Disposition and Metabolism of the Bisphenol Analogue, Bisphenol S, in Harlan Sprague Dawley Rats and B6C3F1/N Mice and In Vitro in Hepatocytes from Rats, Mice, and Humans

Suramya Waidyanatha, Sherry R. Black, Rodney W. Snyder, Yun Lan Yueh, Vicki Sutherland, Purvi R. Patel, Scott L. Watson, and Timothy R. Fennell.
Toxicology and Applied Pharmacology (2018) DOI: https://doi.org/10.1016/j.taap.2018.05.008 PMID: 29753715

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Abstract

With the removal of bisphenol A (BPA) from many consumer products, the potential use of alternatives such as bisphenol S (BPS) and its derivatives is causing some concerns. These studies investigated the comparative in vitro hepatic clearance and metabolism of BPS and derivatives and the disposition and metabolism of BPS in rats and mice following gavage and intravenous administration. The clearance of BPS and its derivatives was slower in human hepatocytes than in rodents. In male rats following gavage administration of 50, 150, and 500 mg/kg [14C]BPS the main route of excretion was via urine; the urinary excretion decreased (72 to 48%) and the fecal excretion increased (16 to 30%) with increasing dose. The disposition was similar in female rats and male and female mice following gavage administration. Radioactivity remaining in tissues at 72 h in both species and sexes was ≤2.4%. In bile duct cannulated rats 53% of a gavage dose was secreted in bile suggesting extensive enterohepatic recirculation of [14C]BPS. Following an intravenous dose in rats and mice, the pattern of excretion was similar to gavage. These data suggest that the dose excreted in feces folowing gavage administration is likely the absorbed dose. Urinary metabolites included the glucuronide and sulfate conjugates with a moderate amount of parent. The pattern of in vitro hepatic metabolsim was similar to in vivo with some difference among derivatives. These data suggest that similar to other bisphenol analogues, BPS was well absorbed following oral expsosure and extensively excreted with minimal tissue retention.

Figures

Figure 1. Comparative clearance of bisphenol S and derivativesa in male and female rat, mouse and human hepatocytes.

^aBPS, bisphenol S;
2,4-BPS, 2,4-bisphenol S;
BPS-MAE, Bis(4-hydroxyphenyl)sulfonylphenyl;
D8, 4-Hydroxy-4’isopropoxydiphenylsulfone;
TGSA, 4,4’Sulfonylbis[2-(2-propenyl)]phenol;
BPS-MPE, 4-Benzyloxyphenyl-4-hydroxyphenyl sulfone;
D90, Bis(2-chloroethyl)ether-4,4”-dihydroxydiphenyl sulfone copolymer

Figure 1 (336 KB)

Figure 2. Concentration of radioactivity 72 h following gavage administration of [¹⁴C]BPS in male Harlan Sprague Dawley rats.

Figure 2 (173 KB)

Figure 3. Cumulative excretion in bile following gavage administration of 150 mg/kg [¹⁴C]BPS in Harlan Sprague Dawley rats.

Figure 3 (89 KB)

Figure 4. Concentration of radioactivity 72 h following gavage administration of 150 mg/kg [¹⁴C]BPS in male and female B6C3F1/N mice.

The radioactivity in adipose, lung, brain, heart, ovaries, pancreas, spleen, testes, and uterus are either very low or below the limit of detection and hence data for those tissues were not included in the figure.

Figure 4 (205 KB)

Figure 5. HPLC radiochromatograms of urine following gavage administration of 150 mg/kg in male mice.

A) before deconjugation
B) after deconjugation with β glucuronidase
C) after deconjugation with sulfatase.

Figure 5 (238 KB)

Figure 6. LC-MS/MS analysis of BPS glucuronide in urine collected 0 to 24 h following gavage administration of BPS (500 mg/kg) to male rats.

A: MRM transition of 425 → 107.9 m/z, indicative of BPS glucuronide.
B: Neutral loss of m/z 176, indicative of glucuronide conjugation.
C: Mass spectrum at 14.76 min, indicative of BPS glucuronide.

Figure 6 (214 KB)

Figure 7. LC-MS/MS Analysis of BPS sulfate in urine collected 0 to 24 h following gavage administration of BPS (500 mg/kg) to male HSD rats.

A) MRM transition of 329 → 107.9 m/z, indicative of BPS sulfate
B) Neutral loss of 80 m/z, indicative of sulfate conjugation
C) Mass spectrum at 27 min, indicative of BPS sulfate.

Figure 7 (213 KB)

Figure 8. Proposed metabolism of bisphenol S in rodents.

SULTs, sulfotransferases;
UGTs, uridine 5′-diphospho-glucuronosyltransferases;
CYP, cytochrome P450

Figure 8 (263 KB)

Tables

Table 1. Bisphenol S and derivatives used in the study.

Table 1 (401 KB)

Table 2. Analytical method qualification parameters for the quantification of BPS and derivatives in hepatocyte incubations.

Table 2 (37 KB)

Table 3. Distribution and cumulative excretion of radioactivity (Harlan Sprague Dawley rats).

Distribution and cumulative excretion of radioactivity following a single gavage or intravenous administration of [14C]BPS in male and female Harlan Sprague Dawley rats.

Table 3 (26 KB)

Table 4. Distribution and cumulative excretion of radioactivity (B6C3F1/N mice).

Distribution and cumulative excretion of radioactivity following a single gavage or intravenous administration of [14C]BPS in male and female B6C3F1/N mice.

Table 4 (26 KB)

Table 5. Estimated percent of administered dose represented by each peak in urine.

Estimated percent of administered dose represented by each peak in urine from Harlan Sprague Dawley rats and B6C3F1/N mice.

Table 5 (22 KB)

Table 6. Summary of metabolism of BPS and BPS derivatives in hepatocytes.

Table 6 (42 KB)

Supplemental Materials

Supplementary Data

Supplementary Data (434 KB)