Exposure to bisphenol A (BPA), an industrial chemical used to make certain plastics and resins, inner coatings for food cans and bottle tops, thermal paper used in store receipts, dental sealants and other products is a concern because of possible adverse health effects, including a reduction in fertility.
BPA Basics
BPA is a chemical that has been used to harden plastics for more than 40 years. It’s everywhere. It’s in medical devices, compact discs, dental sealants, water bottles, the lining of canned foods and drinks, and many other products.
More than 90% of us have BPA in our bodies right now. We get most of it by eating foods that have been in containers made with BPA. It’s also possible to pick up BPA through air, dust, and water.
BPA was common in baby bottles, sippy cups, baby formula cans, and other products for babies and young children. Controversy changed that.
Now, the six major companies that make baby bottles and cups for infants have stopped using BPA in the products they sell in the U.S. Many manufacturers of infant formula have stopped using BPA in their cans, as well.
According to the U.S. Department of Health, toys generally don’t contain BPA. While the hard outer shields of some pacifiers do have BPA, the nipple that the baby sucks on does not.
Risk
The FDA maintains that studies using standardized toxicity tests have shown BPA to be safe at the current low levels of human exposure.
But based on other evidence – largely from animal studies – the FDA expressed “some concern” about the potential effects of BPA on the brain, behavior, and prostate glands in fetuses, infants, and young children.
How could BPA affect the body?
Here are some areas of concern.
- Hormone levels. Some experts believe that BPA could theoretically act like a hormone in the body, disrupting normal hormone levels and development in fetuses, babies, and children. Animal studies have had mixed results.
- Brain and behavior problems. After a review of the evidence, the National Toxicology Program at the FDA expressed concern about BPA’s possible effects on the brain and behavior of infants and young children.
- Cancer. Some animal studies have shown a possible link between BPA exposure and a later increased risk of cancer.
- Heart problems. Two studies have found that adults with the highest levels of BPA in their bodies seem to have a higher incidence of heart problems. However, the higher incidence could be unrelated to BPA.
- Other conditions. Some experts have looked into a connection between BPA exposure and many conditions — obesity, diabetes, ADHD, and others. The evidence isn’t strong enough to show a link.
- Increased risk to children. Some studies suggest that possible effects from BPA could be most pronounced in infants and young children. Their bodies are still developing and they are less efficient at eliminating substances from their systems.
Although this list of possible BPA risks is frightening, keep in mind that nothing has been established. The concern about BPA risks stems primarily from studies in animals.
A few studies in people have found a correlation between BPA and a higher incidence of certain health problems, but no direct evidence that BPA caused the problem.
Other studies contradict some of these results. Some experts doubt that BPA poses a health risk at the doses most people are exposed to.
A study performed at Harvard Medical School (HMS) in the United States by Maria Fernanda Hornos Carneiro and her research group shows that the harmful effects of BPA can be reversed by administering a supplement known as CoQ10 (coenzyme Q10), a substance naturally produced by the human body and found in beef and fish. Hornos Carneiro is a former São Paulo Research Foundation – FAPESP scholarship awardee.
The article published in the journal Genetics is the first to present this strategy for reversing the effects of BPA in the organism.
In this study, the researchers tested the antioxidant action of CoQ10 in nematodes of the species Caenorhabditis elegans exposed to BPA.
As an excellent antioxidant, CoQ10 is an electron donor. By donating its electrons, it stabilizes free radicals, reducing the oxidative stress and cell damage caused by BPA.
“BPA has oxidation potential as it’s chemically unstable and produces reactive oxygen and nitrogen species. When the antioxidant reserves in cells [electron donors] run out, the amount of reactive oxygen and nitrogen increases.
Because of their chemical instability, they ‘poach’ electrons from mitochondria and other cellular organelles, cell membranes, proteins, and even DNA, damaging cells significantly and potentially causing cell death.
If this problem becomes extensive, it poses a major threat to the organism,” Hornos Carneiro told.
The study measured the number of fertilized eggs laid and hatched and the number of progeny that reached adulthood. The problems detected can be compared to difficulty in becoming pregnant, miscarriages and chromosome anomalies in humans.
“BPA is a chemical contaminant that acts as an endocrine disruptor, causing cellular oxidative stress [an imbalance between oxidant and antioxidant molecules], which results in damage to gametes and embryos,” said Hornos Carneiro, who conducted the study under the supervision of HMS Professor Monica Paola Colaiácovo.
