BPA link to precursor of type 2 diabetes

Experimental BPA Exposure and Glucose-Stimulated Insulin Response in Adult Men and Women

A first-of-its-kind study of a small group of people exposed to a very small amount of bisphenol-A (BPA) is raising questions about the federal government’s stance that low doses of the common chemical are safe — as well as the ethics of conducting such an experiment on humans. The controversial study suggests that BPA exposure deemed safe by the feds could alter the amount of insulin released and elevate people’s type 2 diabetes risk, Environmental Health News reports.
Featured image credit Simon Zhu.

2018 Study Abstract

Aims
Human cross-sectional and animal studies have shown an association of the chemical bisphenol A (BPA) with insulin resistance, type 2 diabetes and other metabolic diseases, but no human experimental study has investigated whether BPA alters insulin/C-peptide secretion.

Methods
Men and post-menopausal women (non-diabetic) were orally administered either the vehicle or a BPA dose of 50-µg/kg body weight, which has been predicted by U.S. regulators (FDA, EPA) to be the maximum safe daily oral BPA dose over the lifetime. Insulin response was assessed in two cross-over experiments using an oral glucose tolerance test (OGTT; experiment 1) and a hyperglycemic clamp (HG clamp; experiment 2). Main outcomes were the percent change of BPA session measures relative to those of the control session.

Results
Serum bioactive BPA after experimental exposure was at levels detected in human biomonitoring studies. In the OGTT, a strong positive correlation was found between HbA1c and the percent change in the insulinogenic index (Spearman=0.92), an indicator of early phase insulin response, and the equivalent C-peptide index (Pearson = 0.97). In the HG clamp study, focusing on the later phase insulin response to a stable level of glucose, several measures of insulin and C-peptide appeared suppressed during the BPA session relative to the control session; the change in insulin Cmax (maximum concentration) was negatively correlated with HbA1c and the Cmax of bioactive serum BPA.

Conclusions
This exploratory study suggests that BPA exposure to a dose considered safe by U.S. regulators may alter glucose-stimulated insulin response in humans.

Endocrine Disrupting Chemicals and Behavior

Special issue of Hormones and Behavior, Volume 101, Pages 1-148, May 2018

The peer-reviewed journal Hormones and Behavior, Volume 101, Pages 1-148 (May 2018), raises concern about how many of the 90,000+ chemicals in use today may disrupt our most basic endocrine systems with significant consequences for neurodevelopment, neurophysiology, healthy brain aging, and behavior.

Several articles address bisphenol A :

About PDBEs, triclosan, and other replacement chemicals :

Other studies included in this special issue address behavioral effects of voluntary taken pharmaceuticals, including birth control pills, and pain medications.

About DES and the BRAIN :

Changes in the vocalization patterns of the mice pups whose parents were exposed to BPA prenatally

Multigenerational effects of bisphenol A or ethinyl estradiol exposure on F2 California mice (Peromyscus californicus) pup vocalizations

California mice is used as a special model for parental behaviors with high relevance to humans, because they are monogamous, with both parents caring for neonates. In this study, Johnson and colleagues found changes in the vocalization patterns of the mice pups whose parents were exposed to BPA prenatally (i.e., through exposure of grandparents). These changes in communication abilities could have impacts on the amount of parental care they receive.

2018 Study Abstract

Rodent pups use vocalizations to communicate with one or both parents in biparental species, such as California mice (Peromyscus californicus). Previous studies have shown California mice developmentally exposed to endocrine disrupting chemicals, bisphenol A (BPA) or ethinyl estradiol (EE), demonstrate later compromised parental behaviors. Reductions in F1 parental behaviors might also be due to decreased emissions of F2 pup vocalizations. Thus, vocalizations of F2 male and female California mice pups born to F1 parents developmentally exposed to BPA, EE, or controls were examined. Postnatal days (PND) 2–4 were considered early postnatal period, PND 7 and 14 were defined as mid-postnatal period, and PND 21 and 28 were classified as late postnatal period. EE pups showed increased latency to emit the first syllable compared to controls. BPA female pups had decreased syllable duration compared to control and EE female pups during the early postnatal period but enhanced responses compared to controls at late postnatal period; whereas, male BPA and EE pups showed greater syllable duration compared to controls during early postnatal period. In mid-postnatal period, F2 BPA and EE pups emitted greater number of phrases than F2 control pups. Results indicate aspects of vocalizations were disrupted in F2 pups born to F1 parents developmentally exposed to BPA or EE, but their responses were not always identical, suggesting BPA might not activate estrogen receptors to the same extent as EE. Changes in vocalization patterns by F2 pups may be due to multigenerational exposure to BPA or EE and/or reduced parental care received.

