Bisphenol F (BPF) and Bisphenol S (BPS)

A Systematic Review and Comparison of the Hormonal Activity of Bisphenol A Substitutes

Systematic review is an approach to answering research questions by systematically selecting, evaluating, and integrating scientific evidence.

Evidence that BPA might be harmful to human health due to its actions as an endocrine-disrupting chemical has prompted the industry to seek alternative chemicals.

This analysis summarizes in vivo and in vitro literature and compare the hormonal potency of BPS and BPF to BPA using the in vitro studies.

Abstract

Background
Increasing concern over bisphenol A (BPA) as an endocrine-disrupting chemical and its possible effects on human health have prompted the removal of BPA from consumer products, often labeled “BPA-free.” Some of the chemical replacements, however, are also bisphenols and may have similar physiological effects in organisms. Bisphenol S (BPS) and bisphenol F (BPF) are two such BPA substitutes.

Objectives
This review was carried out to evaluate the physiological effects and endocrine activities of the BPA substitutes BPS and BPF. Further, we compared the hormonal potency of BPS and BPF to that of BPA.

Methods
We conducted a systematic review based on the Office of Health Assessment and Translation (OHAT) protocol.

Results
We identified the body of literature to date, consisting of 32 studies (25 in vitro only, and 7 in vivo). The majority of these studies examined the hormonal activities of BPS and BPF and found their potency to be in the same order of magnitude and of similar action as BPA (estrogenic, antiestrogenic, androgenic, and antiandrogenic) in vitro and in vivo. BPS also has potencies similar to that of estradiol in membrane-mediated pathways, which are important for cellular actions such as proliferation, differentiation, and death. BPS and BPF also showed other effects in vitro and in vivo, such as altered organ weights, reproductive end points, and enzyme expression.

Conclusions
Based on the current literature, BPS and BPF are as hormonally active as BPA, and they have endocrine-disrupting effects.

BPA alternatives BPAF and BPS also alter mammary gland development

Evaluation of Prenatal Exposure to Bisphenol Analogues on Development and Long-Term Health of the Mammary Gland in Female Mice

Abstract

Background
Continued efforts to phase out bisphenol A (BPA) from consumer products have been met with the challenges of finding safer alternatives.

Objectives
This study aimed to determine whether early-life exposure to BPA and its related analogues, bisphenol AF (BPAF) and bisphenol S (BPS), could affect female pubertal mammary gland development and long-term mammary health in mice.

Methods
Timed pregnant CD-1 mice were exposed to vehicle, BPA (0.5, 5, 50mg/kg), BPAF (0.05, 0.5, 5mg/kg), or BPS (0.05, 0.5, 5mg/kg) via oral gavage between gestation days 10–17. Mammary glands were collected from resulting female offspring at postnatal day (PND) 20, 28, 35, and 56, and at 3, 8, and 14 months for whole mount, histopathological evaluation, and quantitative real-time polymerase chain reaction (qPCR); serum steroid concentrations were also measured at these time points.

Results
In the bisphenol-exposed mice, accelerated mammary gland development was evident during early puberty and persisted into adulthood. By late adulthood, mammary glands from bisphenol-exposed female offspring exhibited adverse morphology in comparison with controls; most prominent were undifferentiated duct ends, significantly more lobuloalveolar hyperplasia and perivascular inflammation, and various tumors, including adenocarcinomas. Effects were especially prominent in the BPAF 5mg/kg and BPS 0.5mg/kg groups. Serum steroid concentrations and mammary mRNA levels of Esr1, Pgr, Ar, and Gper1 were similar to controls.

Conclusions
These data demonstrate that prenatal exposure of mice to BPAF or BPS induced precocious development of the mammary gland, and that siblings were significantly more susceptible to spontaneous preneoplastic epithelial lesions and inflammation, with an incidence greater than that observed in vehicle- and BPA-exposed animals.

