Perinatal BPA exposure induces chronic inflammation in offspring by modulating gut bacteria

Exposure to Bisphenol A During Pregnancy Induces Chronic Inflammation in Rabbit Offspring via Modulation of Gut Bacteria and Their Metabolites

A chemical called bisphenol A (BPA) used in plastic packaging and in the linings of food and beverage cans, may be passed from a mother to her offspring during pregnancy and cause changes in the gut bacteria of the offspring.

Emerging evidence from a research study in rabbits suggests that environmental toxicants may influence inflammation-promoted chronic disease susceptibility during early life. BPA exposure just before or after birth leads to reduced gut bacterial diversity, bacterial metabolites such as short-chain fatty acids (SCFA) and elevated gut permeability – three common early markers of inflammation-promoted chronic diseases.

The researchers observed that exposure to BPA during pregnancy caused chronic inflammation in the offspring’s intestines and liver. The researchers also noted signs of increased gut permeability – or leaky gut – and a decrease in the diversity of gut bacteria and anti-inflammatory bacterial metabolites, such as short-chain fatty acids.

2017 Study Abstract

Bisphenol A (BPA) accumulates in the maturing gut and liver in utero and is known to alter gut bacterial profiles in offspring. Gut bacterial dysbiosis may contribute to chronic colonic and systemic inflammation. We hypothesized that perinatal BPA exposure-induced intestinal (and liver) inflammation in offspring is due to alterations in the microbiome and colonic metabolome. The 16S rRNA amplicon sequencing analysis revealed differences in beta diversity with a significant reduction in the relative abundances of short-chain fatty acid (SCFA) producers such as Oscillospira and Ruminococcaceae due to BPA exposure. Furthermore, BPA exposure reduced fecal SCFA levels and increased systemic lipopolysaccharide (LPS) levels. BPA exposure-increased intestinal permeability was ameliorated by the addition of SCFA in vitro. Metabolic fingerprints revealed alterations in global metabolism and amino acid metabolism. Thus, our findings indicate that perinatal BPA exposure may cause gut bacterial dysbiosis and altered metabolite profiles, particularly SCFA profiles, leading to chronic colon and liver inflammation.

IMPORTANCE
Emerging evidence suggests that environmental toxicants may influence inflammation-promoted chronic disease susceptibility during early life. BPA, an environmental endocrine disruptor, can transfer across the placenta and accumulate in fetal gut and liver. However, underlying mechanisms for BPA-induced colonic and liver inflammation are not fully elucidated. In this report, we show how perinatal BPA exposure in rabbits alters gut microbiota and their metabolite profiles, which leads to colonic and liver inflammation as well as to increased gut permeability as measured by elevated serum lipopolysaccharide (LPS) levels in the offspring. Also, perinatal BPA exposure leads to reduced levels of gut bacterial diversity and bacterial metabolites (short-chain fatty acids [SCFA]) and elevated gut permeability-three common early biomarkers of inflammation-promoted chronic diseases. In addition, we showed that SCFA ameliorated BPA-induced intestinal permeability in vitro. Thus, our study results suggest that correcting environmental toxicant-induced bacterial dysbiosis early in life may reduce the risk of chronic diseases later in life.

Sources

  • Perinatal Bisphenol A Exposure Induces Chronic Inflammation in Rabbit Offspring via Modulation of Gut Bacteria and Their Metabolite, msystems asm, DOI: 10.1128/mSystems.00093-17, 2017 Oct.
  • Exposure to chemical during pregnancy may cause health problems for offspring, The Pennsylvania State University, story/491849, November 8, 2017.
  • Microbial responses to the perinatal bisphenol A (BPA) exposure in rabbit offspring featured image credit PMC5634791/figure/fig2, 2017 Oct 10.

Prenatal and postnatal bisphenol A exposure and social impairment in 4-year-old children

BPA linked to social deficits in offspring, particularly in girls

2017 Study Abstract

Background
Prenatal and postnatal exposure to bisphenol A (BPA) may affect early brain development. Rodent studies suggest that prenatal and postnatal neurodevelopmental toxicity from BPA exposure may manifest as social deficits in offspring. We investigated the association between prenatal and postnatal exposure to BPA and social impairments in a sample of 4-year-old children.

