An Endocrine Disrupter Chemical (EDC) is an exogenous substance which alters the functions of the endocrine system causing adverse health effects. Endocrine disrupters such as phthalates, BPA (Bisphenol A) and dichlorodiphenyldichloroethylene (DDE) have recently been linked to diabetes diagnosis. In adult Americans diabetes is the primary cause of kidney failure, blindness and amputations (nontraumatic). Diabetes also has been implicated in the development of cardiovascular disease which is a major killer in the United States. Bisphenol A (BPA) is the most common and widespread EDC linked to development of diabetes, for this reason I have chosen to discuss BPA in detail. Over 800,00 tons of BPA products are produced every year in the United States and have been in commercial use worldwide since the 1950’s. (Washan et al…2006) Everyday items such beverage cans, the lining of foods, dental sealants, CD’s, cash register receipts all contain BPA. Clinical observational studies carried out have revealed a positive link between exposure to BPA and the development of diabetes mellitus (type 2). This report will focus on key areas such as how BPA was first originally implicated in causing Diabetes, the mechanism of exposure, how cohort and case-control studies have been used to implicate BPA in causing Diabetes, the mechanism as to how BPA can increase the risk of diabetes.
How the toxicant was originally implicated in the disease?
Obesity has rose steadily over the last 5 decades in both developed and developing regions of the world. Obesity is a major contributor to several noncommunicable diseases including diabetes mellitus. Cross sectional studies and in vivo studies on animals were first used to imply a correlation between BPA exposure and obesity. The in vivo and cross-sectional studies hypothesised that diabetes is concomitant but not as direct consequence of BPA exposure more as a side effect of obesity. Numerous NHANES cohorts would later prove that BPA exposure and diabetes mellitus to be directly linked.
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Cross sectional studies measure exposure and disease at one point in time. Most cross-sectional studies on BPA use data from NHANES (National Health and Nutrition Examination Survey). The first study examining the correlation between exposure to BPA and development of diabetes mellitus was Lang et al 2008. Lang et al 2008 aimed to study if there was any correlation between urinary BPA concentrations and adult health status. Using data from NHANES between 2003/2004 a cross sectional analysis of BPA concentrations and the general health of the adult population in the United States was published. 1455 adults aged between 18-74 had BPA levels measured in their urine as part of the cohort. Regression models were adjusted for race, sex, age and BMI. Analysis was carried out on blood glucose levels as a determination of diabetes. The study was comprised of 694 men and 761 women and there was found to be no significant difference between the sexes in terms of BPA concentration in urine. There were significant differences in BPA levels in urine between a person of recommended BMI had a mean BPA reading of 3.91 ng/ml whereas a person classed as obese category II had a mean reading of 6.93 ng/ml. Lang et al 2008 found that higher BPA concentrations in samples of urine were correlated to the development of diabetes and cardiovascular disease.
Using the same data from the NHANES and including data from 2005/2006 Melzer et al 2008 aimed to estimate the association between BPA exposure and adverse health effects such as obesity, diabetes and cardiovascular disease. Melzer et al conducted a cross sectional compromising of 1455 participants from 2003/2004 and 1493 participants from 2005/2006. These participants were aged from 18-74 and represented the general population of the US. As in Lang et al 2008 regression models were adjusted were adjusted for sex, race age and BMI. Again, serum blood glucose levels were measured. From the data analysed from the year 2003/2004 Melzer et al 2010 reported associations between high BPA concentrations and development of diabetes These results support Lang et al 2008 findings and further strengthen the hypothesis that high BPA concentrations increase the risk of developing diabetes. The urinary concentrations of BPA in the participants in the years 2005/2006 were much lower than the previous years. 1.79 was the mean value obtained in 2005/2006 where as in 2003/2004 the mean obtained was 2.49 this is a drop of 30%. This made it difficult to determine statistically significant results. However, when the high concentration readings were pooled together associations between high levels of BPA and diabetes remained. Melzer et al 2010 concluded that although associations were found further studies are needed to provide clear evidence that BPA exposure can result in diabetes.
Mechanism of exposure
The leaching of BPA has been widespread through ingestion of food and drink items which have been in contact with BPA materials. Nearly all food and drinks are stored in polycarbonate plastics which leach harmful chemicals such as BPA into the foods and drinks which we ingest. BPA has been detected in up to 95% of human blood samples in the US. (Washan et al 2006) Polycarbonate plastics are used in baby bottles which is a major cause of concern as BPA exposure is most detrimental to those in early stage of development such as infants. Carwile et al 2009 examined whether the use of polycarbonate water bottles cause urinary BPA levels to rise. This study involved 77 participants who began with a 7-day phase where they only drank from stainless steel so that they could minimise their BPA intake so that any BPA readings would be representative of that caused by the polycarbonate bottles. Next phase involved only drinking from polycarbonate bottles for 7 days. Carwile et al 2009 reported that urinary levels of BPA rose by 69% suggesting that one of the mechanism to which BPA is exposed to the human body is ingestion from polycarbonate bottles. Le et al 2008 investigated how much BPA was leached from polycarbonate drinking bottles. Le et al 2008 also measured whether if a new bottle or used bottle would alter the rate at which BPA was leached. They also investigated if temperature influenced the rate of BPA being leached. Results revealed that bottles at room temperature showed an increase of BPA concentrations over the seven days. After 7 days the BPA concentrations for the new bottles was 1.0 mg/ml and 0.7 mg/ml for the used. They tested the effect of temperature by adding 100 ml of 100 degrees Celsius HPLC grade water to each bottle and the concentration of BPA in both the used and the new bottles was found to have doubled. This is cause for concern as many baby bottles contain polycarbonate plastics.