Our findings suggest that exposure to BPAF and BPS by consumers such as women of child-bearing age or infants and children should be restricted. The fetal mammary gland is a sensitive target organ for these chemicals. BPAF and BPS prenatally exposed female mice developed proliferative epithelial lesions by midlife, concomitant with a significant inflammatory response that may predispose them to tumor formation later in life. In fact, animals in the high-dose BPS group developed adenocarcinomas prior to one year of life and those diagnoses triggered a necropsy at 14 months of age in the remaining animals. Most neoplasia incidents in this study (7/8) occurred in the BPS-exposed animals. The extended presence of TEBs into adulthood (confirmed by histopathology), the significant prepubertal spikes in serum estradiol, and the altered immune responses (e.g., increased perivascular inflammation) may have been important modifiers of the persistent adverse effects observed later in life. To our knowledge, this study is the first report of BPAF- and BPS-induced adverse developmental effects in the mammary gland, and these findings warrant further studies to determine relevance of these findings for human breast cancer susceptibility. Featured image credit PNAS.

BPF, BPS and other bisphenol analogues found more estrogenic than BPA

“BPA-free” may mean very little for consumers trying to protect their health from endocrine disrupting chemicals

Six popular BPA alternatives all mimic estrogen in breast cancer cells; three of them more so than BPA itself, according to new research.

2017 Study Abstract

Background
Plasticizers with estrogenic activity, such as bisphenol A (BPA), have been reported to have potential adverse health effects in humans. Due to mounting evidence of these health effects and public pressure, BPA is being phased out by the plastics manufacturing industry and replaced by other bisphenol variants in “BPA-free” products.

Objectives
We have compared estrogenic activity of BPA to 6 bisphenol analogues (bisphenol S, BPS; bisphenol F, BPF; bisphenol AP, BPAP; bisphenol AF, BPAF; bisphenol Z, BPZ; bisphenol B, BPB) in three human breast cancer cell lines.

Methods
Estrogenicity was assessed by cell growth in an estrogen receptor (ER)-mediated cell proliferation assay, and by the induction of estrogen response element (ERE)-mediated transcription in a luciferase assay. Gene expression profiles were determined in MCF-7 human breast cancer cells by microarray analysis and confirmed by Illumina-based RNA sequencing.

Results
All bisphenols showed estrogenic activity in promoting cell growth and inducing ERE-mediated transcription. BPAF was the most potent bisphenol, followed by BPB > BPZ ~ BPA > BPF ~ BPAP > BPS. The addition of ICI 182,780 antagonized the activation of ERs by bisphenols. Data mining of ToxCast high-throughput screening assays confirms our results but also shows divergence in the sensitivities of the assays. The comparison of transcriptome profile alterations resulting from BPA alternatives with an ERα gene expression biomarker further indicates that all BPA alternatives act as ERα agonists in MCF-7 cells. These results were confirmed by RNA sequencing.

Conclusion
In conclusion, BPA alternatives are not necessarily less estrogenic in a human breast cancer cell model. Three bisphenols (BPAF, BPB, and BPZ) were more estrogenic than BPA. The relevance of human exposure to BPA alternatives in hormone-dependent breast cancer risk should be investigated.

Sources and More Information
  • Transcriptome profiling reveals bisphenol A alternatives activate estrogen receptor alpha in human breast cancer cells, bioRxiv, Mar. 2, 2017.
  • BPA-free? Substitutions mimic hormones in breast cancer cells, environmentalhealthnews, March 16, 2017.
  • BPA Free by Mark Morgan.

Evidence that bisphenol S crosses the human placenta

Common BPA alternative, BPS, crosses into placenta

Bisphenol S (BPS), found in baby bottles, personal care products and thermal receipts, is a replacement chemical for BPA and was introduced when concern was raised about possible health effects of that plastic compound.

As with BPA, there is evidence that BPS is an endocrine disruptor. Canadian and Chinese scientists have found the “first evidence” that BPS can cross the human placenta.

2017 Study Abstract

Human studies show associations between maternal bisphenol A (BPA) exposure and developmental effects in children, yet biomonitoring of BPA metabolites in maternal and fetal serum remains limited, and less is known for BPA alternatives. BPA-glucuronide, BPA-sulfate, and bisphenol S (BPS) were quantified in 61 pairs of maternal and cord sera from Chinese participants.