About DES and the BRAIN ;

The potential for behavioral and other effects of BPA to be inherited by subsequent generations

Effects of maternal or paternal bisphenol A exposure on offspring behavior

2018 Study Highlights

  • No significant behavioral effects of preconception paternal BPA exposure.
  • Increased anxiety-like behavior in juvenile offspring maternally exposed to BPA.
  • Increased duration and median frequency of ultrasonic vocalizations in BPA pups.
  • Females outperform males in an operant reversal learning task.
  • BPA females earn fewer rewards than control females during operant training.

Abstract

Bisphenol A (BPA) is an endocrine disrupting chemical used in the production of polycarbonate plastics and resins. Exposure to BPA during gestation has been proposed as a risk factor for the development of neurobehavioral disorders, such as autism spectrum disorder. To address the behavioral impact of developmental exposure to BPA, we tested offspring of mice exposed to a daily low dose of BPA during pregnancy. We also asked if preconception exposure of the sire affected behaviors in offspring.

Sires that consumed BPA for 50 days prior to mating weighed less than controls, but no effects on any reproductive measures were noted. Juvenile offspring exposed to BPA maternally, but not paternally, spent less time in the open arms of the elevated plus maze than controls, indicating increased anxiety-like behavior. However, neither parental exposure group differed significantly from controls in the social recognition task.

We also assessed the behaviors of maternally exposed offspring in two novel tasks: ultrasonic vocalizations (USVs) in pups and operant reversal learning in adults.

Maternal BPA exposure increased the duration and median frequency of USVs emitted by pups during maternal separation. In the reversal learning task, females responded more accurately and earned more rewards than males. Additionally, control females received more rewards than BPA females during the acquisition phase of the task.

These are among the first studies conducted to ask if BPA exposure via the sire affects offspring behavior and the first study to report effects of gestational BPA exposure on pup USVs and adult operant responding.

About DES and the BRAIN ;

The disruptive effects of BPA on growth and development

A plurality of molecular targets: The receptor ecosystem for bisphenol-A (BPA)

2018 Study Highlights

  • Bisphenol-A exerts a range of non-estrogenic effects.
  • Care should be taken in selecting positive controls, given BPA’s range of activity.
  • Non-estrogenic effects can account for many phenotypes produced by BPA exposure.

Abstract

Bisphenol-A (BPA) is a well-known endocrine disrupting compound (EDC), capable of affecting the normal function and development of the reproductive system, brain, adipose tissue, and more. In spite of these diverse and well characterized effects, there is often comparatively little known about the molecular mechanisms which bring them about. BPA has traditionally been regarded as a primarily estrogenic EDC, and this perspective is often what guides research into the effects of BPA. However, emerging data from in-vitro and in-silico models show that BPA binds with a significant number of hormone receptors, including a number of nuclear and membrane-bound estrogen receptors, androgen receptors, as well as the thyroid hormone receptor, glucocorticoid receptor, and PPARγ. With this increased diversity of receptor targets, it may be possible to explain some of the more puzzling aspects of BPA pharmacology, including its non-monotonic dose-response curve, as well as experimental results which disagree with estrogenic positive controls.

This paper reviews the receptors for which BPA has a known interaction, and discusses the implications of taking these receptors into account when studying the disruptive effects of BPA on growth and development.

About DES and the BRAIN ;

The effects of gestational BPA exposure on neural developmental mechanisms and resulting behaviors

Opening the black box of endocrine disruption of brain development: Lessons from the characterization of Bisphenol A

2018 Study Highlights

  • Bisphenol A (BPA) is a commonly studied endocrine disrupting chemical.
  • Gestational BPA exposure is known to cause lasting cognitive and behavioral alterations.
  • The neurodevelopmental targets of gestational BPA exposure remain poorly understood.
  • Identifying mechanisms of BPA-mediated alterations in brain development should be a priority.

