Over the years, industrial accidents and military actions have led to unintentional, large-scale, high-dose human exposure to environmental contaminants with endocrine-disrupting action. These historical events, in addition to laboratory studies, suggest that exposure to toxicants such as dioxins and polychlorinated biphenyls negatively impact the reproductive system and likely influence the development of gynecologic diseases. Although high-level exposure to a single toxicant is rare, humans living in industrialized countries are continuously exposed to a complex mixture of manmade and naturally produced endocrine disruptors, including persistent organic pollutants and heavy metals. Since minorities are more likely to live in areas with known environmental contamination; herein, we conducted a literature review to identify potential associations between toxicant exposure and racial disparities in women’s health. Evidence within the literature suggests that the body burden of environmental contaminants, especially in combination with inherent genetic variations, likely contributes to previously observed racial disparities in women’s health conditions such as breast cancer, endometriosis, polycystic ovarian syndrome, uterine fibroids, and premature birth.

Resistance to androgen receptor (AR)–targeted therapies for prostate cancer (PCa) is characteristic of an aggressive subtype called castration-resistant prostate cancer (CRPC) and is often associated with tumor relapse. Both relapse and poor prognosis in patients with CRPC are associated with increased abundance of the E3 ubiquitin ligase SKP2. Therefore, we investigated the therapeutic potential of combined inhibition of AR and SKP2 for CRPC. We found that combined targeting of AR and SKP2 with small-molecule inhibitors decreased proliferation in two CRPC cell lines in culture and in xenografts in humanized mice. Furthermore, combined therapy in mice markedly decreased the growth of Pten/Trp53 double-knockout tumors, a particularly invasive model of CRPC, whereas disruption of either AR or SKP2 alone only modestly suppressed their growth. Mechanistically, the inhibition of SKP2 in CRPC cells induced autophagy-dependent apoptosis and promoted luminal-associated phenotypes, which promoted responsiveness to AR-targeted therapy. These effects were further enhanced by coinhibition of AR and were not induced by the AR inhibitor alone. Our findings indicate that targeting both AR and SKP2 signaling pathways is necessary to treat CRPC.

New bronchopulmonary dysplasia (BPD) is a neonatal disease that is theorized to begin in utero and manifests as reduced alveolarization due to inflammation of the lung. Risk factors for new BPD in human infants include intrauterine growth restriction (IUGR), premature birth (PTB) and formula feeding. Using a mouse model, our group recently reported that a paternal history of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure increased his offspring’s risk of IUGR, PTB, and new BPD. Additionally, formula supplementation of these neonates worsened the severity of pulmonary disease. In a separate study, we reported that a paternal preconception fish oil diet prevented TCDD-driven IUGR and PTB. Not surprisingly, eliminating these two major risk factors for new BPD also significantly reduced development of neonatal lung disease. However, this prior study did not examine the potential mechanism for fish oil’s protective effect. Herein, we sought to determine whether a paternal preconception fish oil diet attenuated toxicant-associated lung inflammation, which is an important contributor to the pathogenesis of new BPD. Compared to offspring of standard diet TCDD-exposed males, offspring of TCDD-exposed males provided a fish oil diet prior to conception exhibited a significant reduction in pulmonary expression of multiple pro-inflammatory mediators (Tlr4, Cxcr2, Il-1 alpha). Additionally, neonatal lungs of pups born to fish oil treated fathers exhibited minimal hemorrhaging or edema. Currently, prevention of BPD is largely focused on maternal strategies to improve health (e.g., smoking cessation) or reduce risk of PTB (e.g., progesterone supplementation). Our studies in mice support a role for also targeting paternal factors to improve pregnancy outcomes and child health.