Bisphenol A Metabolites and Bisphenol S in Paired Maternal and Cord Serum, Environmental Science & Technology, DOI: 10.1021/acs.est.6b05718, January 22, 2017.

Total BPS was only detectable in four maternal (<0.03–0.07 ng/mL) and seven cord sera (<0.03–0.12 ng/mL), indicating low exposure but providing the first evidence that BPS crosses the human placenta. Total BPA metabolites in cord serum were significantly higher than in maternal serum (p < 0.05), suggesting that these may be formed in the fetus or cleared more slowly from the fetoplacental compartment. Unlike the pharmacokinetic results from controlled oral exposure studies in which BPA-glucuronide is the major BPA metabolite, here, BPA-sulfate was the dominant metabolite (GM: 0.06 and 0.08 ng/mL), significantly higher than BPA-glucuronide (GM: 0.02 and 0.04 ng/mL) (p < 0.01) in both maternal and cord sera. Moreover, the proportion of BPA-sulfate increased with total BPA.

These are the first human data for BPA metabolites in paired maternal and cord serum, and results suggest that the human fetus and pregnant mother have unique exposure to BPA metabolites. Direct analysis of BPA metabolites in serum provides complementary information for evaluating early life-stage exposure and risks of BPA.

BPS plastics compound may alter behavior and brain regions

Bisphenol S (BPS) alters maternal behavior and brain in mice exposed during pregnancy/lactation and their daughters

BPS, found in baby bottles, personal care products and thermal receipts, is a replacement chemical for BPA and was introduced when concern was raised about possible health effects of that plastic compound. As with BPA, there is evidence that BPS is an endocrine disruptor.

In the first study of its kind, environmental health scientist Laura Vandenberg and neuroscientist Mary Catanese at the University of Massachusetts Amherst examined the effects of the compound bisphenol S (BPS) on maternal behavior and related brain regions in mice. They found subtle but striking behavior changes in nesting mothers exposed during pregnancy and lactation and in their daughters exposed in utero.

Abstract

Estrogenic endocrine disrupting chemicals (EDCs) have been shown to disrupt maternal behavior in rodents. We investigated the effects of an emerging xenoestrogen, bisphenol S (BPS), on maternal behavior and brain in CD-1 mice exposed during pregnancy and lactation (F0 generation) and in female offspring exposed during gestation and perinatal development (F1 generation).

BPS affects maternal behavior as well as maternally relevant neural correlates

We observed different effects in F0 and F1 dams for a number of components of maternal behavior including time on the nest, time spent on nest-building, latency to retrieve pups, and latency to retrieve the entire litter. We also characterized expression of estrogen receptor (ER) alpha (α) in the medial preoptic area (MPOA) and quantified tyrosine hydroxylase (TH) immunoreactive cells in the ventral tegmental area (VTA), two brain regions critical for maternal care. BPS-treated females in the F0 generation had a significant increase in ERα expression in the caudal subregion of the central MPOA (cMPOA) in a dose dependent manner. In contrast, there were no significant effects of BPS on the MPOA in F1 dams or the VTA in either generation.

Uncovering effects of environmental chemicals that might influence proper maternal care have broad social and public health implications

This work demonstrates that BPS affects maternal behavior and brain with outcomes depending on generation, dose and postpartum period. Many studies examining effects of EDCs view the mother as a means by which offspring can be exposed during critical periods of development. Here, we demonstrate that pregnancy and lactation are vulnerable periods for the mother. We also show that developmental BPS exposure alters maternal behavior later in adulthood. Both findings have potential public health implications.

Biomonitoring of human exposures to chlorinated derivatives and structural analogs of bisphenol A

BPS, BPF, BPB and chlorinated derivatives likely to have similar effects than BPA

Bisphenol A (BPA) is a chemical that is widespread in the environment. Researchers reviewed and critically discussed the sources and routes of human exposure to chlorinated derivatives (ClxBPA) and alternatives to BPA (BPF, BPS), as well as their metabolism, toxicity and concentrations in human tissues. The researchers suggest BPA alternatives and derivatives may have similar effects, and provide directions for future research.

