Methylsulfonyl Metabolites of PCBs and DDE in Human Milk in Sweden, 1972-1992

The persistent adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE (MeSO(2)-DDE) was originally identified in Baltic grey seals, a population suffering from adrenocortical hyperplasia. In mice, MeSO(2)-DDE induces mitochondrial degeneration and cellular necrosis in the adrenal zona fasciculata. In this study, we used precision-cut tissue slice culture to examine local CYP11B1-catalyzed irreversible binding of MeSO(2)-DDE in the murine adrenal cortex. We also examined effects on steroid hormone secretion, histology, and ultrastructure. As determined by microautoradiography, selective binding occurred in zona fasciculata of slices exposed to MeSO(2)-[(14)C]-DDE. Quantification of binding by phosphorautoradiography revealed a 3-fold reduction of binding in slices co-exposed to the CYP11B1 inhibitor metyrapone. As measured by HPLC, corticosterone and 11-deoxycorticosterone secretion to the medium increased linearly for at least 24 hr. Addition of the ACTH analog tetracosactide caused an 8-fold increase in corticosterone secretion. Addition of metyrapone reduced corticosterone secretion 4-fold. Exposure of slices to MeSO(2)-DDE (50 microM) reduced the rate of corticosterone secretion by 90% after 24 hr of incubation. As determined by electron microscopy, vacuolated mitochondria were present in zona fasciculata of slices exposed to MeSO(2)-DDE (50 microM) for 24 hr. Our findings show that all effects of MeSO(2)-DDE previously reported in vivo could be reproduced in adrenal slice culture ex vivo. This test system allows analysis of zone-specific irreversible binding and effects on steroid hormone secretion and target cell ultrastructure. We propose adrenal slice culture as a simple ex vivo test system with which to examine the adrenocorticolytic activity of xenobiotics in human and wild animal tissue.

Section: Discussionmentioning

confidence: 99%

Irreversible binding and adrenocorticolytic activity of the DDT metabolite 3-methylsulfonyl-DDE examined in tissue-slice culture.

Lindhe

Lund²,

Bergman³

et al. 2001

“…The recoveries of MeSO2-IS have been shown to correlate well with the recoveries of MeSO2-CBs (16,1?) and 3-MeSO2-DDE (16).…”

Section: Resultsmentioning

confidence: 99%

“…In environmental samples, MeSO2-CBs and MeSO2-DDEs were first identified in seal blubber from the Baltic (14); since then, such metabolites have been found in several species of animals (6) and in humans (7,8,15). Recently, MeSO2-CBs and MeSO2-DDEs were determined in Swedish mother's milk (16) and MeSO2-CBs were determined in human blood plasma (17).…”

mentioning

confidence: 99%

Methylsulfonyl metabolites of PCBs and DDE in human tissues.

Weistrand

Norén²

1997

Methylsulfonyl metabolites of chlorinated biphenyls (MeSO2-CBs) and p,p'-DDE (MeSO2-DDEs) were determined in human adipose and liver tissues obtained at autopsy of seven Swedish individuals 47-80 years of age. Twenty MeSO2-CBs and two MeSO2-DDEs were found in the analyzed samples. In adipose tissue, most of the 4-MeSO2-CBs were found at higher concentrations than the corresponding 3-MeSO2-CBs and, in all samples of adipose tissue, 4-MeSO2-2,2',3',4',5-pentaCB (4-87) and 4-MeSO2-2,2',3,4',5',6-hexaCB (4-149) occurred at higher concentrations than other MeSO2-CBs. In the liver, 3-MeSO2-2,2',3',4',5,6-hexaCB (3-132) was by far the most abundant MeSO2-CB, contributing to 61-82% of the sum of MeSO2-CBs. In this tissue, most of the other 3-MeSO2-CBs were also found at higher concentrations than the corresponding 4-MeSO2-CBs. The ratios of the sum of MeSO2-CBs to the sum of determined chlorinated biphenyls (CBs) were 1/250 and 1/28 in adipose tissue and the liver, respectively, calculated from the median values. The concentration of 2-MeSO2-DDE was lower than that of 3-MeSO2-DDE in both adipose tissue and liver, except in the liver from one of the individuals. The concentration ratios of 2-MeSO2-DDE to 3-MeSO2-DDE were about 10 times higher in liver than in adipose tissue. The ratios of the sum of MeSO2-DDEs to p,p'-DDE were 1/455 and 1/61 in adipose tissue and liver, respectively, calculated from the median values. MeSO2-CBs and MeSO2-DDEs were also determined in lung tissue from one of the individuals. In this sample, the profiles of MeSO2-CBs and MeSO2-DDEs were similar to the profiles of these compounds in adipose tissue.ImagesFigure 1.Figure 2.Figure 3.

“…The concentration of these two compounds in pooled milk was 0.6 ng/g (lipid weight) in most abundant and 3-MeSO2-CB 149 being the third most abundant methyl sulfone. The concentration of these two compounds in pooled milk was 0.6 ng/g (lipid weight) in 1992 (19). Much higher concentrations of PCB methyl sulfones have been found, for example, in Baltic seals (20), suggesting that some species are more subject to biological effects of PCB methyl sulfones than humans.…”

Section: Discussionmentioning

confidence: 99%

Interactions between methylsulfonyl PCBs and the glucocorticoid receptor.

Johansson

Nilsson

Lund

1998

Persistent polychlorinated biphenyl (PCB) metabolites were studied with respect to their interaction with the human glucocorticoid receptor (GR). 3-Methylsulphonyl-2,5,6,2',4',5'-hexachlorobiphenyl (3-MeSO2-CB149) was shown to compete with 3H-dexamethasone for binding to the GR, with an IC50 (concentration that inhibits 50%) of approximately 1 microM. Using GRAF cells expressing human GR, glucocorticoid responsive element, and a reporter enzyme, we demonstrated that 3-MeSO2-CB149 functionally acts as an antagonist at the GR (IC50 = 2.7 microM). In accordance with the receptor binding, the antagonism mainly appeared to be of a competitive nature. When studying the competitive binding of 24 methylsulfonyl PCBs (relative to dexamethasone) to GR from mouse liver cytosol, seven compounds had a higher affinity to GR than 3-MeSO2-CB149. Structure-activity relationship studies indicated that the presence of three chlorine atoms in the ortho-position and chlorine and methyl sulfone groups on either end of the molecule (4 and 4'-position) increased the affinity to GR. The relevance of this finding for human health is not known, but PCB methyl sulfones are ubiquitous pollutants present in mother's milk. The results stress the need for studying endocrine disruptors that affect hormonal systems other than sex and thyroidogenic hormones.ImagesFigure 1Figure 3Figure 4Figure 5