How Cohort and Case studies have been used to implicate the toxicant in the disease?
Shankar et al 2011 developed upon the work done by Lang et al 2008 and Melzer et al 2010 again using data from NHANES 2003 – 2008. This study focused on people who had already been diagnosed with diabetes. As with the previous cross-sectional study BPA levels where monitored in urine samples. A positive correlation was found between increasing BPA levels in urine samples and development of diabetes mellitus. This analysis used guidelines from the American Diabetes Association (ADA) which sets the criteria for diabetes. This includes a serum glucose level of greater than 200 mg dL-1 for participants who had fasted for less than 8 hours and for those who had fasted longer than 8 hours a level greater than 126 mg dL-1 and HbA1c value of 6.5% or greater. HbA1c is the average blood glucose sugar levels over the last two or three months. This study used the full spectrum of ways to diagnose diabetes mellitus and found a positive correlation between BPA exposure and development of diabetes. Shankar et al 2011 results are independent of gender, age, race, serum cholesterol levels and BMI as the participants were between 18-74.
The NHANES studies are a credible source of data as they follow a standardized methodology and provide a decent sample size. As well as the magnitude of the effects being studied are large and the affected outcomes are very specific. The disadvantages of NHANES are that being a cross sectional study means that it less rigorous than a prospective cohort study. In NHANES only adult exposures and outcomes were measured whereas in a prospective cohort study, participants are chosen regardless of their exposure or outcome status. The fact that the results from the individual studies for the most part all corroborate strengthens further the link between BPA exposure and development of diabetes mellitus.
The NHANES studies were put under scrutiny in terms of the validity of their results. Lakind et al 2012 claimed that they consistently found no associations between urinary BPA levels and diabetes. The study concluded that using cross sectional data such as that provided by NHANES is inappropriate to prove that this short lived environmental chemical BPA can cause such complex diseases like diabetes. The NHANES studies were further enriched and the objections by Lakind et al 2012 were put to rest by Sabanyagam et al 2013 which studied the urinary levels of BPA and prediabetes. This study measured 3516 participants between 2003-2008. As previously prediabetes was defined as per the American Diabetes Association. The criteria set were fasting glucose serum levels of 100 – 125 mg dL-1or a reading of 5.7 % – 6.4% for the HbA1c value. Sabanyagam et al 2013 found a correlation between BPA exposure and pre-diabetes. It also found that woman or obese participants are more susceptible of developing diabetes from high exposure to BPA.
Much of studies investigating the relationship between BPA exposure and development of diabetes mellitus are cross sectional studies. Cross sectional studies have limitations due to the fact that exposure and outcome are simultaneously assessed, meaning that there is generally no evidence of a temporal relationship between suspected exposure and outcome. The strongest method to show the evidence for the ability of BPA exposure to contribute to the development of diabetes mellitus comes from longitudinal studies. A longitudinal study is a study which takes place over a period in which the exposure is measured before the suspected disease develops.
Sun et al 2014 used data from the U.S Nurses Health Studies 1 and 2 in the first longitudinal study investigating urinary concentration of BPA and phthalate metabolites with risk of type 2 diabetes. The study involved two cohorts The Nurses’ Health Study 1 (NHS 1) and The Nurses’ Health study 2 (NHS 2). NHS 1 was comprised of woman with an average age of 66 (post-menopausal) whereas NHS 2 was comprised of younger woman pre-menopausal with an average age of 46. The cohort of the premenopausal found there to be a clear association between levels of BPA in urine samples and development of diabetes. Whereas the cohort carried out on the older women found there to be no association between the two. Sun et al 2014 hypothesized a possible reason for the difference in younger woman developing diabetes and older woman not, being down to menopausal status. The hypothesis is that BPA interferes with the receptors in the pancreatic β cells. This of course would have a greater effect on premenopausal women. Therefore, the results from the first longitudinal study reinforce the idea that BPA exposure can increase the risk of developing diabetes mellitus.
Another hypotheses as to how BPA may contribute to the development of diabetes mellitus is by increasing insulin resistance. Hong et al 2009 comprised a study of 950 participants in which fasting serum glucose and insulin levels were measured to evaluate insulin resistance. These were measured within participants to evaluate the association of exposure to BPA. To evaluate the effects of BPA on fasting blood sugar levels participants with high BPA exposure levels were compared against their less than high exposure counterparts. As shown in Figure 1 the high exposure to BPA increased fasting blood sugar levels.
