EGFR binding was associated with a significant decrease in postnuclear (7000 x g supernatant) PTK activity, but this activity was stimulated after 72 h of TCDD treatment. TCDD altered the level of tyrosine phosphorylation in proteins with molecular weights 35, 40, 43, 45, 60, and > 205 kDa. TCDD caused a significant increase in postnuclear cAMP-dependent protein kinase (PKA) after 24 h of treatment. The actions of TCDD on protein kinases were partially blocked by the protein synthesis inhibitor, cycloheximide. On the other hand, TCDD increased nuclear PTK and decreased nuclear PKA activity. E2 inhibited the postnuclear and nuclear activity of both PTK and PKA in control samples, but did not affect TCDD actions on either postnuclear or nuclear PTK activity. However, E2 abolished the stimulatory effect of TCDD on PKA activity in postnuclear protein. In the presence of insulin, TCDD did not induce any additional changes in postnuclear or nuclear PTK. Forskolin (FK) alone inhibited postnuclear PTK activity and stimulated its nuclear activity. The addition of TCDD 20 min after FK resulted in an increase in postnuclear PTK, but there was little change in nuclear PTK as compared to the effect of FK alone. The stimulatory effect of TCDD on postnuclear PKA activity was enhanced by insulin and TCDD reversed the negative effect of FK, but there was no effect of either insulin or FK on the inhibition by TCDD of nuclear PKA activity. TCDD decreased the activity of MAP2 kinase and reduced the binding activity of AP-1 DNA when given alone, and also blocked the E2 stimulation of MAP2K. These findings suggest that TCDD may interrupt the endocrine function of hLGCs through the blockage of the mitotic signal directly or indirectly through the interaction of PTK/MAP2K and PKA signaling. (Enan et al, 1996)

Study #65

dioxin activated insulin-like growth factor (IGF-I) signaling pathways under insulin-deficient conditions
dioxin (and dioxin-like PCBs) may alter cell growth in human mammary epithelial cells via mimicry of growth factor receptor signaling pathways

Previous studies in this laboratory have shown that polycyclic aromatic hydrocarbons, such as benzo[a]pyrene (BaP), and certain halogenated aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), modulate receptor signaling pathways in human lymphoid and non-lymphoid cells. We have recently demonstrated that BaP produces a weak mitogenic signal in human mammary epithelial cells, perhaps by mimicking growth factor signaling pathways. In the present studies we found that BaP and TCDD activated insulin-like growth factor (IGF-I) signaling pathways under insulin-deficient conditions. The effects of BaP and TCDD were evaluated in the human MCF-10A mammary epithelial cell line grown under epidermal growth factor- and insulin-dependent conditions. BaP (0.3 microM) and TCDD (30 nM) were found to restore a moderate insulin-like signal in MCF-10A cells grown in the absence of added insulin. TCDD was more potent and produced better activation of cell growth than did BaP. Both TCDD and BaP appeared to mimic signaling through the IGF-I receptor (IGF-IR), as evidenced by increased tyrosine phosphophorylation of IGF-IRbeta, IRS-1 and Shc. In addition, both BaP and TCDD significantly increased the activity of phosphatidylinositol 3-kinase (PI3K). The PI3K inhibitor LY294002 was found to inhibit the growth-promoting effects of TCDD seen under insulin-deficient conditions. The results of these studies show that under certain conditions BaP and TCDD can mimic growth factor signaling pathways in human mammary epithelial cells, demonstrating that environmentally prevalent carcinogenic compounds may alter cell growth in human mammary epithelial cells via mimicry of growth factor receptor signaling pathways. (Tannheimer et al, 1998)

Study #66

study overview

The mechanisms of various industrial toxins in causing disease of the thyroid, testes, ovary and pancreas are reviewed. Toxins include: polyhalogenated biphenyls, polyhalogenated dibenzodioxins and dibenzofurans, organochlorine pesticides, polycyclic aromatic hydrocarbons, hydroxyphenols and hydroxy pyridines, phthalates, lithium, iodine and radiation. The importance of medical surveillance in the workplace is emphasized in the light of the increasing numbers of women in industry and the associated potential reproductive risks. (Barsano et al, 1992)