Abstract

Bisphenol A (BPA) is among the best-studied endocrine disrupting chemicals, known to act via multiple steroid hormone receptors to mediate a myriad of cellular effects. Pre-, peri-, and postnatal BPA exposure have been linked to a variety of altered behaviors in multiple model organisms, ranging from zebrafish to frogs to mammalian models. Given that BPA can cross the human placental barrier and has been found in the serum of human fetuses during gestation, BPA has been postulated to adversely affect ongoing neurodevelopment, ultimately leading to behavioral disorders later in life. Indeed, the brain has been identified as a key developmental target for BPA disruption. Despite these known associations between gestational BPA exposure and adverse developmental outcomes, as well as an extensive body of evidence existing in the literature, the mechanisms by which BPA induces its cellular- and tissue-specific effects on neurodevelopmental processes still remains poorly understood at a mechanistic level.

In this review we will briefly summarize the effects of gestational BPA exposure on neural developmental mechanisms and resulting behaviors, and then present suggestions for how we might address gaps in our knowledge to develop a fuller understanding of endocrine neurodevelopmental disruption to better inform governmental policy against the use of BPA or other endocrine disruptors.

About DES and the BRAIN ;

BPA bad for children’s hearts, study suggests

Early BPA exposure may influence cardiac function, according to new study in neonatal rats

A new study paves the way for translational research examining cardiovascular disease risk factors associated with short-term BPA exposure in infancy. By examining neonatal rat heart cells, researchers find the immature heart may respond to BPA with a slowed heart rate, irregular heart rhythm and calcium instabilities. The significance of this research is that plastics revolutionized the way doctors treat young patients, especially patients with compromised immune or cardiac function.

2018 Study Abstract

Bisphenol chemicals are commonly used in the manufacturing of polycarbonate plastics, polyvinyl chloride plastics, resins, and thermal printing applications. Humans are inadvertently exposed to bisphenols through contact with consumer products and/or medical devices. Recent reports have shown a link between bisphenol-a (BPA) exposure and adverse cardiovascular outcomes; although these studies have been limited to adult subjects and models. Since cardiac physiology differs significantly between the developing and adult heart, we aimed to assess the impact of BPA exposure on cardiac function, using a neonatal cardiomyocyte model. Neonatal rat ventricular myocytes were monitored to assess cell viability, spontaneous beating rate, beat rate variability, and calcium-handling parameters in the presence of control or bisphenol-supplemented media. A range of doses were tested to mimic environmental exposure (10−9–10−8M), maximum clinical exposure (10−5M), and supraphysiological exposure levels (10−4M). Acute BPA exposure altered cardiomyocyte functionality, resulting in a slowed spontaneous beating rate and increased beat rate variability. BPA exposure also impaired intracellular calcium handling, resulting in diminished calcium transient amplitudes, prolonged calcium transient upstroke and duration time. Alterations in calcium handling also increased the propensity for alternans and skipped beats. Notably, the effect of BPA-treatment on calcium handling was partially reversible. Our data suggest that acute BPA exposure could precipitate secondary adverse effects on contractile performance and/or electrical alternans, both of which are dependent on intracellular calcium homeostasis.

More Information

  • Disruption of neonatal cardiomyocyte physiology following exposure to bisphenol-a, nature, 09 May 2018.
  • Early BPA exposure may influence cardiac function, according to new study in neonatal rats, sciencedaily, May 14, 2018.
  • Image credit James Graham.

Exposure to low levels of BPA during pregnancy can lead to altered brain development

These findings suggest that gestational exposure to BPA can lead to lasting and permanent changes in the brain

Chicago, IL – New research in mice provides an explanation for how exposure to the widely used chemical bisphenol A (BPA) during pregnancy, even at levels lower than the regulated “safe” human exposure level, can lead to altered brain development and behavior later in life. The research was presented Monday, March 19 at ENDO 2018, the 100th annual meeting of the Endocrine Society in Chicago, Ill.

BPA is a chemical that is added to many commercial products, including water bottles, paper receipts, can liners and food storage containers. It is known as an endocrine-disrupting chemical—a chemical that interferes with the body’s hormones.

