Bisfenol A
Bisphenol A -BPA
-lipophilic compound [68]
- Detectable at nanomolar levels [68]
- In food [68]
- Tap water [68]
- In rivers, lakes and sea [68]
- In human blood samples and urine worldwide [68]
- In the placenta [68]
- In amniotic fluid of pregnant women [68]
- In human milk [68]
- Acute toxicity to aquatic organisms
- In the range of 1–10 g/ml for freshwater and marine species (Alexander et al., 1988) [87]
Výskyt BPA
- Key monomer in the production of the polycarbonate (74%) and epoxy resins (20%) [91]
- Primarily to make polycarbonate plastic
- Epoxy resins
- Phenol resins
- Polycarbonates
- Polyacrylates
- Polyesters
- Lacquer coatings on food cans (Staples et al., 1998) [87]
- Canned goods [57]
- BPA epoxy resin films to prevent corrosion [92]
- Compound used ubiquitously in the plastic manufacturing industry [57]
- In products containing polycarbonate plastics [68]
- Plastic food and beverage containers
- Including baby bottles
- water bottles
- Lining for metal cans [68]
- Dental sealants (Maserejian et al. 2014) [57]
- Wide use of BPA in water bottles [57]
- Electronics, sports safety equipment
- Adhesives
- Cash register receipts (thermal printing paper ) [92]
- Medical devices
- Dialysis patients appear to have higher rates of exposure [92]
- Eyeglass lenses
- water supply pipes
- Adjunct in the production of
- Brominated flame retardants
- Brake fluid
- BPA derivatives
- bisphenol A-glycidyl methacrylate
- bisphenol A-dimethacrylate
- Incorporated into the dental fillings and sealants
- Main exposure to BPA occurs through the diet
- Contaminated food and drinking water (Kang et al. 2006)
- Main factors influencing the migration of BPA from can surfaces are:
- Heating times
- Temperatures
- In the manufacturing process !!! [87]
- High levels of BPA were identified from
- Leachates of waste landfill
- (Yamada et al., 1999; Behnisch et al., 2001; Yamamoto et al., 2001; Filho et al., 2003) [87]
- Leaching of BPA from plastic wastes into water was also reported
- Highest levels (9.8 and 139 ug/g) were identified from polyvinylchloride products
- Use BPA as a stabilizer (Yamamoto and ara,1999)
- At room temperature, leaching of BPA occurred into the contained fluid
- Increased 55-fold if boiling water was added !!! [92]
- Exposure levels increased also with repeated use of a container !!! [92]
- All canned foods are autoclaved after canning
- The fact that bisphenol A is leached into water during autoclaving in these experiments suggests that any product packed in similar cans will contain bisphenol A
- It is also likely that substantially more bisphenol A will leach into fatty products [93]
- Synthetic estrogen and ubiquitous industrial contaminant
- Inducing DNA hypomethylation at Avy and another metastable epiallele, CabpIAP (Dolinoy et al., 2007) [1]
Metabolismus bisfenolu A mikroorganismy v prostředí
- Metabolites of BPA can enhance estrogenicity or toxicity [87]
- Many bacteria capable of biodegrading BPA have beeb identified from soils (Sasaki et al., 2005), river waters [87]
- Bacteria capable of biodegrading BPA are distributed in river waters [87]
- Half-lives for BPA biodegradation averaged below 5 days [87]
Bakterie
Gram-negative aerobic bacterium (strain MV1)
- Minor pathway
- Bisphenol A is first oxidized to a triol [86]
- Major pathway
- Intermediates 4-hydroxybenzoate and 4-hydroxyacetophenone
- Converted to carbon dioxide and biomass (Spivack et al., 1994) [86]
Sphingobium xenophagium Bayram and Sphingomonas sp. strain TTNP3
- Can metabolize bisphenol A
- Ipso-substitution mechanism
- Ring hydroxylation at the site of the substituent
- Product can be cleaved to form hydroquinone and a proposed 2-(4-hydroxyphenyl)-isopropyl cation
- To 4-(2-hydroxypropan-2-yl)phenol
- Dehydrogenation to form 4-isopropenylphenol
- Reduced to 4-isopropylphenol
- Other possible routes
- Formation of a 2-(4-hydroxyphenyl)-isopropyl anion (Gabriel et al., 2007, Kolvenbach et al., 2007) [86]
Sphingobium fuliginis TIK-1
- Can metabolize and grow on 4-isopropylphenol [86]
S. fuliginis
- Proposed to hydroxylate 4-ispropylphenol to 4-isopropylcatechol
- Metabolized by a meta-cleavage pathway
- 3-Methyl-2-butanone was the major degradation product observed (Toyama et al., 2010) [86]
Efektivita biodegradace
- Only two strains showed high BPA biodegradability (about 90%)
- Pseudomonas sp.