Methods
We recruited second-trimester pregnant women between 2008 and 2011, and measured their creatinine-adjusted prenatal urine BPA levels. In 2014-2015, a subset of 4-year-old children born to these women underwent neurobehavioral assessment and physical examination. We collected urine and blood from the children and assessed social impairments, including deficits in social interaction, social communication, and other behavior patterns using the Korean version of the Social Communication Questionnaire (K-SCQ) (n = 304). We examined social impairments associated with prenatal exposure at mid-term pregnancy and postnatal exposure to BPA at 4 years of age, using linear and piecewise linear regression models.

Results
The relationship between prenatal BPA exposure and social communication was non-linear and statistically significant at or above the flexion point for BPA levels of 3.0 μg/g creatinine in girls (58.4%, 95% confidence interval [CI], 6.5% to 135.8%). Each 2-fold increase in postnatal BPA exposure was significantly associated with an 11.8% (95% CI, 0.6% to 24.3%) increase in impairment in social communication in 4-year old girls, as indicated by the linear regression model.

Conclusion
Prenatal and postnatal BPA exposure is associated with social impairment at 4 years of age, particularly in girls.

The prospective cohort study design is a strength of this study investigating the relationships between prenatal and postnatal BPA concentrations and social impairments at 4 years of age. Although the study has several limitations, including parent-reported questionnaires to evaluate social impairments and no participants with severe social impairments, the study makes a significant contribution to research on endocrine disruptors’ impact on children health because the relationship between BPA exposure and neurodevelopmental effects has not been fully elucidated in humans, and our results elucidate BPA exposure effects related to social impairments. Specifically, prenatal BPA exposure was significantly associated with impairments at or above the flexion point of 3.0 μg/g creatinine, whereas there was a linear association for postnatal BPA exposure. Further studies to evaluate the health implications and underlying mechanisms of these findings are warranted.

4 years old girl featured image credit kiwi huang.

Perturbateurs endocriniens, liste des substances anthropiques

Office parlementaire d’évaluation des choix scientifiques et technologiques, Rapport 2011

En 2011, à l’occasion d’une proposition de loi visant à interdire le Bisphénol A dans les plastiques alimentaires, l’Office parlementaire d’évaluation des choix scientifiques et technologiques a été saisi pour réaliser une étude portant sur la question des perturbateurs endocriniens et l’état des recherches.

Les substances anthropiques représentent des milliers de produits et comprennent des produits de l’industrie chimique (phtalates, bisphénol A, métaux lourds, etc.) et les produits phytosanitaires utilisés en agriculture (herbicides, fongicides, insecticides, etc.).

PRINCIPALES SOURCES DES PERTURBATEURS ENDOCRINIENS CONFIRMÉS OU POTENTIELS

Produits pharmaceutiques

  • DES (Distilbène), éthynil-oestradiol (contraceptif), kétokonazole (traitement du pityriasis, pommade)…

Produits dentaires

  • Bisphénol A

Produits vétérinaires

  • DES, trenbolones (augmentent la masse musculaire)…

Produits de combustion

  • Dioxines, furanes, HAP (hydrocarbure aromatique polycyclique)…
  • Produits à usage industriel ou domestique
  • Phtalates, bisphénol A, styrène (polystyrène)…
  • Polybromodiphényl éthers (PBDE), polychlorobiphényls, organoétains…
  • Alkylphénols, parabens (conservateurs dans les produits de beauté)…
  • Arsenic, cadmium…

Produits phytosanitaires

  • Organochlorés (DDT, chlordécone…)
  • Vinchlozoline (retirée en avril 2007), linuron (herbicide)…

Phytooestrogènes

  • Isoflavones (soja, trèfle)…

Mycotoxines

  • Zéaralénone…

Perturbateurs endocriniens, le temps de la précaution

Le Distilbène DES, en savoir plus

Toxic Time Bombs

Decades of evidence point to the untoward health effects of endocrine disruptor exposures, yet little is being done to regulate the chemicals

Abstract

… “Although the U.S. has been slow to control endocrine disruptors, pressure is mounting for legislators to make significant regulatory changes in Europe, although the European Commission has also dragged its feet. In December 2015, the European Union’s Court of Justice decreed that the Commission had breached EU law by failing to adopt scientific criteria for identifying and regulating endocrine disruptors. The European Parliament met in February 2017 to consider a proposal defining those criteria, but member states decided to postpone a decision. France did not wait for the E.U. to take effective action. As of January 2015, new French legislation outlawed any contact between the known endocrine disruptor bisphenol A (BPA) and beverages or food.