“Decades of research in over 1,000 animal and 100 human epidemiological studies have demonstrated a link between BPA exposure and adverse health outcomes,”

said lead researcher Deborah Kurrasch, Ph.D., Associate Professor at the University of Calgary in Calgary, Canada.

“This is especially true for the developing brain, which is particularly sensitive to the estrogen-promoting effects of BPA during gestation. Indeed, several human studies have now correlated early life BPA exposure with behavioral problems later in childhood, suggesting BPA permanently alters brain development that leads to lasting effects on neural functioning.”

she noted.

Governmental agencies around the world, including the U.S. Food and Drug Administration, Health Canada, and European Food Safety Authority, declare BPA to be safe.

“One reason for this disparity is the absence of a smoking gun: if BPA is so toxic to developing brains, then where is the evidence of defective brains?”  “Our study is the first to use environmentally relevant doses of BPA and show exposure to the chemical during brain development can affect the timing of the birth of nerve cells, or neurons.”

Kurrasch said.

The researchers studied three groups of pregnant mice. One group ate food without BPA; a second group at food with high doses of BPA; and a third ate low-dose BPA food. They found an increase in the number of neurons created during early development in mouse pups exposed to high and low doses of BPA during pregnancy, compared with those not exposed to BPA.

“This is important because specific neurons are known to be born at a very distinct time points, and if they are born early—as is the case here—then presumably these early neurons will migrate to the wrong place and form the wrong connections. These findings start to provide a rationale as to how BPA might affect developing brains,”

Kurrasch said.

Siblings to these pups were given behavioral tests to assess whether the early birth of neurons led to changes that affected brain function later in life. The researchers found mice that were exposed to BPA-high and BPA-low food during gestation exhibited some behaviors that match those observed in human children whose mothers had high levels of BPA during pregnancy.

“The public is becoming well educated on the debate surrounding BPA safety, as well as other chemicals.” “Although there is still work to be done to translate these rodent effects to human pregnancy, this research could provide expectant mothers with important information on what to avoid to best protect their babies.”

Kurrasch said.

Early exposure to BPA linked to increased hyperactivity

Prenatal exposure to bisphenol A and hyperactivity in children: a systematic review and meta-analysis

Bisphenol-A, widely used in plastics, receipt paper and canned food linings, is a culprit in some children developing hyperactivity : a July 2017 review, available online 7 March 2018, of more than 30 scientific studies, concludes early life exposure to the endocrine disrupting chemical BPA leaves children more susceptible to hyperactivity later in life.

Study Highlights

  • We used the OHAT systematic review framework to examine if early exposure to BPA has an effect on hyperactivity
  • We found that, in both rodents and humans, early exposure to BPA is linked to increased hyperactivity
  • Integration of animal and human evidence finds that BPA is a presumed hazard to human health
  • We suggest the development of clinical recommendations for avoiding BPA exposure, especially for pregnant women and children

2018 Study Abstract

Background
Attention-deficit hyperactivity disorder (ADHD) has increased in prevalence in the past decade. Studies attempting to identify a specific genetic component have not been able to account for much of the heritability of ADHD, indicating there may be gene-environment interactions underlying the disorder, including early exposure to environmental chemicals. Based on several relevant studies, we chose to examine bisphenol A (BPA) as a possible contributor to ADHD in humans. BPA is a widespread environmental chemical that has been shown to disrupt neurodevelopment in rodents and humans.

Objectives
Using the Office of Health Assessment and Translation (OHAT) framework, a systematic review and meta-analysis was designed to determine the relationship between early life exposure to BPA and hyperactivity, a key diagnostic criterion of ADHD.

Data sources
Searches of PubMed, Web of Science, and Toxline were completed for all literature to January 1, 2017.

Study eligibility criteria
For inclusion, the studies had to publish original data, be in the English language, include a measure of BPA exposure, and assess if BPA exposure affected hyperactive behaviors in mice, rats or humans. Exposure to BPA had to occur at <3 months of age for humans, up to postnatal day 35 for rats and up to postnatal day 40 for mice. Exposure could occur either gestationally (via maternal exposure) or directly to the offspring.

Study appraisal and synthesis methods
Studies were evaluated using the OHAT risk of bias tool. The effects in humans were assessed qualitatively. For rodents exposed to 20 μg/kg/day BPA, we evaluated the study findings in a random effects meta-analytical model.