“In the study, the worms exposed to BPA and given CoQ10 displayed lower egg cell death rates, less DNA breakage and fewer abnormalities in chromosomes during cell division, as well as less cellular oxidative stress.”
In the experiment, worms were exposed to different combinations of BPA, CoQ10 and a solvent (DMSO): solvent only, solvent and CoQ10, BPA only, and BPA plus CoQ10.
The amount of exposure to BPA mimicked the estimated amount in humans. “We know it’s practically impossible to avoid exposure to BPA and similar contaminants in this day and age, so we looked for a strategy to minimize the harm done.
Many studies have shown that age reduces fertility in women, and because exposure to BPA [and other endocrine disruptors] occurs throughout life, it’s not yet possible to estimate separately the extent to which observed infertility is due to exposure to toxic chemicals in the external environment and how much is due to aging,” Hornos Carneiro said.
The nematodes used in the study were transgenic, with a fluorescent protein sequence inserted into their DNA to enable in vivo observation of protein expression.
Fluorescent antibodies were also used, as well as advanced microscopy and molecular biology techniques. The researchers were thereby able to observe in real time the effects produced at the cellular and molecular levels during the process of cell division (meiosis) and embryo formation in the worms.
Estrogen mimic
According to Hornos Carneiro, BPA’s chemical structure is similar to that of estrogen, a female sex hormone that plays a key role in ovulation. As a result, BPA can bind to estrogen receptors in humans, leading to a number of significant effects.
“Depending on the tissue, the effects may be pro-estrogenic or anti-estrogenic, with an impact not just on the reproductive system but also on other systems and processes that are important to a person’s health,” she said.
Hornos Carneiro is currently a professor in the School of Chemistry and Pharmacy at the Pontifical Catholic University of Chile. She conducted the study at the University of São Paulo’s Ribeirão Preto School of Pharmaceutical Sciences (FCFRP-USP) in Brazil with the support of a FAPESP scholarship for postdoctoral research internship abroad.
DNA breakage and mitochondrial dysfunction
According to Hornos Carneiro, exposure of the worms to BPA alone resulted in more DNA breaks. “This was potentially due to the action of reactive oxygen species formed as a result of the presence of the contaminant in the organism,” she said. “We found that the breaks were not correctly repaired in this group of worms.”
The damage was observed by monitoring a protein involved in DNA breakage and repair when genetic material is exchanged between homologous chromosomes during meiosis.
This exchange of genetic material, known as crossing over, is important for increasing genetic diversity and driving evolution. “One hypothesis is that the increase in DNA breakage [and inefficient repair] was due to a rise in gonad oxidative stress caused by BPA,” she said.
Another finding was that mitochondrial dysfunction increased. Mitochondria are energy-producing organelles in cells.
“Because of oxidative stress, mitochondrial membrane potential was significantly altered in the worms exposed only to BPA, while in the group that received the CoQ10 supplement, this marker was much improved,” Hornos Carneiro said.
Effect on embryos
The effect of BPA on embryos was also studied in this experiment. As a hermaphrodite, C. elegans self-fertilizes, and it is therefore possible to observe in its gonads all stages of germinative cell development in meiosis up to the polar corpuscle and embryo formation.
“In the study, we observed embryo formation in vivo using a technique called live imaging,” Hornos Carneiro explained. “The benchmark for analysis of the occurrence of defects was the first cell division [the precise moment at which the unicellular embryo divides in two]. In the group exposed only to BPA, a larger number of defects were observed, such as formation of chromatin bridges and cell division cessation.”
Bisphenol-A (BPA) is defined as an endocrine disruptor like dioxins and polychlorinated biphenyls (Feni- chel et al., 2013). It possesses a lipophilic property (Hormann et al., 2014) and exhibits low steroid-like activity (Fenichel et al., 2013). BPA is used in epoxy resins and polycarbonate plastics such as baby feeding and water bottles (D’Cruz et al., 2012).
The epoxy resins are used for coating the inner surface of metal boxes used for packaging of food and beverages such as seafood, vegetables, beer, soft drinks, and milk powder.
Moreover, they are used to make storage containers that contain fluids such as wine and water, as well as different types of food transport containers (Matsumoto et al., 2003).
The contamination risk of BPA increases in people due to the wide range of its usage. Human beings are exposed to BPA through consumption of food, inhalation, and dermal absorp- tion (Vandenberg et al., 2012).
