The prevalence of asthma, particularly in children in developed countries, has been increasing rapidly over the last 30 years (Borna et al., 2019). Perinatal exposures have a significant role in the current asthma epidemic. Asthma is more prevalent in females than males from puberty to menopause (Borna et al., 2019). Asthma can be reactivated in women taking estrogen-dominant hormone replacement therapy (Bonds and Midoro-Horiuti, 2013, Choi, 2011, Dratva, 2010). These findings strongly suggest a role for endogenous and exogenous estrogens in the development of asthma. Therefore, we elucidated the potential roles of environmental estrogen (EE) exposure in the development and morbidity of asthma.

We reported that perinatal exposure to bisphenol A (BPA), a common EE, which is detectable in the majority of humans (Kovacic et al., 2020), promotes the development of an asthma-like phenotype in our mouse model (Midoro-Horiuti et al., 2010, Nakajima et al., 2012). We also noted that this phenotype was perpetuated in the 2nd and 3rd generations, after eliminating the BPA exposure after the weaning of 1st generations (Sowers et al., 2020). Epidemiologic studies also describe associations between maternal BPA exposures with wheezing among infants and decreased pulmonary function (Donohue et al., 2013, Gascon et al., 2015, Spanier et al., 2012). Also, associations between personal BPA urinary excretion and allergic asthma later in life have been described (Vaidya and Kulkarni, 2012). Even after the US Food and Drug Administration stopped approval of BPA usage in consumer products, BPA containing micro-and nano-plastics in the environment can be an important source of BPA (Chen et al., 2017, Kwon et al., 2020). Bisphenol S (BPS), the substitute for BPA, which is now detected in about 80% of humans, may have similar effects to BPA (Dualde et al., 2021, Gys et al., 2021, Vinas and Watson, 2013).

The effects of steroid hormones that occur independently from widely known gene transcription have been termed nongenomic to distinguish them from the direct, or genomic effects of their receptors as transcription factors in the nucleus (Vinas and Watson, 2013, Watson et al., 2012). Walker et al. have identified a novel role for this nongenomic signaling by xenoestrogens via activation of membrane-associated ER and regulation of enhancer of zeste homolog 2 (EZH2) to reprogram the developing uterus (Walker, 2011). They found that in response to both 17-β estradiol (E2) and the xenoestrogen diethylstilbestrol (DES), ER signaling via PI3K/AKT phosphorylates EZH2 at S21, and reducing H3K27me3 levels in hormone-responsive uterine myometrial (Bredfeldt et al., 2010) and prostate cancer cells (Wang et al., 2016). Although ERα expression is reported in the T cells (Kassi et al., 2001, Rider et al., 2000), the specific mechanisms by which EEs reprogram the developing epigenome were unknown in immune cells, including T cells. We recently reported that in vitro and in vivo exposures to EEs induce the overexpression of zinc finger DHHC domain-containing (ZDHHC)1 and stimulators of interferon genes (STING) at the mRNA and protein levels (Sowers et al., 2020). Based on these findings, we propose this study to understand the intracellular signaling pathways by which EE alters the expression of the immune-modulating genes and the epigenetic mechanisms that may perpetuate these pathologic responses.