- Pseudomonas putida strain [87]
- Streptomyces sp. strain isolated from river water
- Has high BPA biodegradability (>90% for 10 days) [87]
- Influenced by temperature and bacterial counts [87]
- BPA in the anaerobic slurry was not biodegraded even after 3 months of incubation
- Anaerobic bacteria have no or little BPA biodegradability
- BPA in anaerobic environment such as anaerobic marine sediment can persist for an extended period of time [87]
Houby
- More effective for BPA biodegradation
- Fusar iumsporotrichioides NFRI-1012
- Fusariummoniliforme 2-2,
- Aspergillus terreus MT-13
- Emericella nidulans MT-98 [87]
- Mainly by
- Lignin-degrading enzymes
- Manganese peroxidase (MnP)
- Laccase
- Produced by white rot basidiomycetes fungi [87]
Plankton
- Chlorella fusca var. vacuolata
- Could biodegrade BPA and removed its estrogenic activity
- C. fusca
- Removal of BPA was
- 85% under light conditions for 120 h
- 22% under dark [87]
- BPA was accumulated in the zooplankton cells through the phytoplankton cells [87]
Rostliny
- Plants can rapidly absorb BPA from water
- Through their roots
- Metabolize it to several glycosidic compounds [87]
- Glycosylation of BPA main route in plants
- Loss the estrogenicity
- Distribution of BPA and its metabolites in plant may be variable according to plant species
Savci
- Free BPA is excreted in feces at the range of 56–82%
- Its metabolites are in urine at the range of 13–28%
- Metabolicke drahy degradace BPA savců
Glucuronidation
- Liver microsomes [87]
- Mediated by UGT2B1 n isoform of UGT
- Slightly less in pregnancy than in nonpregnancy
- Because multidrug resistance-associated protein II
- UGT decrease in pregnancy [87]
- UGT levels in the human fetal liver are lower / none compared to the adult liver [87]
Sulfation
- Sulfotransferases in the liver
- Humans:
- Simple phenol (P)-phenol sulfotransferase (SULT1A1)
- Thermostable phenol sulfotransferase (ST1A3)
PA exposure has been linked to: [57]
- Risk of miscarriages [57]
- Obesity [57]
- Cancer (Rochester 2013) [57]
- Breast and prostate
- Exposure of breast epithelial cells to BPA was found to alter gene expression of 170 genes [92]
- Increase their vulnerability to other carcinogens [92]
- Silencing of lysosomal-associated membrane protein 3
- Occurs in ER?-positive breast cancer [92]
- Irregular cycles [92]
- Multiple ovarian cysts [92]
- Reduction in primordial follicles [92]
- Placental dysfunction [92]
- Increased incidence of miscarriage and neonatal mortality [92]
- Precocious puberty [92]
- Erectile dysfunction [92]
- Decreased libido [92]
- Ejaculation difficulties [92]
- Workers producing this compound and its products (eg, epoxy resins) have been exposed to time-weighted average air levels to about 10 mg/m3 over decades
Bisphenol A
Synonyma
- BPA
- 2,2-bis(4-hydroxyphenyl)propane
- CAS Registry No. 80-05-7
- Composed of
- Two phenol rings
- Connected by a methyl bridge
- Two methyl functional groups attached to the bridge [87]
Chemické vlastnosti
- Made by combining acetone and phenol [87]
Historie
- 1930s
- Initially investigated for its potentially therapeutic estrogenic properties
- Diethylstilbestrol (DES) was found to be more potent [91]
- 1950s
- Commercial value was reassessed
- As a fundamental component in the manufacturing of some plastics
- Key monomer in the production of the most common form of clear and shatter-proof polycarbonate plastic [91]
Epidemiologie zamoření [68]
- One of the highest volume chemicals in worldwide production
- Estimated at 10-billion pounds per year in 2011 [68]
- All human fetuses that have been examined
- Have measurable blood levels of BPA [64]
- Mean or median levels found in humans
- Higher than levels in fetal and neonatal mice in response to maternal doses
- Increase postnatal growth [64]
- Lipophilic compound [68]
- Detectable at nanomolar levels [68]
- In food [68]
- Tap water [68]
- In rivers, lakes and sea [68]
- In human blood samples and urine worldwide [68]
- In the placenta [68]
- In amniotic fluid of pregnant women [68]
- In human milk [68]
- Acute toxicity to aquatic organisms
- In the range of 1–10 g/ml for freshwater and marine species (Alexander et al., 1988) [87]
Výskyt BPA
- Key monomer in the production of the polycarbonate (74%) and epoxy resins (20%) [91]
- Primarily to make polycarbonate plastic
- Epoxy resins
- Phenol resins
- Polycarbonates
- Polyacrylates
- Polyesters
- Lacquer coatings on food cans (Staples et al., 1998) [87]
- Canned goods [57]
- BPA epoxy resin films to prevent corrosion [92]
- Compound used ubiquitously in the plastic manufacturing industry [57]
- In products containing polycarbonate plastics [68]
- Plastic food and beverage containers
- Including baby bottles
- water bottles
- Lining for metal cans [68]
- Dental sealants (Maserejian et al. 2014) [57]
- Wide use of BPA in water bottles [57]
- Electronics, sports safety equipment
- Adhesives
- Cash register receipts (thermal printing paper ) [92]
- Medical devices
- Dialysis patients appear to have higher rates of exposure [92]
- Eyeglass lenses
- water supply pipes
- Adjunct in the production of
- Brominated flame retardants
- Brake fluid
- BPA derivatives
- bisphenol A-glycidyl methacrylate
- bisphenol A-dimethacrylate
- Incorporated into the dental fillings and sealants
- Main exposure to BPA occurs through the diet
- Contaminated food and drinking water (Kang et al. 2006)
- Main factors influencing the migration of BPA from can surfaces are:
- Heating times
- Temperatures
- In the manufacturing process !!! [87]
- High levels of BPA were identified from
- Leachates of waste landfill
- (Yamada et al., 1999; Behnisch et al., 2001; Yamamoto et al., 2001; Filho et al., 2003) [87]
- Leaching of BPA from plastic wastes into water was also reported
- Highest levels (9.8 and 139 ug/g) were identified from polyvinylchloride products
- Use BPA as a stabilizer (Yamamoto and ara,1999)
- At room temperature, leaching of BPA occurred into the contained fluid
- Increased 55-fold if boiling water was added !!! [92]
- Exposure levels increased also with repeated use of a container !!! [92]
- All canned foods are autoclaved after canning
- The fact that bisphenol A is leached into water during autoclaving in these experiments suggests that any product packed in similar cans will contain bisphenol A
- It is also likely that substantially more bisphenol A will leach into fatty products [93]
- Synthetic estrogen and ubiquitous industrial contaminant
- Inducing DNA hypomethylation at Avy and another metastable epiallele, CabpIAP (Dolinoy et al., 2007) [1]
Chození kolem horké kaše
- Regulatory agencies in the USA and Europe have focused on a very narrow set of BPA studies that followed regulatory guidelines and used “good laboratory practices (GLP)” protocols.