Figure1: Graph showing BPA exposure levels and blood fasting glucose levels (>90%) high BPA exposure and (10-90%) less than high exposure. Hong et al 2009
Mechanism which BPA exerts its affect
Numerous studies have been carried out to understand the mechanism of exposure of BPA. Due to its low binding affinity for oestrogen receptors (ER’s) in comparison to oestradiol (E2) it was thought to be a weak environmental oestrogen. Oestradiol is the major female sex hormone involved in the regulation of the female menstrual cycle. BPA has a binding affinity of EC50 = 2-7 x 10-5 M whereas Oestradiol EC50 = 1-6 x 10-13. (Khetan et al 2014) Since the binding affinity between the oestrogen receptor and BPA are quite low it seemed likely that they didn’t interact directly with one another. Watson et al … 2011 found that BPA finds other pathways to induce its toxic effects at low doses. This may be explained through the use of non-genomic actions or non-classical pathways. BPA is now described as an imperfect potent oestrogen due to the fact it has been found to be equally as potent as Oestradiol when acting via non-genomic pathway.
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BPA can interfere with genes that regulate transcription which can lead to obesity. BPA tells the body to reduce the number of fat cells but programmes it to incorporate more fat leading to fewer fat cells but meaning that the fat cells which remain are very large. Masuno et el 2005 and Wada et al 2007 found that in vitro that micromolar levels of BPA can enhance lipid accumulation and adipocyte differentiation.
Khetan et al 2014 showed that BPA binds to the oestrogen receptors ERα and ERβ which triggers nonclassical oestrogenic effects which are initiated outside the nucleus. The oestrogen receptors as a result don’t act as transcription factors. BPA interferes with the function of key cell types involved in metabolism through non-classical ER-triggered pathways. These cells include pancreatic β cells which have numerous functions. One of their main functions is to control the storage and release of insulin. Alonso-Magadelena et al 2011 showed that nanomolar concentrations of BPA have the ability of promoting the release of insulin in pancreatic β-cells in mice which at long exposures caused an alteration in glucose metabolism which is a key risk factor for development of diabetes. Alonso-Magadelena et al 2011 reported that a single low dose of 10µg/kg of either E2 or BPA to an adult mouse can induce a rapid reduction in glycaemia which causes a rise in plasma insulin. Prolonged exposure to BPA resulted in an increase in pancreatic β-cell insulin content which was visible after just 2 days at a concentration of 10 μg/kg/day. Chronic hyperinsulinemia had developed at day 4 in the adult mice. Alonso-Magadelena et al 2011 also reported that the mice insulin and glucose tolerance levels were altered. These in vitro studies reveal a correlation between abnormal levels of BPA and the risk of developing diabetes mellitus.
How the toxicant interacts with the human genome to produce differing consequences for different genotypes
Lin et al 2018 aimed to evaluate whether the oxidative stress gene GTSP1 has a correlation between BPA exposure and development of Asthma. Genetic polymorphism of oxidative stress genes such as glutathione S-transferases have been hypothesised as being related to BPA exposure. Lin et al 2018 conducted a case control study which comprised 126 asthmatic children and 327 controls. Ultra-performance liquid chromatography with tandem mass spectrometry was used to measure the levels of BPAG (Bisphenol A glucuronide) in Urine. Lin et al 2018 found a positive correlation between the GSTP1 AA genotype, high levels of BPAG concentration in Urine and increased risk of asthma in kids. It was observed that children with GSTP1 AA genotype with high levels of BPA metabolites in their urine were 4.84-fold more susceptible to asthma. Results obtained support the hypothesis made by Lin et al 2018 that the GTSP1 gene participates in BPA detoxification. Lin et al 2018 suggests that the polymorphism of the gene coding for GTSP1 may be the cause of differing individuals excreted levels of BPA. The polymorphism of the oxidative stress gene GSTP1 rs 1695 seems to modify exposure to BPA with susceptibility of asthma development. Since children with the GSTP1 AA genotype were largely the only ones to suffer adverse effects as a result of the BPA exposure, Lin et al 2018 suggested that measures should be brought in to avoid BPA exposure to these susceptible children.
Donohue et al 2013 also assessed urinary BPA concentrations and the susceptibility of asthma. The Columbia Centre for Children Environmental Health recruited 568 pregnant women to perform a birth cohort study. Mothers in the third trimester and children aged from 3, 5, 7 gave urinary samples. BPA concentration was measured by performing high performance liquid chromatography with mass spec. Asthma development was measured by a physician once the children were between the age of 5-12 years. Donohue et al 2013 reported that high levels of BPA in urine samples at ages of 3, 5, 7 years of age to be associated with development of asthma at age 5-12 years old. The results of Lin et al 2018 and Donohue et al 2013 complement each other and suggest that BPA exposure can increase the susceptibility of becoming asthmatic however more studies are needed to prove this so it can stand up against scrutiny.
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