# Exploring the Oncogenic Potential of Bisphenol F in Ovarian Cancer Development
## 1 Introduction  
Globally, ovarian cancer (OC) is the eighth most common cancer with 324,603 incident cases and 206,956 deaths [1]. The five-year survival rate for early-stage OC patients is 93%, as opposed to only 31% for those diagnosed at advanced stages, emphasizing the importance of early detection [2] for improving survival outcomes. In the past few years, bisphenol-A (BPA), a commonly used chemical for polycarbonate plastic production dating back to the 1950s, has been linked with cytotoxicity [3, 4], thereby regarding it as a public health concern. Human exposure to bisphenol is primarily attributed to its gradual degradation into its monomeric form [5], prompting several regulatory bodies to impose restrictions on its use [5]. This has led to increased use of BPA analogs, including BPS, Bisphenol F (BPF), andBPAF. Although initially discovered as a safer alternative to BPA, the eight BPA analogs, including BPF have been implicated in potentially adverse health effects [6; 7; 8]. There has been a surge in epidemiological studies exploring the association between bisphenol exposure and cancer risk. Higher urinary levels of BPA and BPS were significantly associated with an increased risk of developing lung cancer, particularly in men [9]. Similarly, elevated urinary BPA levels were associated with a higher risk of prostate cancer [10], and non-small cell lung cancer [11]. BPA contributes to tumor development by modulating cellular properties such as cell proliferation, migration and cell death by regulating various cancer signaling cascades such as PI3K/AKT, MAPK, and STAT3 pathways [12]. In papillary thyroid cancer, BPA reduced E-cadherin levels and increased vimentin levels, thereby inducing epithelial-mesenchymal transition, and cell invasiveness [13]. In OC, BPA-enhanced cell proliferation, invasion and migration through \(\text{E}\alpha/\text{AKT}/\text{mTOR}\), HIF-1\(\alpha\) cascade [14]. Similar to BPA, BPS regulates key cellular features involved in carcinogenesis. BPS promoted cell proliferation and induced elevated levels of vascular endothelial growth factor as well as stem cell marker (CD44) in breast cancer [15]. Further, BPS enhanced cell proliferation and invasion in prostate cancer [16], and migration in non-small cell lung cancer [17]. In OC, BPS and BPA promoted cancer cell stemness through the PINK1/p53 mitophagic cascade [18]. BPF is widely used in the manufacturing of epoxy resins, constituted in materials such as water pipes, plastics, varnishes and food containers [19]. Owing to its structural resemblance to BPA, BPF has been regarded as an endocrine-disrupting chemical [19]. Further, given the widespread occurrence in the environment, BPF has been detected in human biological samples, posing a threat to human health [20]. In a previous study, over 85% of urine samples from healthy individuals tested positive for BPF [5]. Similarly, another finding demonstrated the presence of urinary BPF in 42-88% of U.S. adults [21]. A wide range of health conditions such as cardiovascular diseases [22; 23], autoimmune disorders [24], diabetes, neurodegenerative issues [25; 26], metabolic disorders [27] and cancer [28; 29], have been reported to have an association with BPF [19; 30]. [PERSON] et al. (2023) [31] observed enhanced cell apoptosis and reduced cell survival in BPF-treated mouse TM3 Leydig cells, indicating the detrimental effects of BPF on the reproductive system. Further, BPF promoted intracellular ROS formation and reduced Nrf levels [31]. Surprisingly, intrinsic and extrinsic apoptosis was activated by BPF in human placental cells, thereby inducing cytotoxicity [32]. Similarly, BPF promoted apoptosis in osteoblasts, thereby preventing cell proliferation and affecting bone health [33]. The widespread detection of BPF in human urine and its function as an endocrine disruptor has raised concerns regarding potential involvement in tumorigenesis. Elevated BPF levels have been documented in papillary thyroid cancer [34].