Results
A review of the literature identified 29 rodent and 3 human studies. A random effects meta-analysis showed significantly increased hyperactivity in male rodents. In humans, early BPA exposure was associated with hyperactivity in boys and girls.

Limitations, conclusions, and implications of key findings
We concluded that early life BPA exposure is a presumed human hazard for the development of hyperactivity. Possible limitations of this systematic review include deficiencies in author reporting, exclusion of some literature based on language, and insufficient similarity between human studies. SRs that result in hazard-based conclusions are the first step in assessing and mitigating risks. Given the widespread exposure of BPA and increasing diagnoses of ADHD, we recommend immediate actions to complete such risk analyses and take next steps for the protection of human health. In the meantime, precautionary measures should be taken to reduce exposure in pregnant women, infants and children. The present analysis also discusses potential mechanisms by which BPA affects hyperactivity, and the most effective avenues for future research.

Sources and Press Releases

BPA detected in urine of 86% of teenagers in the UK

Exposure to Bisphenol A ‘hard to avoid’ in everyday life

86 per cent of UK students aged between 17 and 19 years have traces of Bisphenol A (BPA), a chemical compound used to make plastics, in their body, an Engaged Research public engagement project in collaboration with the University of Exeter has found. Manneken Pis image credit David Kenny.

2018 Research Abstract

Objective
Bisphenol A (BPA) has been associated with adverse human health outcomes and exposure to this compound is near-ubiquitous in the Western world. We aimed to examine whether self-moderation of BPA exposure is possible by altering diet in a real-world setting.

Design
An Engaged Research dietary intervention study designed, implemented and analysed by healthy teenagers from six schools and undertaken in their own homes.

Participants
A total of 94 students aged between 17 and 19 years from schools in the South West of the UK provided diet diaries and urine samples for analysis.

Intervention
Researcher participants designed a set of literature-informed guidelines for the reduction of dietary BPA to be followed for 7 days.

Main outcome measures
Creatinine-adjusted urinary BPA levels were taken before and after the intervention. Information on packaging and food/drink ingested was used to calculate a BPA risk score for anticipated exposure. A qualitative analysis was carried out to identify themes addressing long-term sustainability of the diet.

Results
BPA was detected in urine of 86% of participants at baseline at a median value of 1.22 ng/mL (IQR 1.99). No effect of the intervention diet on BPA levels was identified overall (P=0.25), but there was a positive association in those participants who showed a drop in urinary BPA concentration postintervention and their initial BPA level (P=0.003). Qualitative analysis identified themes around feelings of lifestyle restriction and the inadequacy of current labelling practices.

Conclusions
We found no evidence in this self-administered intervention study that it was possible to moderate BPA exposure by diet in a real-world setting. Furthermore, our study participants indicated that they would be unlikely to sustain such a diet long term, due to the difficulty in identifying BPA-free foods.

Discussion

Exposure to the EDC BPA is ubiquitous, with growing evidence that it may be associated with adverse health outcomes. Here, 94 researcher participants aged 17–19 years designed and undertook a quantitative and qualitative engaged research project designed to assess the potential for reduction of personal exposure to BPA through moderation of diet, which would have utility in a ‘real-world’ setting. We conclude that the ‘real-world’ diet designed to reduce BPA exposure had no effect on creatinine-adjusted urinary BPA concentrations in our cohort over a period of 7 days in our dataset.

Although concentrations of urinary BPA in our study cohort were slightly lower at the outset of the study than in others, measurable concentrations were present in the vast majority of our participants. Participants were unable to achieve a reduction in their urinary BPA over the 7-day trial period, despite good compliance to supplied guidelines. Avoidance of BPA was not easily achieved on an individual level in our study population, with qualitative analysis indicating that participants experienced feelings of restriction and difficulties in sourcing BPA-free food due to inadequate labelling of foods and food packaging. This suggests that the intervention would be difficult to sustain in the longer term.