Abstract

Biomonitoring of human exposures to chlorinated derivatives and structural analogs of bisphenol A, ScienceDirect, Environmental Pollution, Volume 85, December 2015, Pages 352–379.

The high reactivity of bisphenol A (BPA) with disinfectant chlorine is evident in the instantaneous formation of chlorinated BPA derivatives (ClxBPA) in various environmental media that show increased estrogen-activity when compared with that of BPA.

The documented health risks associated with BPA exposures have led to the gradual market entry of BPA structural analogs, such as bisphenol S (BPS), bisphenol F (BPF), bisphenol B (BPB), etc. A suite of exposure sources to ClxBPA and BPA analogs in the domestic environment is anticipated to drive the nature and range of halogenated BPA derivatives that can form when residual BPA comes in contact with disinfectant in tap water and/or consumer products.

The primary objective of this review was to survey all available studies reporting biomonitoring protocols of ClxBPA and structural BPA analogs (BPS, BPF, BPB, etc.) in human matrices. Focus was paid on describing the analytical methodologies practiced for the analysis of ClxBPA and BPA analogs using hyphenated chromatography and mass spectrometry techniques, because current methodologies for human matrices are complex. During the last decade, an increasing number of ecotoxicological, cell-culture and animal-based and human studies dealing with ClxBPA exposure sources and routes of exposure, metabolism and toxicity have been published. Up to date findings indicated the association of ClxBPA with metabolic conditions, such as obesity, lipid accumulation, and type 2 diabetes mellitus, particularly in in-vitro and in-vivo studies. We critically discuss the limitations, research needs and future opportunities linked with the inclusion of ClxBPA and BPA analogs into exposure assessment protocols of relevant epidemiological studies.

Exposure to Bisphenol-A derivatives: BPA alternatives likely to have similar effects

Newer analogues may also have endocrine-disrupting effects

Bisphenol A (BPA) is present in many modern consumer products. It is found in common household equipment, food and drink cans, bottles and storage containers, CDs and vehicles, and has been found at high levels in cash-register receipts. Some scientific reports have linked exposure to BPA to endocrine (hormone) disruption, and lowered testosterone levels. In February this year, France proposed BPA as a REACH regulation candidate substance of very high concern.

Exposure to BPA derivatives: newer analogues may also have endocrine-disrupting effects, Science for Environment Policy News Alert, 08 April 2016.

As a result of these concerns, alternative substances have been introduced, with a similar but not identical structure to BPA. These analogues include bisphenol S and F (BPS, BPF), which have entered the consumer product market to provide the same functionality of BPA in a safer way. However, these compounds may still pose a risk to human health.

Biomonitoring of human exposures to chlorinated derivatives and structural analogs of bisphenol A, ScienceDirect, Environmental Pollution, Volume 85, December 2015, Pages 352–379.

When BPA comes into contact with chlorine in tap water, it forms chlorinated derivatives (ClxBPA), which humans may be exposed to through water use. Findings on the health effects of ClxBPA have been based on in vitro and in vivo experiments and suggest a 10–40 times higher estrogenic activity than BPA. The health risks of BPA analogues have also been studied in the lab, which have shown links to endocrine disturbance.

Measurement of chemicals in biological substances, such as urine or blood, is called biomonitoring, and is an important method of assessing human exposure to toxic compounds.

This study, which received support from European Structural Funds, explored the findings of biomonitoring studies on ClxBPA and BPA analogues. The researchers carried out an extensive literature search to identify studies reporting biomonitoring of ClxBPA and BPA structural analogues in human samples. This led to the selection of 23 relevant articles.

The first reported human biomonitoring of ClxBPA was in 2005, while for BPA alternatives it was in 2010. Since then, 21 peer-reviewed studies have been published reporting internal exposure measurements of ClxBPA and BPA alternatives in various human samples. Articles reporting ClxBPA in human samples include fatty tissue, placenta, breast milk, urine, plasma and serum, while those reporting BPA alternatives included only urine and breast milk. The authors could not identify any studies looking at BPA analogues in other biological samples, reflecting their newer status.