- This name does not imply “good science”
- GLP was instituted as a result of fraud in record keeping by commercial chemical testing laboratories [68]
- Lack of use of GLP protocols
- Greatly increase the cost of the research
- An inappropriate basis for rejecting studies for inclusion in assessing the health hazards of BPA [68]
- Selektivní výběr propagačních studií chemického průmyslu k obhajobě "neškodnosti" Bisfenolu A
- “For the third time since 2007, and as a result of a comprehensive review of more than 800 recent studies, EFSA has again confirmed that bisphenol A (BPA) is safe for use in products that come in contact with food,” said Steven G. Hentges, Ph.D., of the American Chemistry Council.
- 2012 U.S. Food and Drug Administration banned BPA in baby bottles and sippy cups. Its use is more broadly banned elsewhere in the world. [89]
- An extensive review conducted in 2007 concluded that
- BPA levels in human blood and/or urine are within the range shown to be dangerous in animals
- Are therefore likely to be biologically active in humans [92]
- Blood and urine testing may underestimate the full extent of exposure and bioaccumulation [92]
- Conversely, an industry-sponsored literature review from 2008 declared that
- Daily human consumption was far below dangerous levels and is therefore of minimal concern [92]
- In 2010 the Minister of Health for the Canadian Government declared the results of a four-year study indicating
- "Our science indicated that Bisphenol A may be harmful to both human health and the environment”
- The Canadian government became the first to prohibit the sale of BPA-containing polycarbonate baby bottles [92]
- France, Denmark and several American states have since implemented similar regulations [92]
Metabolismus bisfenolu A mikroorganismy v prostředí
- Metabolites of BPA can enhance estrogenicity or toxicity [87]
- Many bacteria capable of biodegrading BPA have beeb identified from soils (Sasaki et al., 2005), river waters [87]
- Bacteria capable of biodegrading BPA are distributed in river waters [87]
- Half-lives for BPA biodegradation averaged below 5 days [87]
Bakterie
Gram-negative aerobic bacterium (strain MV1)
- Minor pathway
- Bisphenol A is first oxidized to a triol [86]
- Major pathway
- Intermediates 4-hydroxybenzoate and 4-hydroxyacetophenone
- Converted to carbon dioxide and biomass (Spivack et al., 1994) [86]
Sphingobium xenophagium Bayram and Sphingomonas sp. strain TTNP3
- Can metabolize bisphenol A
- Ipso-substitution mechanism
- Ring hydroxylation at the site of the substituent
- Product can be cleaved to form hydroquinone and a proposed 2-(4-hydroxyphenyl)-isopropyl cation
- To 4-(2-hydroxypropan-2-yl)phenol
- Dehydrogenation to form 4-isopropenylphenol
- Reduced to 4-isopropylphenol
- Other possible routes
- Formation of a 2-(4-hydroxyphenyl)-isopropyl anion (Gabriel et al., 2007, Kolvenbach et al., 2007) [86]
Sphingobium fuliginis TIK-1
- Can metabolize and grow on 4-isopropylphenol [86]
S. fuliginis
- Proposed to hydroxylate 4-ispropylphenol to 4-isopropylcatechol
- Metabolized by a meta-cleavage pathway
- 3-Methyl-2-butanone was the major degradation product observed (Toyama et al., 2010) [86]
Efektivita biodegradace
- Only two strains showed high BPA biodegradability (about 90%)
- Pseudomonas sp.
- Pseudomonas putida strain [87]
- Streptomyces sp. strain isolated from river water
- Has high BPA biodegradability (>90% for 10 days) [87]
- Influenced by temperature and bacterial counts [87]
- BPA in the anaerobic slurry was not biodegraded even after 3 months of incubation
- Anaerobic bacteria have no or little BPA biodegradability
- BPA in anaerobic environment such as anaerobic marine sediment can persist for an extended period of time [87]
Houby
- More effective for BPA biodegradation
- Fusar iumsporotrichioides NFRI-1012
- Fusariummoniliforme 2-2,
- Aspergillus terreus MT-13
- Emericella nidulans MT-98 [87]
- Mainly by
- Lignin-degrading enzymes
- Manganese peroxidase (MnP)
- Laccase
- Produced by white rot basidiomycetes fungi [87]
Plankton
- Chlorella fusca var. vacuolata
- Could biodegrade BPA and removed its estrogenic activity
- C. fusca
- Removal of BPA was
- 85% under light conditions for 120 h
- 22% under dark [87]
- BPA was accumulated in the zooplankton cells through the phytoplankton cells [87]
Rostliny
- Plants can rapidly absorb BPA from water
- Through their roots
- Metabolize it to several glycosidic compounds [87]
- Glycosylation of BPA main route in plants
- Loss the estrogenicity
- Distribution of BPA and its metabolites in plant may be variable according to plant species
Ptáci a ryby
Farmakokinetika BPA (savci a lidi)
- P.o. absorbed BPA
- Subject to greater first pass metabolism in the liver versus parental apl. [68]
- Serum unconjugated BPA in adult rodents
- Maximum value reached after a bolus administration
- Average exposure over the 24 hr after administration does not differ based on route of administration