Upcoming Research (Incomplete Study)

MATSUMURA F. BIOCHEMICAL CAUSES FOR HYPERTRIGLYCERIDEMIA. Crisp Data Base National Institutes Of Health Author Address: UNIVERSITY OF CALIFORNIA, ITEH, DAVIS, CA 95616

prospective study
PCBs are known to cause acute and chronic hyperlipidemia accompanied with the loss of body fat
the most predominant toxic expression of dioxin is hypertriglyceridemia (some PCBs are dioxin-like)
lipid metabolism is known to play a vital role in nutritional homeostasis
dioxin and dioxin-like PCBs affect insulin

Dioxin-type chemicals including PCBs are known to cause acute and chronic hyperlipidemia accompanied with the loss of body fat in several experimental animal species. Not only that most of these chemicals are hardly metabolized by detoxification enzymes and coupled with their extreme lipophilicity, concentrate in the adipose tissues where they remain for a long time period, often for the entire lifespan of the animal. We have previously found that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes significant reduction in the lipoprotein lipase (LPL) levels in the adipose tissue of guinea pigs and rabbits. Such an observation helps to explain why in these species the most predominant toxic expression of TCDD is hypertriglyceridemia. We have also found evidence that TCDD causes early atherosclerosis and reduction in the contraction force of the heart atrial muscles. Since lipid metabolism is known to play a vital role in nutritional homeostasis, and since these dioxin-type chemicals are now commonly found in adipose tissues of various animals including humans, we propose to study this further. In more specific terms, we plan to study (1) acute and chronic effects of TCDD on adipose LPL, synthesis and the ability of the affected adipocytes to respond to high glucose to produce LPL, (2) since TCDD causes a drastic increase in protein kinase activities in the adipose, as in the case of other tissues, characterize the nature of protein kinases, and identify the major substrate proteins for those TCDD affected protein kinases, including insulin and B-adrenergic receptor, (3) establish an in vitro adipocytes system which adequately reproduces the effect of TCDD particularly that on LPL synthesis processes, and (4) by using the knowledge gained by the above studies develop a reliable biomarker to indicate the extent of exposure to hardly metabolizable congeners of PCBs, dioxins and PCDFs. The markers proposed for study are levels of mRNA for LPL, 3H-TCDD binding to the adipocyte nuclear receptor, protein kinase C, protein tyrosine kinase (using antibodies against phosphotyrosine), pp6Olsrc (using specific antibody), and (125)I-insulin binding to its receptor.

Studies Without Abstracts

BASLER A. ROEHRBORN G. MUTAGENICITY OF ORAL HYPOGLYCEMIC AGENTS. EXP PATH 19:49-52,1981 Keywords: PCBs (as inducer), diabetes

Carpenter DO. Human health effects of polychlorinated biphenyls. Cent Eur J Public Health 2000 Jul;8 Suppl:23-4. Department of Environmental Health and Toxicology, School of Public Health, University at Albany, NY 12144, USA. carpent@cnsvax.albany.edu (Keywords: diabetes, PCBs)

Kimbrough RD. Pancreatic-type tissue in livers of rats fed polychlorinated biphenyls. J Natl Cancer Inst 1973 Aug;51(2):679-81

NORDBACK I. ACUTE NECROTIZING PANCREATITIS AFTER EXPOSURE TO POLYCHLORINATED BIPHENYLS. ITAL J GASTROENTEROL; 19 (5). 1987. 278-279.

REIF AE. THE CAUSES OF CANCER. WHILE SOME CANCERS ARE GENETICALLY FATED TO APPEAR, MOST HAVE NOW BEEN TRACED TO ENVIRONMENTAL FACTORS. AM. SCI. 1981, 69() 437-447 EIS: Epidemiology Information System

Wong O. Pancreatic cancer in workers at a transformer manufacturing plant. Am J Ind Med; VOL 27, ISS 6, 1995, P905-10 Author Address: Applied Health Sciences, Inc., San Mateo, CA 94401, USA.