This work represents the largest group of unrelated participants in a high exposure demographic to date, since previous work has focused on families and related individuals, who may share common sources of BPA. Although other population demographics such as young children may have higher concentrations of BPA than our chosen study population, it would not have been possible to do the sort of engaged research project that we envisaged in this group. Our intervention is a ‘real-world’ diet, designed to a set of guidelines (such as reduction in the usage of tinned foods or foods with high levels of processing), rather than the strict, prescribed diets that have been used in other studies, which suggested that it was possible for participants to reduce their urinary BPA excretion by approximately 60% in a period of just 3 days. In our self-designed, self-administered study this was unachievable. This may reflect the difficulty in identifying and sourcing foods free of BPA in the current commercial environment. Finally, the qualitative thematic analysis has given an indication that adherence to even a ‘real-world’ BPA reduction diet with fewer restrictions and more choice over the longer term was unlikely in our study population due to difficulties in identifying foodstuffs likely to contain less BPA.

BPA has a terminal half-life of 6 hours. Spot samples may therefore not be as accurate as continuous sampling strategies (24 hours urine collection). However, recent studies suggest that despite its short half-life, measurable BPA remains present for up to 43 hours postfasting, indicating non-food exposures or accumulation in body tissues such as fat. We identified no impact of time of sample collection on BPA concentrations in our sample set, in either creatinine-adjusted or unadjusted data, indicating that our measurements were not influenced by time since the last meal. Spot sampling as used here may therefore represent an acceptable compromise and remains a practical option in the community setting. The large variability in urinary BPA within an individual sampled at different times may also have reduced our ability to observe an effect. This could be facilitated by the use of multiple sampling or pools of multiple urines, but was not feasible within the confines of our study.

Calculating an accurate BPA risk score is challenging. Data were self-reported, and foodstuffs are not labelled for BPA content. It is difficult to generalise across food types and large variations in BPA concentrations occur between different products of the same food type or even different lots of the same product. Foods that were free of BPA-containing packaging (as far as it was possible to tell) may have been highly processed or contain food items from a variety of sources. Highly processed and ‘fast’ food has previously been demonstrated to be a source of BPA. A study of the temporal trends seen in composite food samples found no change in the overall BPA content of the food, despite large reduction in the BPA content of some individual food items, illustrating the difficulties in effectively excluding BPA from a varied diet. Participants may therefore have changed BPA-containing foods for other, perceived healthier choices, which may still contain BPA by virtue of processing.

BPA enters foodstuffs by leaching from polycarbonate or epoxy resin after manufacture, or by hydrolysis of the polymer itself. The migration rate of BPA increases with higher temperatures, and with time and use, for example, repeated use of polycarbonate water bottles. Exposure to BPA can also occur through routes other than food, including dust ingestion and dermal absorption and this was not taken into account in our study. A study of volunteers who purposefully handled thermal receipts showed an increase in urinary BPA excretion of up to 84%, and their BPA levels took longer to return to pre exposure levels, suggesting a difference in the bioavailability of BPA through skin and oral routes. It is also possible that some manufacturers may have voluntarily reduced the amount of BPA-containing food packaging compared with their previous usage, given the attention that EDCs have received in the media. However, measurable levels of BPA were still detected in the majority of participants in our study, which suggests that there may be other, non-dietary, sources of BPA, and that exposure to BPA remains an issue. We may also have been underpowered to detect subtle changes in urinary BPA, given the heterogeneity in food choice; detection of such effects may need thousands of participants. Finally, our study, like other studies of its type, does not take account of interindividual differences in the metabolism and excretion of BPA arising from differences in genetic background between people. BPA is metabolised primarily by uridine 5′-diphospho-glucuronosyltransferases, and altered activity polymorphisms of these enzymes have been reported.

Emerging evidence suggests that that BPA may be linked to several chronic human health conditions, suggesting that continued study of the human health effects of BPA exposure is justified. The opinion of the European Food Safety Authority (EFSA), is that while uncertainty over the human health effects of BPA exists, caution should be exercised in ingestion of BPA. Our data suggest that in our study population, it is unlikely that participants could moderate their own BPA exposure in the long term by self-directed modification of diet in a ‘real-world’ setting, and furthermore, participants would have been reluctant to adopt such a lifestyle change in the longer term due to the restrictions in dietary choice and the effects on day-to-day life. Most of these barriers appear to arise from the pervasiveness of BPA in our food chain, and inadequate labelling of foods packaged in BPA-containing substances. We propose that until a definitive assessment of the health risks of BPA is available, informed choice over whether or not to consume BPA and similar chemicals in foodstuffs should be facilitated by better labelling.