- Between 12 – 24 hr after administration [68]
- Average internal concentration of BPA over the 24 hr after administration via oral or sc route is actually not very different
- Dramatically contradicts assumptions made by the European Food Safety Agency [68]
- In newborn rodents
- Route of administration is even less of a factor than the relatively small effect it has in adults
- Adult prostate disease as a result of neonatal exposure
- To the same low 10 µg/kg/day dose of BPA oral or sc administration [68]
- Pharmacokinetics of BPA does not differ between mice, rhesus monkeys and humans [68]
Savci
- Free BPA is excreted in feces at the range of 56–82%
- Its metabolites are in urine at the range of 13–28%
- Metabolicke drahy degradace BPA savců
Glucuronidation
- Liver microsomes [87]
- Mediated by UGT2B1 n isoform of UGT
- Slightly less in pregnancy than in nonpregnancy
- Because multidrug resistance-associated protein II
- UGT decrease in pregnancy [87]
- UGT levels in the human fetal liver are lower / none compared to the adult liver [87]
Sulfation
- Sulfotransferases in the liver
- Humans:
- Simple phenol (P)-phenol sulfotransferase (SULT1A1)
- Thermostable phenol sulfotransferase (ST1A3)
Potkani
- After glucuronidation or sulfation in the rat liver
- Metabolites of BPA are excreted mainly into the bile [87]
- The venous excretion of metabilites increases three-fold in pregnancy [87]
- Mainly BPA glucuronide, in the liver [88]
- After 2-3 days, excretion of BPA and its metabolites, mainly in the feces, is mostly complete [88]
- A very small fraction, less than 1%, is retained in the tissues [88]
- Microsomal cytochrome P450 enzymes in rat liver
- Inhibitor of the cytochrome P450 system, SKF 525-A, inhibited the metabolism of BPA
- Metabolize BPA into bisphenol-o-quinone via
- 5-hydroxy BPA
- A bisphe-nol semiquinone [87]
- BPA can inhibit human hepatic cytochromeP450s
- Metabolites of BPA produced by microsomal cytochrome P450s
- Enhanced toxic activity
- DNA adduct formation with BPA metabolites (Atkinson and Roy, 1995a,b) [87]
- Bisphenol-o-quinone, could bind DNA in vitro and in vivo
- Estrogenni aktivita zesilena
- 4-methyl-2,4-bis(p-hydroxyphenyl)pent-1-ene (MBP)
Humans
- Three males and three females, and four males [85]
- Administered d(16)-bisphenol A (5 mg)
- Blood and urine samples were taken in intervals (up to 96 h)
- D(16)-Bisphenol A glucuronide
- Was the only metabolite of d(16)-bisphenol A detected in urine and blood samples [85]
- Concentrations of free d(16)-bisphenol A
- Were below the limit of detection both in urine (6 nM) and blood samples (10 nM) [85]
- D(16)-Bisphenol A glucuronide
- Cleared from human blood and excreted with urine
- With terminal half-lives of less than 6 h [85]
- Applied doses
- Completely recovered in urine as d(16)-bisphenol A glucuronide [85]
- Maximum blood levels of d(16)-bisphenol A glucuronide
- Approximately 800 nM
- 80 min after p.o. administration of d(16)-bisphenol A (5 mg) [85]
- Enterohepatic circulation of bisphenol A glucuronide
- In rats results in a slow rate of excretion
- By humans - bisphenol A is rapidly conjugated and excreted due to the absence of enterohepatic circulation [85]
- Efficient glucuronidation of bisphenol A and the rapid excretion of the formed glucuronide [85]
- In humans, 100% of BPA-G was cleared via urinary elimination
- Whereas in rodents there was extensive excretion via the bile
- In humans and other primates p.o. BPA
- Free BPA in blood was typically below detection limits
- Or represented a very small fraction of the total circulating metabolites
- The predominant form of circulating BPA was BPA-G [91]
- Cave - novorozenci
- Undeveloped constitutive expression of uridine glucuronosyltransferase (UGT) [91]
- Absorpce rychlejsi u lidi a primatu nez u potkanu
- Longer time to eliminate BPA from serum in primates than in rats [87]
- Human liver microsomes can’t glucuronidate BPA as extensively as the rat liver microsomes
- The very complete conversion to the BPA glucuronide means that
- Effects in rodents due to the parent compound (BPA) are unlikely to be found in humans [88]
- Glucuronide metabolite, which is formed rapidly and almost exclusively in humans
- Does not bind to the estrogen receptor
- Suggests that BPA is even less likely to be an endocrine modulator than was concluded on the basis of the results of the rodent-metabolism studies [88]
- BPA-glucuronide and the minor urinary metabolite BPA-sulphate do not interfere with hormonal regulation of reproduction [90]
- Dubbed MBP
- 2004, Shin'ichi Yoshihara, PhD, and colleagues at Hiroshima International University
- Produced when BPA was metabolized
- MBP has a 100-fold to 1,000-fold stronger bond to the estrogen receptor than BPA [89]
- MBP’s longer structure allows both ends of the chemical to interact with the estrogen receptor in a way similar to estradiol.
