Disposition of bisphenol AF, a bisphenol A analogue, in hepatocytesin vitroand in male and female Harlan Sprague-Dawley rats and B6C3F1/N mice following oral and intravenous administration

Abstract

1. Bisphenol AF (BPAF) is used as a crosslinking agent for polymers and is being considered as a replacement for bisphenol A (BPA). 2. In this study, comparative clearance and metabolism of BPAF and BPA in hepatocytes and the disposition and metabolism of BPAF in rodents following oral administration of 3.4, 34 or 340 mg/kg [(14)C]BPAF were investigated. 3. BPAF was cleared more slowly than BPA in hepatocytes with the rate: rat > mouse > human. 4. [(14)C]BPAF was excreted primarily in feces by 72 h after oral administration to rats (65-80%) and mice (63-72%). Females excreted more in urine (rat, 15%; mouse, 24%) than males (rat, 1-4%; mouse, 10%). Residual tissue radioactivity was <2% of the dose at 72 h. Similar results were observed following intravenous administration. 5. In male rats, 52% of a 340 mg/kg oral dose was excreted in 24 h bile and was mostly comprised of BPAF glucuronide. However, >94% of fecal radioactivity was present as BPAF, suggesting extensive deconjugation in the intestine. 6. Metabolites identified in bile were BPAF-glucuronide, -diglucuronide, -glucuronide sulfate and -sulfate. 7. In conclusion, BPAF was well absorbed following gavage administration and highly metabolized and excreted mostly in the feces as BPAF.

A Demonstration of the Uncertainty in Predicting the Estrogenic Activity of Individual Chemicals and Mixtures From anIn VitroEstrogen Receptor Transcriptional Activation Assay (T47D-KBluc) to theIn VivoUterotrophic Assay Using Oral Exposure

“…BPAF has been shown to bind ERa (Laws et al, 2006;Matsushima et al, 2010), activate ER regulated gene transcription (Bermudez et al, 2010), stimulate MCF-7 cell proliferation (Hashimoto et al, 2001;Perez et al, 1998), and stimulate a uterotrophic response via subcutaneous administration (Akahori et al, 2008;Yamasaki et al, 2003). Toxicokinetic studies of BPAF following oral administration indicated that it is largely glucuronidated and/or sulfated and excreted in the feces similar to BPA, although more slowly (Waidyanatha et al, 2015;Yang et al, 2012). Currently, BPAF is undergoing extensive evaluations for in vivo toxicity by the National Toxicology Program.…”

Bisphenol AF as an Inducer of Estrogen Receptor β (ERβ): Evidence for Anti-estrogenic Effects at Higher Concentrations in Human Breast Cancer Cells

“…27) Thus, the toxicological impact of BPAF may be expected to be lower than that of BPA. However, Waidyanatha et al 28) previously reported that BPAF was absorbed well after its administration to experimental animals, and its clearance from the hepatocytes of rats and mice was slower than that of BPA, implicating "abnormalities" in BPAF, which allows its unexpected toxicological effects.…”

Bisphenol AF as an activator of human estrogen receptor β1 (ERβ1) in breast cancer cell lines

“…We recently reported that BPAF has the potential to up-regulate ERβ at the mRNA/protein level in human breast cancer cells at relatively "higher concentrations" (25 μM) ( Okazaki et al ., 2017 ). In addition, BPAF has been shown to exhibit abnormal behavior; although its log P ow ( i.e ., n -octanol/water: 2.82) is smaller than that of BPA (3.32), its clearance from hepatocytes is markedly slower than BPA, indicating that BPAF accumulates in cells, possibly leading to unwanted toxicological outcomes ( HSDB, 2001 ;NTP, 2008 ;Waidyanatha et al ., 2015 ). These fi ndings suggest that BPAF acts as an endocrine disruptor underlying the dual activation of ERβ1, i) a direct activator for the ERβ1 ligand at low concentrations (nM order) and ii) the induction of ERβ at high concentrations (μM order).…”

“…Among these bisphenols, the abnormal nature of BPAF (a fluorinated derivative of BPA: -CF 3 ) (See Fig. 1A) has been reported; it has been shown to more strongly accumulate in hepatocytes than parent BPA even though the hallmark of lipophilicity (e.g., P ow ) of BPAF is not as high as that of BPA (HSDB, 2001;NTP, 2008;Waidyanatha et al, 2015). Furthermore, studies on BPA and BPAF demonstrated that the activity of the latter for "ERβ" depended on the cell type employed (Matsushima et al, 2010;Li et al, 2012).…”