Lifetime-dependent effects of bisphenol A on asthma development in an experimental mouse model

Abstract

Background: Environmental factors are thought to contribute significantly to the increase of asthma prevalence in the last two decades. Bisphenol A (BPA) is a xenoestrogen commonly used in consumer products and the plastic industry. There is evidence and an ongoing discussion that endocrine disruptors like BPA may affect human health and also exert alterations on in the immune system. The aim of this study was to investigate age-dependent effects of BPA on the asthma risk using a murine model to explain the controversial results reported till date.

Methods: BALB/c mice were exposed to BPA via the drinking water for different time periods including pregnancy and breastfeeding. To induce an asthma phenotype, mice were sensitized to ovalbumin (OVA), followed by an intrapulmonary allergen challenge.

Results: BPA exposure during pregnancy and breastfeeding had no significant effect on asthma development in the offspring. In contrast, lifelong exposure from birth until the last antigen challenge clearly increased eosinophilic inflammation in the lung, airway hyperreactivity and antigen-specific serum IgE levels in OVA-sensitized adult mice compared to mice without BPA exposure. Surprisingly, BPA intake during the sensitization period significantly reduced the development of allergic asthma. This effect was reversed in the presence of a glucocorticoid receptor antagonist.

Conclusions: Our results demonstrate that the impact of BPA on asthma risk is strongly age-dependent and ranges from asthma-promoting to asthma-reducing effects. This could explain the diversity of results from previous studies regarding the observed health impact of BPA.

Figure 1. Prenatal BPA exposure did not affect the asthma phenotype in the offspring.

Mice were exposed to 5 µg/ml BPA via drinking water during pregnancy. In the offspring an asthma phenotype was induced by sensitization to ovalbumin (OVA) followed by an intrapulmonary allergen challenge as described in Materials and Methods. BPA exposure did neither affect total cell number in BAL fluid (a), lung inflammation (b), lung resistance (c), OVA-specific IgE serum levels (d) nor cytokine production in splenocytes (e) or lymph node cells (f). Data are expressed as mean ± SEM, n≥11 animals per group.

Figure 2. Perinatal BPA exposure showed no effect on the asthma phenotype in the offspring.

Mice were exposed to 5 µg/ml BPA via drinking water during pregnancy and breastfeeding. In the offspring an asthma phenotype was induced by sensitization to OVA followed by an intrapulmonary allergen challenge as described in Materials and Methods. BPA exposure did neither affect total cell number in BAL fluid (a), lung inflammation (b), lung resistance (c), OVA-specific IgE serum levels (d) nor cytokine production in splenocytes (e) or lymph node cells (f). Data are expressed as mean ± SEM, n≥22 animals per group. *P<0.05.

Figure 3. Lifelong exposure to BPA significantly increased the allergic airway inflammation.

Nursing mice were exposed to 5 µg/ml BPA via drinking water and offspring during their lifetime. The asthma phenotype was induced by sensitization to OVA followed by an intrapulmonary allergen challenge as described in Materials and Methods. BPA exposure increased total cell number in BAL fluid (a), lung inflammation (b), lung resistance (c), and OVA-specific IgE serum levels (e). Cytokine production was not affected (e+f). Data are expressed as mean ± SEM, n≥6 animals per group. *P<0.05.

Figure 4. Exposure of adult mice to BPA during sensitization reduced the allergic immune response.

Adult mice were exposed to 5 µg/ml BPA via drinking water during OVA-immunization. BPA exposure reduced total cell number in BAL fluid (a), lung inflammation (b), lung resistance (c), OVA-specific IgE serum levels (e) and Th2 cytokine production from lymph node cells (f), while cytokine production from spleen was not affected (e). Data are expressed as mean ± SEM, n≥18 animals per group. *P<0.05.

Figure 5. Glucocorticoid receptor antagonist RU486 abolished the decreased immune response induced by BPA.

Adult mice were exposed to 5 µg/ml BPA via drinking water. RU486 was given intraperitoneally 3 times/week during OVA-immunisation. Treatment with RU486 reversed the BPA-induced effect on total cell number in BAL fluid (a), lung inflammation (b), lung resistance (c) and OVA-specific IgE serum levels (d). Data are expressed as mean ± SEM, n≥5 animals per group. *P<0.05 OVA and ^#P<0.05 OVA+BPA+RU486 vs. OVA+BPA.