- MBP is one (of perhaps several BPA metabolites) that causes disruption of estrogen signaling in humans and other animals [89]
- P.o. unconjugated BPA
- Biologically active form of BPA
- Historically been thought to be:
- Rapidly conjugated in the liver
- Then excreted through bile or urine, with a half life of cca 5.3 h
- Rapid excretion has been the basis of reassuring safety evaluations and declarations given by some public health authorities worldwide [92]
- Particularly in the lungs, livers and kidneys in rats, and the placenta of animals and humans
- ß-glucuronidase enzyme is present at detectable concentration
- Deconjugate BPA and release its active form again
- In pregnancy fetal exposure in utero [92]
- May also result in bioaccumulation of some portion of BPA after exposure
- Most plasma BPA (about 95%) is bound to serum proteins
- At low concentrations BPA has lipophilic affinity:
- Fat: blood coefficient of 3.3
- In fat, the accumulation of BPA was cca 3 x higher than in other tissues [92]
- In normal circumstances the daily volume of urine is much higher than sweat
- Urine remains an important mode of elimination of BPA from the human body [92]
Vlivy na organismus [53]
- Environmentally BPA doses
- Induce changes in gene expression [53]
- Affect their activity [53]
- Large number of genes are modulated by BPA
- Induce negative health effects (Singh & Li 2012) [53]
- Endocrine disruption [92]
- Epigenetic modification [92]
- Cytokine release [92]
- Oxidative stress [92]
PA exposure has been linked to: [57]
- Risk of miscarriages [57]
- Obesity [57]
- Cancer (Rochester 2013) [57]
- Breast and prostate
- Exposure of breast epithelial cells to BPA was found to alter gene expression of 170 genes [92]
- Increase their vulnerability to other carcinogens [92]
- Silencing of lysosomal-associated membrane protein 3
- Occurs in ER?-positive breast cancer [92]
- Irregular cycles [92]
- Multiple ovarian cysts [92]
- Reduction in primordial follicles [92]
- Placental dysfunction [92]
- Increased incidence of miscarriage and neonatal mortality [92]
- Precocious puberty [92]
- Erectile dysfunction [92]
- Decreased libido [92]
- Ejaculation difficulties [92]
- Interference with the production and signaling of sex hormones [92]
- Led to neurological impairment [92]
- Synapse formation during development is regulated by estrogen and androgens [92]
- Levels deemed safe by the US Environment Protection Agency [92]
- Completely abolish the response of synapses to estrogen in the prefrontal cortex and hippocampus [92]
- Metabolic syndrome
- Obesity
- Non-insulin-dependent diabetes mellitus
- Allergies and asthma
- ADHD, autism, cognitive decline, memory impairment
- Depression, and anxiety
- Accumulate in fat
- With 50% of breast adipose tissue from women containing BPA (Fernandez et al. 2007) [57]
- Workers producing this compound and its products (eg, epoxy resins) have been exposed to time-weighted average air levels to about 10 mg/m3 over decades
Děti
- Human neonates
- Glucuronidation (2-5 fold lower in premature neonates)
- Glomerular filtration (1.7 fold lower)
- Within one and seven months after birth
- Considered sufficient capacity in the neonate to conjugate BPA at doses below 1 mg/kg bw [90]
- That exposures at the TDI of 0.05mg/kg bw are 20 fold lower than this [90]
Hormonální dirupce
- Endocrine disruptor
- Activation of estrogen receptors alfa and ß (ERß) (Wozniak et al. 2005, Welshons et al. 2006, Le et al. 2008, Kim et al. 2012, Li et al. 2012, Chen Zee et al. 2013) [57]
- Competing with endogenous hormones [53]
- estrogen-like properties [53]
- Low environmentally doses - can act as an estrogen antagonist [53]
- Non-classical ER pathways (Li et al. 2012, Boucher et al. 2014) [53]
- Increases in weight and size of the prostate gland in male offspring of treated mice
- Decreases in sperm efficiency in young mice [88]
- Disrupting effects on the: [53]
- Classical nuclear receptors estrogen receptors alpha and beta (ER alfa and ER beta) [53]
- Non-classical membrane estrogen receptor (ncmER) [53]
- estrogen-related receptor gamma (ERR gamma) [53]
- G protein-coupled receptor 30 (GPR30) [53]
- Aryl hydrocarbon receptor (AhR) (Hugo et al. 2008, Alonso-Magdalena et al. 2012) [53]
Animal models, BPA has been shown to disrupt:
- Thyroid hormones [53]
- Estrogens [53]
- testosterone [53]
- Corticosteroids [53]
- Growth hormone [53]
- Leptin [53]
- Alter adipogenesis [53]
- Beta-cell and endocrine pancreas function [53]
- Inflammation [53]
- Insulin sensitivity [53]
- Found to be oestrogenic in the MCF-7 human breast cancer cell culture in 1993 (Krishnan et al., 1993)
- Concentrations as low as 2-5 ppb (2-5 µg/l)
- Can also act as an antiandrogen
- Blocking the action of dihydrotestosterone in a yeast screen containing a human androgen receptor (Sohoni and Sumpter, 1998)
- Cca as potent as flutamide, a well known anti-androgen
- Liquor containing bisphenol-A obtained from tinned vegetables
- Found to be oestrogenic to human breast cancer cells
- Identical effects to oestradiol on rat uterus and vagina
- Exposure of developing male mice
- Enlarge their prostate glands
- Female mice exposed in the womb to low doses of bisphenol a (2.4 micro-g per kg per day to the mother)
- Significantly reduced delay between vaginal opening and first vaginal oestrus (Howdeshell et al., 1999)
Estrogens
- Shared homology with estrogen [57]
- Upregulation of downstream targets [57]
- Peroxisome proliferator-activated receptor gamma (PPARG) [57]
- Lipoprotein lipase (LPL) genes on rodents (Melzer et al. 2011) [57]
- Regulate cellular metabolism by programming gene expression in adipocytes
- Implicated in metabolic disorder restoration
- In adipose tissue
- ERß is less expressed than ER alfa (Hugo et al. 2008) [57]
- Overexpression of ERR alfa
- High binding affinity of BPA for ERR alfa (Takayanagi et al. 2006, Okada et al. 2008)
- ERR alfa
- A constitutive activator of transcription
- Able to modulate the estrogen-signaling pathway not by binding directly to E2
- By controlling the transcription of essential genes that regulate metabolic processes (Liu et al. 2007, Giguere 2008) [53]
- Expression also increased after E2 treatment
- Lack of estrogens
- Increases fat mass
- Impairs glucose tolerance
- Lead to insulin resistance (Vom Saal et al. 2012) [53]
Low doses of BPA
- Modulated the abundance of the ER alfa transcript
- no changes in ERß mRNA levels were found [57]
- BPA may exert its action through non-classical estrogen receptors
- Independent effects (Hugo et al. 2008, Tohme et al. 2014)
- High BPA accumulation in adipose tissue
- Increasing the abundance of ERR alfa transcripts [57]
- BPA activity varies depending on
- Specific estrogen receptor expression
- Distribution of those receptors within tissues [57]
- BPA elicit
- Rapid responses by binding GPR30
- Activating alternative non-genomic estrogen signaling pathways (Thomas & Dong 2006)
- GPR30 knockout mice displayed
- Impaired glucose tolerance
- Reduced body growth
- Increased body weight (Martensson et al. 2009, Ford et al. 2011) [57]
- Increased plasma concentrations of estrogens [68]
- Associated with a reduction in food intake
- Red. body weight in adults [68]
- Loss of ovarian estrogen secretion related to menopause in women
- Results in weight gain
- During critical periods in development, estrogenic chemicals
- Can have unexpected effects
- Differentiation of adipocytes [68]
- Postnatal growth [68]
- “programming” of obesity related to exposure to environmental estrogens during critical periods in organogenesis
- Adult mice - estradiol-17 beta - via estrogen receptor alfa
- Inhibitory effect on adipocyte number and lipogenesis [68]
- Ovariectomy or genetic mutation in the gene controlling the enzyme aromatase (CYP19)
- Impaired glucose tolerance
- Insulin resistance
- Increased fat mass [68]
- Central effects on food consumption and energy expenditure
- Overall inhibitory effects on adipose deposition in adults [68]
- Estrogens and other hormones
- Can cause permanent changes - “organizational” effects
- By programming gene expression when cells are differentiating - “critical periods ” [68]
- Mechanisms that determine:
- Which genes in a cell can be transcribed
- The level at which transcription occurs [68]
- Jsou ovlivňovány i:
- Epigenetic modifications of DNA
- Associated histone proteins [68]
- estrogenic EDCs can:
- Program gene activity via epigenetic changes during critical periods in development
- With long-term consequences [68]
- Methylation sensitive promoter
- Genistein (increased methylation)
- bisphenol A (decreased methylation)
- Predicted an adult phenotype of yellow coat color, diabetes, tumors and obesity [68]
- Coat color
- Obesity in mice [68]
- “fetal estrogenization syndrome” [68]
Obezitogenní
- Increase fat cell numbers or sizes [53]
- Increases expression of FABP4 and CD36 [53]
- Involved in lipid metabolism [53]
- BPA exposure during adipocyte differentiation
- Affects gene expression
- Modulates adipose tissue functions:
- PPAR
- C/EBP
- LPL
- GLUT4
- CYP19 [57]
- GPAT
- DGAT
- Leptin (OB) (Vom Saal et al. 2012, Boucher et al. 2014, Ohlstein et al. 2014) [57]
- Increases lipoprotein lipase gene expression
- Tím i enzymatic activity
- Leads to triacylglycerol accumulation (Masuno et al. 2002) [57]
- Increase glucose transporter GLUT4 levels
- Alter glucose uptake (Masuno et al. 2002, Sakurai et al. 2004)
- Up-regulation of leptin mRNA levels (Angle et al. 2013) [57]
- Jako důkaz většího obsahu tuku v tukové tkáni
FABP4
- Produced in adipocytes
- Fatty acid uptake and metabolism
- Important contributor to metabolic dysfunction in obesity-induced chronic inflammation and dyslipidemia (Hardaway & Podgorski 2013)
- Elevated FABP4 plasma levels
- Associated with metabolic syndrome (Xu et al. 2007)
- Obesogenic role for BPA
- BPA Up-regulation of FABP4 and CD36
- Significant increase in intracellular lipid droplets and in triglyceride concentration
- BPA affects adipocyte lipid storage which leads to cellular hypertrophy
- Results in a resistin secretion increase
- Decrease in adiponectin production in vitro
- (C Menale, A Grandone, C Nicolucci, G Cirillo, S Crispi, A Di Sessa, S Rossi, D G Mita, L Perrone, E M Del Giudice, N Diano, unpublished observations)
- Might impair glucose metabolism
- Confirmed by preliminary experiments performed in a mouse model (C Menale, personal communication)
- Might increase the oxidative stress of hypertrophic adipocytes
- Might contribute to the inflammation and dysregulation of free fatty acid efflux (Zha & Zhou 2012)
PC1/3
- Cleaves pro-insulin to produce active insulin
- Mutations of or deficiencies in PC1/3
- Cause early obesity (Creemers et al. 2012, Turpeinen et al. 2013)
- Deficiency of PCSK1
- Leads to serious multi-hormonal disorder marked by early-onset obesity (Jackson et al. 1997) [57]
BPA mediates adipogenesis through an ER-dependent pathway gen expression
- 1. signif. elevace exprese adipogennních genů již 7. den po oš. BPA: [53]
- Mid-stage adipogenesis [53]
- C/EBP [53]
- Late adipogenic genes [53]
- IGF1 [53]
- LPL [53]
- The greatest induction !!! [53]
- Master transcriptional regulator of adipogenesis [53]
- PPAR [53]
- Upon treatment with the ER antagonist ICI 182 780
- The effect of BPA on adipogenic differentiation was blocked [53]
- Prenatal exposure to BPA in rodents
- Increased white adipose depots
- Increased expression of C/EBP?, PPAR?, and LPL [57]
- Induction of DLK and IGF1 mRNA transcripts
- DLK expression has been linked to adipogenesis
- Target of PPAR transcriptional activity (Couture & Blouin 2011) [57]
- IGF1 has been associated with obesity, insulin resistance, and adipogenesis (De Pergola & Silvestris 2013, Xie & Wang 2013) [57]
- In mouse 3T3-L1 cells BPA increased
- Lipoprotein lipase (LPL) activity
- Triacylglycerol accumulation
- Presence of larger lipid droplets in the differentiated cells [68]
- Insulin and BPA interacted synergistically to further accelerate these processes
- BPA also stimulated an
- Increase in the glucose transporter GLUT4
- Glucose uptake into 3T3-F442A adipocytes [68]
- Up-regulation of GLUT4
- Increased basal and insulin-induced glucose uptake into adipocytes
Koncentrace BPA
- BPA has a maximal effect at a concentration of 1 µM [57]
- Significant increase in adipogenesis in ASCs treated for 14 days at levels as low as 100 pM was observed
- Average BPA serum levels
- Between 1 and 20 nM [57]
- With BPA showing activity in cellular assays as low at 1 pM to 1 nM
- Robust response to BPA at 21 days
- Substantial increase in transcriptional activity at day 7 was observed
- Increased adipogenesis at 14 days in response to lower concentrations of BPA was noted [57]
- Even low-level exposure to BPA can expedite differentiation of ASCs into a mature adipocytes [57]
- Maximal effect at a concentration of 1 µM [68]
- Observed cell death at a concentration of 10 µM [68]
Prozánětlivý
- Increases the expression of pro-inflammatory cytokines [53]
CCL20
- Gen pro cytokine
- Hldina v krvi directly correlated with BMI (Hashimoto et al. 2006, Duffaut et al. 2009, Villaret et al. 2010) [53]
- Elevated serum CCL13 and CCL20 concentrations [53]
- In overweight subjects during chronic inflammation [53]
- IL18 and IL1B [53]
- Regulators of inflammatory responses
Diabetogenní
- Decreases the expression of PCSK1 [53]
- Involved in insulin production [53]
- Involved in the onset of metabolic dysfunction [53]
- Reduced insulin-stimulated tyrosine phosphorylation of insulin receptors
- In adult adipocytes treated with BPA [53]
- Reduction of insulin downstream signaling [53]
- Associations between serum and urinary concentrations of persistent organic pollutants and diabetes have been described
- Women with Polycystic Ovary Syndrome (PCOS)
- Insulin resistance
- Low-grade chronic inflammation
- Elevated serum BPA levels [59]
BPA exposure
- Cultured adipose cells derived from human subcutaneous tissue
- 3T3-L1 adipocytes
- Impaired
- Insulin sensitivity
- Glucose utilization
- Enhanced
- Release of pro-inflammatory compounds
- Even in the absence of major derangement of adipocyte differentiation [59]
- Nanomolar BPA concentrations [59]
- May induce an inflammation-like response in human adipocytes [59]
- Increases the release of IL-6 and IFN [59]
- Aktivace JNK, JAK/STAT and NF-kB pathways [59]
- Binds G protein-coupled receptor 30 (GPR30)
- Novel non-classical membrane ER
- Might induce biological effects in different cell types, including adipocytes [59]
- BPA-treated adipocytes were less sensitive to insulin in terms of glucose utilization
- Effect was already detectable upon treatment of the cells with 1 nM BPA [59]
- BPA stimulated an increase in GLUT4 and glucose uptake in adipocytic cell models
- Required doses considerably higher than those found in human tissues [59]
- Increased basal glucose utilization
- Increased levels of GLUT1 [59]
- BPA-induced insulin sensitivity
- May contribute to worsen the pro-inflammatory profile [59]
- Reduced insulin-stimulated tyrosine phosphorylation of insulin receptor
- Reduction of downstream signalling
- Can be responsible for a worsening in insulin signalling via PKB/Akt and ERK
- Reduction in insulin sensitivity in fat tissue [59]
- Insulin suppresses the inflammatory process (in BPA treated adipocytes)
- Preventing hyperglycemia [59]
- Modulating key inflammatory molecules [59]
- Decrease of leptin levels observed in BPA-treated adipocytes
- May be due to reduced insulin promotion of leptin gene expression [59]
- Inhibition of JNK activity
- Almost completely restored insulin receptor signalling
- Largely rescued insulin-stimulated glucose utilization in BPA-treated adipocytes [59]
- Suggesting a primary involvement of inflammatory factors [59]
- Exposure to BPA
- Impairs insulin sensitivity
- Induces the release of inflammatory factors in adipocytes [59]
- One possible mechanism
- BPA activates JNK, via TLRs or ERs [59]
- May directly impair insulin action [59]
- Release of IL-6 and IFN
- Contribute to JNK activation in the adipocytes
- Down-regulate insulin-stimulated glucose uptake [59]
PCSK1
- Encodes pro-protein convertase subtilisin/kexin type 1 (PC1/3) [53]
- Pro-insulin-processing enzyme
- Regulates insulin biosynthesis
- BPA effectively impairs active insulin production [53]
- Its decrease is related to PCSK1 mRNA down-regulation [53]
- PCSK1 could be considered a new player that is involved in the endocrine disruption that is caused by BPA
- Key role in the deregulation of insulin biosynthesis [53]
- BPA exposure in the mouse impairs glucose tolerance by compromising insulin production and/or secretion
CD36
- Integral membrane protein that binds oxidized lipoproteins and lipids (Endemann et al. 1993) [53]
- Key role in fatty acid and glucose metabolism [53]
- Dysregulation in glucose intolerance and diabetes (Hajri et al. 2002, Rac et al. 2007) [53]
- CD36 null mice [53]
- Display enhanced insulin responsiveness [53]
- Associated with a reduction in fat deposition (Hajri et al. 2002) [53]
IL1B [53]
- Associated with insulin resistance and type 2 diabetes (Tack et al. 2012) [53]
- Its inhibition reduces hyperglycemic inflammation in obese mice (Owyang et al. 2010) [53]
- Low doses of BPA
- Stimulated rapid secretion of insulin in mouse pancreatic ß cells in primary culture
- Through a non-classical, non-genomic estrogen-response system
- Magnitude of the response was the same at equal doses of BPA and estradiol [68]
- Prolonged exposure to a low oral dose of BPA (10 µg/kg/day)
- Stimulation of insulin secretion in adult mice
- Mediated by the classical nuclear estrogen receptors [68]
- Later was followed by insulin resistance [68]
Děti
- Higher and more dangerous in infants and children
- Can lead to the onset of several diseases [53]
- Cancer [53]
- Endometriosis [53]
- Birth defects [53]
- Developmental and neuronal disorders (Rochester 2013, Delclos et al. 2014) [53]
- Associated with obesity and metabolic disorders (Rochester 2013, Lakind et al. 2014)
- Specifically in children (Trasande et al. 2012, Lee et al. 2013, Nicolucci et al. 2013) [53]
- Environmentally relevant BPA concentrations in adipocytes from children [53]
- Increase the expression and the enzymatic activity of 11ß-hydroxysteroid dehydrogenase type 1 ::53:---key enzyme in adipocyte differentiation and lipid synthesis !!!