The challenge to developing appropriate regulations for endocrine disruptors is that evidence from epidemiology for health effects is indirect and difficult to collect. Cancers abound in modern industrialized societies. Environmental factors are surely involved, yet hard to pinpoint. It took three decades to establish that DDT (dichloro-diphenyl-trichloroethane) and DES (diethylstilbestrol) impair health. Both are now strictly controlled, but their effects persist across generations.” …

  • Read Opinion: Toxic Time Bombs, by Robert Martin for The Scientist, September 25, 2017.
  • Featured image Portrait of Sir Edward Charles Dodds credit wikimedia.
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Efficient technology to remove BPA and similar chemicals from water

A multidisciplinary investigation of the technical and environmental performances of TAML/peroxide elimination of Bisphenol A compounds from water

As water treatment plants struggle to keep up with the chemical cocktail heading into our pipes, researchers say they’ve come up with a solution to remove one of the most ubiquitous contaminants—BPA.

There now exists economically viable, efficient technology to remove bisphenol A (BPA) and a host of similar chemicals from water.

2017 Study Conclusion

In developing Green Chemistry, it is important that chemists come to understand the scope of the challenges posed by everyday-everywhere endocrine disruptors (EDs) to the sustainability of both the chemical enterprise and our complex global civilization. The most troubling such EDs, like BPA, invariably hold their protected positions in the economy because of seductive technical and cost performances that enable large, diverse, profitable markets. For sustainable chemicals, the health, environmental and fairness performances also have to be integral components of the value proposition. Understanding the negative performances of unsustainable chemicals helps in mapping the properties sustainable chemicals should not have. Key aspects of this understanding include the knowledge of which chemicals are and are not EDs and are and are not capable of eliciting low dose adverse effects by non-endocrine processes, the extent and routes by which the environment and people are exposed to commercial EDs, the environmental and human health consequences of ED exposures, the methods of assessment of endocrine activity including the TiPED, the mechanisms of the low dose adverse effects, the design approaches to attaining new and replacement chemicals free of such effects, and the stewardship methodologies that are currently deployed or might be deployed to better protect health and the environment from commercial EDs. This BPA case study traverses the appropriate multidisciplinary landscape with emphasis on the integration of chemistry and environmental health science in the development of endocrine disruption-free processes to aid the chemical enterprise and society in reducing BPA exposures. Importantly, the litany of unfortunate facts presented about BPA exposures and health and environmental performances is relieved to some extent by the possibility of reduced releases arising from the TAML/H2O2 technology mapped out in the empirical section.

This experimental component demonstrates that TAML/H2O2 provides simple, effective water treatment methodologies, which depending on the pH, either decompose BPA or isolate it in low solubility oligomers. Both processes require only very low concentrations of TAML activator and H2O2 in further reflection of the remarkable efficiencies of the peroxidase enzymes that are faithfully mimicked by TAML activator and in marked contrast with the much higher relative iron- and peroxide-requiring Fenton processes. It remains to be established whether the current laboratory studies project to real world scenarios. These may include treatment of BPA-contaminated landfill leachates and paper plant processing solutions where the concentrations are similar to those employed in this study. In such scenarios, TAML/H2O2 would present an enzyme-mimicking method which in the case of TAML activator is comprised exclusively of biochemically common elements and has passed multiple TiPED assays that, in contrast with existing real world processes, avoids generation of BPA-contaminated sludges and associated subsequent releases to soil, that does not generate a contaminated adsorbent which must be replaced or regenerated at elevated temperature, that does not generate chlorinated forms of BPA, that does not generate a concentrated retentate, and that is remarkably simple to deploy using very low and cheap chemical inputs with all the positive potential consequences thereof for capital and operating expenses.

Finally, in order to avoid the habit or perception of greenwashing, a realistic perspective is essential to the integrity of green chemistry. We view the sustainability challenges posed by BPA as enormous—the experimental work presented could evolve into a solution for some of these problems but is, by no means, a general quick fix. BPA markets large and small are expanding rapidly, especially as the industry has learned how to produce even more effective replacements for glass and metal products. Huge new markets are developing such as those of plastic glass houses, and even houses, and automobile body parts that are comprised primarily of BPA. In this build-up, BPA’s unfortunate health and environmental performances continue to be given short shrift. