Academic journal article Environmental Health Perspectives

Effect of Bisphenol A on Murine Immune Function: Modulation of Interferon-[Gamma], IgG2a, and Disease Symptoms in NZB X NZW [F.Sub.1] Mice

Academic journal article Environmental Health Perspectives

Effect of Bisphenol A on Murine Immune Function: Modulation of Interferon-[Gamma], IgG2a, and Disease Symptoms in NZB X NZW [F.Sub.1] Mice

Article excerpt

To investigate the effects of the estrogen receptor-binding molecule bisphenol A (BPA) on murine immune function in vivo, we fed a low dose of 2.5 [micro]g BPA/kg body weight/day to both normal C57BL/6 and lupus-prone NZB x NZW [F.sub.1] (NZB/NZW) 5-week-old mice for 1 week. Analysis of concanavalin A (ConA)-stimulated splenic mononuclear cells by ELISA demonstrated that BPA-fed C57BL/6 males produced, on average, 40% less interferon-[gamma] (IFN-[gamma]; p < 0.01) and C57BL/6 females 28% less IFN-[gamma] (p < 0.05) compared with controls. Treated female NZB/NZW mice were monitored for lupus disease symptoms, defined as proteinuria (> 100 mg/dL albumin in urine for 2 consecutive weeks). Before the development of proteinuria, BPA-fed NZB/NZW mice produced significantly less ConA-stimulated IFN-[gamma] than did controls and displayed an average reduction of 50% in immunoglobulin G2a (IgG2a) antibody production from lipopolysaccharide (LPS)-stimulated splenocytes (p < 0.05). It is striking that 5-week-old female NZB/NZW mice fed a 7-day low-dose course of BPA developed proteinuria an average of 7 weeks later than did controls. Once proteinuria developed, splenocytes were stimulated with ConA for cytokine analysis. The BPA-fed mice showed a dramatic reduction of 64% in IFN-[gamma] production and a 32% reduction in ConA-stimulated interleukin-10 (p < 0.05). The long-lasting effects of BPA on IFN-[gamma] and IgG2a production likely contributed to the increased symptom-free period of the NZB/NZW mice. Key words: bisphenol A, C57BL/6, estrogen receptor, IgG2a, interferon-[gamma], lupus, NZB x NZW. Environ Health Perspect 111:1883-1887 (2003). doi:10.1289/ehp.6359 available via http://dx.doi.org/ [Online 29 August 2003]

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Cells of the immune system respond to sex hormones, including estrogen (McMurray 2001). Upon binding of estrogen to the estrogen receptor (ER), the ligand-receptor complex dimerizes and mediates the transcriptional activity of genes containing estrogen response elements (EREs) and/or AP-1 sites. Recent studies detected ER-[alpha] in murine splenic B and T cells by both fluorescent activated cell sorting analysis and reverse-transcriptase polymerase chain reaction (Sakazaki et al. 2002). Additionally, Grimaldi et al. (2002) identified the more recently described ER-[beta] in murine splenic B cells. It remains unclear whether ER-[beta] is expressed in murine splenic T cells. Estrogen has been shown to alter cytokine production and T-cell subset distribution (Ahmed et al. 1985; Correale et al. 1998). Both interferon-[gamma] (IFN-[gamma]) and interleukin-10 (IL-10) are modulated by estrogen (Kanda and Tamaki 1999; Karpuzoglu-Sahin et al. 2001). The IFN-[gamma] promoter contains ERE-like sequences, and estrogen reportedly up-regulates IFN-[gamma] production (Fox et al. 1991). In addition to modulating EREs, estrogen may modulate the expression of genes through AP-1 sites, sites found in many cytokine gene promoters, including IFN-[gamma] (Kushner et al. 2000). Both ER subtypes interact with Fos and Jun elements at AP-1 sites, but with opposite outcomes (Paech et al. 1997).

Estrogen provides a possible link between cytokines and the autoimmune disorder systemic lupus erythematosus (SLE), because both IFN-[gamma] and IL-10 have been implicated in lupus (Csiszar et al. 2000; Gonzalez-Amaro et al. 1998). Lupus occurs at a ratio of > 8:1 in females compared with males and commonly strikes in women during the childbearing years when circulating estrogen levels are highest (Kotzin 1996). SLE is characterized by high levels of IgG autoantibodies, including anti-double-stranded DNA (anti-dsDNA) autoantibodies. Female NZB x NZW [F.sub.1] (NZB/NZW) mice spontaneously develop a disease comparable with human lupus, displaying glomerulonephritis, arthritis, and elevated levels of IgG autoantibodies, in particular the complement-activating IgG2a class (Zeng et al. 2000). The reduced average life span of female NZB/NZW mice of 40 weeks compared with 64 weeks in males implicates female sex hormones in the disease process (Walker et al. …

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