- Stimulate preadipocyte differentiation and adipogenesis
- Can thus promote obesity in childhood [53]
- Non-linear effects during childhood [53]
- Exposure to BPA just prior to puberty
- Increase body weight [68]
Epigenetické vlivy
- Maternal exposure
- Synthetic estrogen and ubiquitous industrial contaminant
- Inducing DNA hypomethylation at Avy and another metastable epiallele, CabpIAP (Dolinoy et al., 2007) [1]
- BPA and estradiol
- Generally equally potent as activators of receptors associated with the cell membrane
- Initiate rapid signaling cascades at concentrations as low as 0.01 pM [68]
- BPA is considered to be a SERM
- Variety of unique effects relative to estradiol [68]
- Exposure during gestation and lactation to BPA
- Result in a wide range of effects
- Disruption of all organs in the male and female reproductive system
- Neuroendocrine effects [68]
- Exposure to low doses of BPA during the perinatal period of development
- Increase in body weight [68]
- Neonatal exposure to a low dose (1 µg/kg/day) of the estrogenic drug diethylstilbestrol (DES)
- Also stimulated a subsequent increase in body weight
- Increase in body fat in mice [68]
- 1 nM or 0.23 ng/ml during the first two days after in vitro fertilization
- Accelerated the rate of cell division of the fertilized oocyte [68]
- After implantation of embryos exposed in vitro for two days to 1 nM BPA into an untreated female mouse
- Accelerated postnatal growth of the offspring [68]
- Developmental exposure of rats to approximately 70-µg/kg/day BPA
- Up-regulation of a number of genes in abdominal adipocytes in adulthood
- PPAR, C/EBP and LPL
- Prenatal exposure to 0.25 µg/kg/day
- Advancement of differentiation of the adipocytes in the mammary gland in fetal female mice
- Mice exposed to a low dose of BPA (10 µg/kg/day) during fetal life
- Were heavier at birth
- At 6 months of age, males prenatally exposed to BPA displayed
- Glucose intolerance
- Insulin resistance
- Altered insulin release from pancreatic cells [68]
- Pregnant mice exposed to this same dose of BPA
- Glucose intolerance relative to untreated controls [68]
- At a higher dose (100 µg/kg/day)
- Trend toward altered insulin sensitivity [68]
- 4 months after delivery, the mice treated during pregnancy with BPA
- Were heavier
- Had decreased insulin sensitivity [68]
- Glucose intolerance [68]
- Permanent effects of BPA on offspring’s metabolic systems
- Occurred at a dose 10-fold lower than the dose required to cause subsequent effects in the adult mother [68]
- Subcutaneous (sc) injection of pregnant CD-1 (ICR) mice with low doses of BPA (2 and 20 µg/kg/day) and DES (0.02, 0.2 and 2 µg/kg/day)
- Accelerated puberty (a common finding)
- Reduced body weight at puberty in the female offspring !!! [68]
- Similar prenatal BPA dose (2.4 µg/kg/day) fed to pregnant CF-1 mice
- Accelerated puberty
- Increased body weight at puberty in female offspring [68]
- Disruption of nursing behavior
- Reported in rats exposed to a low dose of BPA throughout pregnancy and lactation [68]
Bisphenol A (BPA)
- Very stable in the environment
- Steadily increasing in levels in humans
- Contributing to obesity in humans and model animals
- Interfering with estrogen and androgen signaling [1]
- Nearly ubiquitous in industrialized societies
- Plasticizer
- Make plastic harder
- Used to:
- Line cans
- Milk cartons
- Other metal - paper-board containers of foods and beverages
- May leach out of plastic storage containers to contaminate
- Foods
- Beverages
- Drinking water
- BPA content is greatest in
- Clear, polycarbonate plastics previously thought to be safe
- Detectable in
- Serum of pregnant women
- Cord serum taken at birth
- 5-fold higher in amniotic fluid at 15–18 weeks gestation, compared with maternal serum
- Placenta up to 100 ng/g
- BPA appears to accumulate in the fetus [1]
Literatura:
[1] Ten Putative Contributors to the Obesity Epidemic. URL < www.ncbi.nlm.nih.gov/pmc/articles/PMC2932668/?tool=pmcentrez >.
