The Effects of Maternal Exposure to Bisphenol A on Allergic Lung Inflammation into Adulthood

Abstract

Bisphenol A (BPA) is a high-production volume chemical classified as an environmental estrogen and used primarily in the plastics industry. BPA's increased usage correlates with rising BPA levels in people and a corresponding increase in the incidence of asthma. Due to limited studies, the contribution of maternal BPA exposure to allergic asthma pathogenesis is unclear. Using two established mouse models of allergic asthma, we examined whether developmental exposure to BPA alters hallmarks of allergic lung inflammation in adult offspring. Pregnant C57BL/6 dams were gavaged with 0, 0.5, 5, 50, or 500 μg BPA/kg/day from gestational day 6 until postnatal day 21. To induce allergic inflammation, adult offspring were mucosally sensitized with inhaled ovalbumin containing low-dose lipopolysaccharide or ip sensitized using ovalbumin with alum followed by ovalbumin aerosol challenge. In the mucosal sensitization model, female offspring that were maternally exposed to ≥ 50 μg BPA/kg/day displayed enhanced airway lymphocytic and lung inflammation, compared with offspring of control dams. Peritoneally sensitized, female offspring exposed to ≤ 50 μg BPA/kg/day presented dampened lung eosinophilia, compared with vehicle controls. Male offspring did not exhibit these differences in either sensitization model. Our data demonstrate that maternal exposure to BPA has subtle and qualitatively different effects on allergic inflammation, which are critically dependent upon route of allergen sensitization and sex. However, these subtle, yet persistent changes due to developmental exposure to BPA did not lead to significant differences in overall airway responsiveness, suggesting that early life exposure to BPA does not exacerbate allergic inflammation into adulthood.

Gestational and lactational exposure to low-dose bisphenol A increases Th17 cells in mice offspring

“…In the present study, gestational and lactational exposure to low-dose BPA was found to induce persistent and more prominent changes in female offspring mice in terms of Th17 cell frequency, IL-17, IL-21, and RORγt mRNA expression. These gender-specific effects are consistent with previous studies showing that perinatal BPA exposure induces inflammation, alterations in energy expenditure, body composition and hormone levels, as well as behavioral changes (Bauer et al, 2012;Anderson et al, 2013;Kundakovic et al, 2013). Differential tissue distribution of BPA in male and female offspring mice may play a critical role in gender dimorphic phenotypes (Doerge et al, 2011).…”

“…In humans, prenatal and postnatal environmental BPA exposure is associated with various autoimmune diseases and inflammation during childhood and adulthood, including allergy, asthma and obesity (Spanier et al, 2012;Trasande et al, 2012;Mikołajewska et al, 2015). In animals, early-life exposure to BPA may produce considerable adverse effects to the immune system, such as cytokine secretion changes, immune-associated gene expression, T helper (Th)1/Th2 cell shifts, decrease in regulatory T cell (Treg) number, immune response abnormality, and allergic inflammation in offspring mice during the life course (Yoshino et al, 2004;Yan et al, 2008;Midoro-Horiuti et al, 2010;Bauer et al, 2012). However, the molecular mechanisms for immune disorders of BPA following perinatal exposure remain to be elucidated (Rogers et al, 2013), in particular the autoimmune-specific pathways.…”

Low dose effects of bisphenol A

“…[141][142][143][144][145] These studies typically show effects of BPA on some aspects of immune response, but not all (i.e., altered innate but not adaptive immune responses, effects in some organs but not others, etc.). Because these studies used different agents to invoke immune responses and assessed different organs' responses, there is not yet enough evidence to determine whether the effects of BPA on the immune system are consistent.…”

“…155 Importantly, many significant effects are observed following administration of doses below the EPA reference dose of 50 μg/ kg body weight/day, and some of these studies show effects in the range of estimated human exposures (≤ 5 μg/kg body weight/ day). 118,124,126,130,132,133,135,136,141,143,150,152, Previous reviews have also noted a relatively large number of studies that demonstrated effects in the range of human exposures from dietary sources. 6,9 Studying actual or suspected human exposure levels in rodents may not be appropriate for risk assessment purposes as this leaves no margin of error for differences in metabolism between species or individuals, the presence of vulnerable human subpopulations, or the possibility that animal models are less sensitive than humans.…”

Low-Dose Exposure to Bisphenol A in Early Life

“…However, recent studies describe the nonmonotonic dose response relationship of BPA. Perinatal exposure to lower dose of BPA than LOAEL has been reported the harmful effects on endocrine system including reproductive system [4][5][6][7], immune system [8][9][10], pituitary gland [11][12][13][14][15][16][17][18][19][20], and metabolic system [21][22][23][24]. Because, the fetus and neonates are extremely sensitive to perturbation by hormone like chemicals, early life exposure to low dose BPA probably is able to affect the epigenetic mechanism.…”