Apoptosis is programmed cell death (Kerr et al., 1972). That occurs both normally (Print and Love- land, 2000) and as a result when tissues are exposed to toxic substances (Richburg, 2000). Li et al. (2009a) reported that BPA exposure induces apoptosis of germ and Leydig cells in mouse by means of Fas- signaling.
Spermatogonial stem cells (SSCs) originate from testicular gonocytes in the postnatal period and from primordial germ cells in the fetal period (Phillips et al., 2010). Undifferentiated embryonic cell transcription factor 1 (UTF-1), a chromatin-bound protein (Mouallif et al., 2014), is a marker for SSCs in testis (Lee et al., 2014).
UTF-1 is specifically demonstrated in the inner cell mass of blastocysts in the fetal period and adult gonads (Kooistra et al., 2009). BPA expo- sure has been reported to diminish sperm manufacture by influencing the SSCs in testes (Vrooman et al., 2015).
BPA exposure is detrimental to the male genital system due to the fact that it causes oxidative stress in experimental animals (Abdel-Wahab, 2014; Aydo- g˘an et al., 2010; Feninichel et al., 2013). The testis is one of the sensitive targets for BPA-induced toxicity (Feninichel et al., 2013).
BPA exposure reduces body, testis, and epididymis weights (Takahashi and Oishi, 2003) in addition to causing damage to the seminiferous tubules (Ahbab et al., 2015; Takahashi and Oishi, 2003).
Moreover, it decreases the diameter of semi-niferous tubules (Gurmeet et al., 2014; Li et al., 2009b), levels of blood–testis barrier-associated proteins (Connexin 43, occluding, N-cadherin) in cultured sertoli cell (Li et al., 2009b), number of SSCs (Vrooman et al., 2015), glutathione-peroxidase (GSH-Px), catalase (CAT), superoxide dismutase (SOD) activities and glutathione (GSH) levels in serum/plasma (Abdel-Wahab, 2014; Chen et al., 2012), serum testosterone level, steroidogenic enzyme activity (Ahbab et al., 2015; Nakamura et al., 2010), epididymal sperm count (Ahbab et al., 2015; Takahashi and Oishi, 2003), and sperm viability and motility (Lukacova et al., 2015).
In addition, it increases the terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate terminal dUTP nick end labeling (TUNEL)-positive tubules (%), number of TUNEL-positive cells per tubule (Li et al., 2009a; Wang et al., 2010), testis malondialde- hyde (MDA) level (Aydog˘an et al., 2010), abnormal sperm rate (Toyama et al., 2004), and lipid peroxida- tion (Abdel-Wahab, 2014).
Coenzyme Q10 (CoQ10) is a 1,4-benzoquinone compound synthesized in all tissues (Crane, 2001). It serves as a component of the electron transport chain in mitochondria (Fouad et al., 2011).
CoQ10 is found in high concentrations in the heart, liver, kidney, and pan- creas. High quantities of CoQ10 are present in meat, fish, broccoli, and cauliflower (Kubo et al., 2008); therefore, it is in-taken with foods exogenously.
CoQ10 shows antioxidative effects by preventing the initiation of lipid peroxidation and damage of bimolecular by interacting with oxygen-based radi- cals and singlet oxygen (Bonakdar and Guarneri, 2005). Additionally, researchers have suggested an antiapoptotic effect of CoQ10 on male genital sys- tems (El-Sheikh et al., 2014; Erol et al., 2010).
CoQ10 treatment decreases apoptosis protease- activating factor-1 formation and active caspase-3 levels within spermatogenic cells that are increased as a result of ischemic/reperfusion injury and doxorubicin-induced toxicity (El-Sheikh et al., 2014; Erol et al., 2010).
Moreover, CoQ10 reduces the ischemic/reperfusion injury (Erol et al., 2010) and damage of testicular tissue in sodium arsenite and doxorubicin-induced toxicity (El-Sheikh et al., 2014; Fouad et al., 2011).
CoQ10 increases testicular GSH, SOD, and CAT activities in damaged testis (El- Sheikh et al., 2014; Fouad et al., 2011), whereas it decreases MDA levels. Also, it increases serum tes- tosterone, testicular GSH and SOD activities (Fouad et al., 2011), sperm count and motility, and daily sperm production in high magnetic field-induced toxicity (Ramadan et al., 2002).
More information: Maria Fernanda Hornos Carneiro et al, Antioxidant CoQ10 Restores Fertility by Rescuing Bisphenol A-Induced Oxidative DNA Damage in the Caenorhabditis elegans Germline, Genetics (2019). DOI: 10.1534/genetics.119.302939
