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. 2005 Mar;113(3):323-8.
doi: 10.1289/ehp.7347.

Acceleration of autoimmunity by organochlorine pesticides in (NZB x NZW)F1 mice

Eric S Sobel  1 , John Gianini, Edward J Butfiloski, Byron P Croker, Joel Schiffenbauer, Stephen M Roberts
Affiliations

Acceleration of autoimmunity by organochlorine pesticides in (NZB x NZW)F1 mice

Eric S Sobel et al. Environ Health Perspect. 2005 Mar.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder that affects women more frequently than men. In the (NZB times NZW)F1 mouse, a murine SLE model, the presence or absence of estrogen markedly influences the rate of progression of disease. Three organochlorine pesticides with estrogenic effects were administered chronically to ovariectomized female (NZB times NZW)F1 mice, and we measured the time to development of renal disease, the principal clinical manifestation of lupus in this model. Treatment with chlordecone, methoxychlor, or o,p -dichlorodiphenyltrichloroethane (o,p -DDT) significantly decreased the time to onset of renal impairment, as did treatment with 17ss-estradiol used as a positive control. In an expanded study of chlordecone, we found a dose-related early appearance of elevated anti-double-strand DNA autoantibody titers that corresponded with subsequent development of glomerulonephritis. Immunohistofluorescence confirmed early deposition of immune complexes in kidneys of mice treated with chlordecone. These observations are consistent with an effect of these organochlorine pesticides to accelerate the natural course of SLE in the (NZB times NZW)F1 mouse. Although we originally hypothesized that the effect on progression of autoimmunity was due to estrogenic properties of the pesticides, autoimmune effects and estrogenicity, assessed through measurement of uterine hypertrophy, were not well correlated. This may indicate that uterine hypertrophy is a poor indicator of comparative estrogenic effects of organochlorine pesticides on the immune system, or that the pesticides are influencing autoimmunity through a mode of action unrelated to their estrogenicity.

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Figures

Figure 1
Figure 1. Time to development of renal disease (plotted as a survival curve) in ovariectomized (NZB × NZW)F1 mice implanted with pellets containing (A) methoxychlor, (B) o,p′-DDT, (C) chlordecone, or (D) 17β-estradiol; ovariectomized mice implanted with control pellets and sham-operated mice are shown for comparison (n = 10/group). The time to development of renal disease was significantly decreased in all OCP-treated groups compared with ovariectomized controls (p < 0.05)
Figure 2
Figure 2. Representative kidney sections taken from (NZB × NZW)F1 mice after 16 weeks of treatment. (A) Sham-operated mouse. (B) Ovariectomized mouse treated with chlordecone (1.8 mg/pellet). (C and D) Two ovariectomized mice, each treated with a control pellet. (A) and (B) show enlarged, cellular, and sclerotic glomeruli (arrows) with tubular atrophy and dilation (asterisks). (C) and (D) show segmental mesangial thickening, but otherwise spared, glomeruli (arrows) with normal tubules (asterisk). Sections were stained with PAS (magnification, 400×).
Figure 3
Figure 3. Time to development of renal disease in ovariectomized (NZB × NZW)F1 mice (n = 20 controls; n = 10 sham operated; n = 10 for each of the chlordecone-treated groups). The time to appearance of renal disease was significantly decreased in mice treated with the 1-mg chlordecone pellets (p < 0.05).
Figure 4
Figure 4. Serum autoantibody titers in ovariectomized (NZB × NZW)F1 mice treated 20 weeks after treatment with chlordecone. Ovariectomized mice implanted with control pellets and sham-operated mice are shown for comparison. Antibody titers from mice treated with 1 mg chlordecone pellets were significantly higher than those of ovariectomized controls (p < 0.01).
Figure 5
Figure 5. Enhanced renal disease and immune complex deposition in ovariectomized, chlordecone-treated mice after 8 weeks of treatment with control pellets or pellets containing chlordecone (1 mg/pellet) or 17β-estradiol (0.05 mg/pellet; n = 6/group). Frequency of appearance of proliferative glomerulonephritis (GN; A), mesangiopathic glomerulonephritis (B), and proteinuria (C), and spleen weight. The frequency of occurrence of proteinuria was significantly increased in both chlordecone-treated and 17β-estradiol–treated mice; spleen weight (D) was significantly increased by 17β-estradiol. (E) Immunofluorescence staining (magnification, 200×) for IgG was absent in control mice, but present in mice treated with either chlordecone or 17β-estradiol after 8 weeks of treatment; later, when renal disease developed in controls, a similar extent of immunofluorescence staining was observed.
Figure 6
Figure 6. Uterine hypertrophy in ovariectomized (NZB × NZW)F1 mice 6 weeks after administration of pellets containing (A) methoxychlor, (B) o,p′-DDT, and (C) higher and (D) lower doses of chlordecone. Results from controls and 17β-estradiol–treated mice are reproduced in A–C to facilitate comparison with OCP-treated mice. Compared with controls, uterine weights were significantly increased in mice treated with 0.05 mg estradiol, 10 mg methoxychlor, 0.9 and 9.0 mg o,p′-DDT, and 36 mg chlordecone.
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