Overall, the evidence suggests that human exposure to ClxBPA and BPA alternatives is widespread. The compounds have been detected in a range of environmental media and consumer products. Although the sources and pathways of exposure remain unclear, evidence suggests that BPA and its chlorinated derivatives enter the body through the airways, skin contact and ingestion.

In vitro and in vivo studies suggest BPA alternatives and chlorinated derivatives may contribute to the development of diabetes and obesity. The authors say there is a need for studies that follow lots of people over time to better understand the human health effects. They discuss methodological advances in biomonitoring protocols, and explain the need for time- and cost-effective sample-preparation procedures, faster chromatography run times and smaller sample volumes. They also discuss the need to monitor other halogenated forms of BPA (in addition to ClxBPA), which have shown adverse health effects in some studies.

Studies on humans could help to close knowledge gaps, such as the pathways that lead to exposure, sources in the environment and the potential endocrine-disrupting properties of the aforementioned BPA compounds. The authors also recommend investigations into whether other phenols in the environment contribute to metabolic disorders.

BPS accelerates embryonic development, disrupts reproductive system

UCLA research suggests common substitute for BPA is not safer

zebrafish-embryo
On the far right, a zebrafish embryo breaks free from a group of unhatched sibling eggs. Zebrafish Lab.

Abstract

Actions of Bisphenol A and Bisphenol S on the Reproductive Neuroendocrine System During Early Development in Zebrafish, Endocrine Society , doi/10.1210/en.2015-1785, December 10, 2015.

Bisphenol A (BPA) is a well-known environmental endocrine-disrupting chemical and bisphenol S (BPS) has been considered a “safer” alternative for BPA-free products.

The present study aims to evaluate the impact of BPA and BPS on the reproductive neuroendocrine system during zebrafish embryonic and larval development, and to explore potential mechanisms of action associated with estrogen receptor (ER), thyroid hormone receptor (THRs) and enzyme aromatase (AROM) pathways.

Environmentally relevant, low levels of BPA exposure during development led to advanced hatching time, increased numbers of Gonadotropin-Releasing Hormone 3 (GnRH3) neurons in both terminal nerve and hypothalamus, increased expression of reproduction-related genes (kiss1, kiss1r, gnrh3, lhβ, fshβ, and erα) and a marker for synaptic transmission (sv2). Low levels of BPS exposure led to similar effects: increased numbers of hypothalamic GnRH3 neurons and increased expression of kiss1, gnrh3, and erα. Antagonists of ER, THRs and AROM blocked many of the effects of BPA and BPS on reproduction-related gene expression, providing evidence that those three pathways mediate the actions of BPA and BPS on the reproductive neuroendocrine system.

‘BPA-free’ plastic accelerates embryonic development, disrupts reproductive system, University of California, 1-FEB-2016.

This study demonstrates that alternatives to BPA used in the manufacture of BPA-free products are not necessarily safer. Further, this is the first study to describe the impact of low-level BPA and BPS exposure on the Kiss/Kissr system during development. It is also the first report of multiple cellular pathways (ERα, THRs and AROM) mediating the effects of BPA and BPS during embryonic development in any species.

BPS and BPF Systematic Review and Comparison of the Hormonal Activity

Why ‘BPA-Free’ May Be Meaningless

plastics image
“We’ve got to do something about putting brand new compounds in products without having consulted with biologists about what they do,” said Cheryl S. Watson, a professor at the University of Texas. Image via Hindrik Sijens.

2015 Study Abstract

Background:
Increasing concern over Bisphenol A (BPA) as an endocrine disrupting chemical and its possible effects on human health have prompted the removal of BPA from consumer products, often labeled “BPA-free.” Some of the chemical replacements however, are also bisphenols, and may have similar physiological effects in organisms. Bisphenol S (BPS) and bisphenol F (BPF) are two such BPA substitutes.

Objectives:
This review was carried out to evaluate the physiological effects and endocrine activities of the BPA substitutes BPS and BPF. Further, we compared the hormonal potency of BPS and BPF to BPA.

Methods:
We conducted a systematic review, based on the Office of Health Assessment and Translation (OHAT) protocol.

