Bisphenol A Increases BeWo Trophoblast Survival in Stress-Induced Paradigms through Regulation of Oxidative Stress and Apoptosis

Abstract

Bisphenol A (BPA) is ubiquitous in the environment and is reported to be present at high concentrations in placental tissue, where its presence raises concerns over its potential to disrupt placental function. This report investigates how BPA interferes with the survival of human choriocarcinoma BeWo cells (a model of placental trophoblasts) under stress-induced paradigms reminiscent of pathways activated in placental development. These include conditions that promote oxidative stress (glutathione depletion) and apoptosis (serum withdrawal) or mimic hypoxia (HIF-1α accumulation via dimethyloxalylglycine treatment). Treatment of BeWo cells with BPA during stress-induced paradigms led to a consistent and significant increase in cell viability, with a concomitant increase in glutathione levels and a reduction in apoptosis. Assessment of the antioxidant capacity of BPA revealed its ability to quench reactive oxygen species and reduce the levels generated during glutathione and serum depletion. BPA was also able to reduce the activation of the antioxidant response element (ARE) through mediation of its activators, nuclear factor erythroid related factor family members (Nrf's). Indeed, the expression and nuclear translocation of Nrf2 (an important ARE activator) were impaired by BPA, while Nrf1 and Nrf3 expression levels were increased. Furthermore, BPA increased the levels of the anti-apoptotic proteins (Bcl-2 and Hsp70) and decreased HIF-1α levels during stress-induced conditions. Together, these results indicate that BPA inhibits trophoblast cell death under conditions of cellular stress. This could have implications on placental trophoblasts during development.

Induction of oxidative stress by bisphenol A and its pleiotropic effects

“…As illustrated here, BPA can induce complex oxidative stress effects in cells related to the estrogen receptor status [LaPensee et al, ; Yin et al, ], the presence of non‐classical estrogen receptors like ERRγ [Ge et al, ], and even in absence androgen receptors [Koong and Watson, ]. Additionally, cellular microenvironment appears to play a key role in BPA's actions as well, with cells already experiencing stress from serum starvation or coexposed to other genotoxic agents showing pro‐survival [Lapensee et al, ; Dobrzyńska and Radzikowska, ; Gassman et al, ; Gassman et al, ] and even antioxidant roles for BPA [Chepelev et al, ; Ponniah et al, ], which have not yet been observed in other cells lines or animal models.…”

“…However, examination of the structure of BPA also illustrates its potential to act as a weak antioxidant via electron loss through the O‐H bond [Kadoma and Fujisawa, ; Kabuto et al, ; Chepelev et al, ]. Several reports have noted a reduction in ROS after BPA exposure and indicated the potential for ROS scavenging by BPA [Kabuto et al, ; Chepelev et al, ; Ge et al, ; Ponniah et al, ]. While the mechanisms underlying this effect have not been determined, contributing factors such as cellular microenvironment changes, cell type, and cell signaling responses could significantly contribute to the observed reduction in oxidative stress, as could differences in ROS measurement methods and time points [Kabuto et al, ; Chepelev et al, ; Ge et al, ; Ponniah et al, ].…”

“…Several reports have noted a reduction in ROS after BPA exposure and indicated the potential for ROS scavenging by BPA [Kabuto et al, ; Chepelev et al, ; Ge et al, ; Ponniah et al, ]. While the mechanisms underlying this effect have not been determined, contributing factors such as cellular microenvironment changes, cell type, and cell signaling responses could significantly contribute to the observed reduction in oxidative stress, as could differences in ROS measurement methods and time points [Kabuto et al, ; Chepelev et al, ; Ge et al, ; Ponniah et al, ]. However, it is interesting to note that like other polyphenolic compounds, BPA may maintain weak antioxidant activities.…”

“…However, it is interesting to note that like other polyphenolic compounds, BPA may maintain weak antioxidant activities. While the overall energetics and competition of stronger antioxidants in the cellular milieu may not normally favor these activities, cells which experience high level of oxidative stress from their environments or functions, like trophoblasts, may have microenvironments that promote BPA's antioxidant activities [Chepelev et al, ; Ponniah et al, ].…”

“…Additionally, gene expression changes in several important oncogenes, such as Myc and Stat3, have also been reported [Goodson et al, ; Dairkee et al, ; Ptak et al, ; Pfeifer et al, ; Weinhouse et al, ; Zhu et al, ], and knockdown of c‐Myc during BPA exposure was shown to reverse the induction of ROS and DNA damage [Pfeifer et al, ]. Conversely, studies that noted a reduction of ROS after BPA exposure observed an increase in Nrf proteins [Chepelev et al, ; Ponniah et al, ], and mRNA levels of heme oxygenase‐1 ( ho‐1 ) and NAD(P)H Quinone Dehydrogenase 1 ( nqo1 ) [Chepelev et al, ]. These changes indicated that BPA, when proposed to act as an antioxidant, stimulated antioxidant response elements in the genome to protect cells from oxidative stress [Chepelev et al, ].…”