Results:
We identified the body of literature-to-date, consisting of 32 studies (25 in vitro only, and seven in vivo). The majority of these studies examined the hormonal activities of BPS and BPF and found their potency to be in the same order of magnitude and of similar action to BPA (estrogenic, anti-estrogenic, androgenic, and anti-androgenic) in vitro and in vivo. BPS also has potencies similar to estradiol in membrane-mediated pathways, which are important for cellular actions like proliferation, differentiation, and death. BPS and BPF also showed other effects in vitro and in vivo, such as altered organ weights, reproductive endpoints, and enzyme expression.

Conclusions:
Based on the current literature, BPS and BPF are as hormonally active as BPA, and have endocrine disrupting effects.

Sources and more information
  • Bisphenol S and F: A Systematic Review and Comparison of the Hormonal Activity of Bisphenol A Substitutes, Environ Health Perspect; DOI:10.1289/ehp.1408989, 16 March 2015, full study PDF.
  • Why ‘BPA-Free’ May Be Meaningless, time, April 15, 2015.

Can some plastics and chemicals like BPA and BPS be unsafe at any dose?

In the debate on plastics and endocrine disruptor chemicals safety, policy lags behind science

woman-and-child
In the debate on plastics and endocrine disruptor chemicals safety, policy lags behind science. Image by Lucas Hermann.

… ” the regulatory and industry approach to determine chemical safety has been to determine whether chemicals act like poisons – and generally not whether they act like hormones. And some scientists are concerned that this could lead to false conclusions of safety.” …

… ” A trillionth of a gram of a hormone in a milliliter of blood …is enough to alter the course of development of tissue in the fetus and lead to disease later on in life, Until plastics are tested at such minute levels, he says, we are in the dark about what levels of exposure are safe — especially for babies developing in the womb. ” …

Sept 2014 Study Abstract

Here we demonstrate that Bisphenol A  (BPA) exposure during a time point analogous to the second trimester in humans has real and measurable effects on brain development and behavior. Furthermore, our study is the first, to our knowledge, to show that bisphenol S, a replacement used in BPA-free products, equally affects neurodevelopment. These findings suggest that BPA-free products are not necessarily safe and support a societal push to remove all structurally similar bisphenol analogues and other compounds with endocrine-disruptive activity from consumer goods. Our data here, combined with over a dozen physiological and behavioral human studies that begin to point to the prenatal period as a BPA window of vulnerability, suggest that pregnant mothers limit exposure to plastics and receipts.

Jan 2014 Study Abstract

We measured serum dBPA in non-pregnant and pregnant female rhesus monkeys, fetuses and amniotic fluid. dBPA was administered by a daily oral bolus or sc implantation of Silastic capsules; both resulted in daily average serum unconjugated dBPA concentrations of <1ng/ml. We observed lower serum concentrations of unconjugated dBPA in pregnant females relative to pre-pregnancy values, and generally lower concentrations in fetal serum than in maternal serum. Differences in pharmacokinetics of dBPA were evident between pre-pregnancy, early and late pregnancy, likely reflecting changes in maternal, fetal and placental physiology. The serum ratio of conjugated to unconjugated dBPA after continuous sc release of dBPA was similar to values reported in human biomonitoring studies and markedly lower than with oral administration, suggesting oral bolus exposure is not an appropriate human exposure model. We report elsewhere that there were numerous adverse effects on fetuses exposed to very low serum dBPA in these studies.

Sources and more information
  • Very easy to read and very well documented, full of link studies links, read In The Debate On Plastics Safety, Policy Lags Behind Science, SoundMedicine, APR 13, 2015.
  • Bisphenol A (BPA) pharmacokinetics with daily oral bolus or continuous exposure via silastic capsules in pregnant rhesus monkeys: Relevance for human exposures, NCBI PMID:24582107, 2014 Jun;45:105-16 , sciencedirect, doi:10.1016/j.reprotox.2014.01.007, Reproductive Toxicology, Volume 45, June 2014.
  • Low-dose exposure to bisphenol A and replacement bisphenol S induces precocious hypothalamic neurogenesis in embryonic zebrafish, pnas, doi: 10.1073/pnas.1417731112, September 16, 2014.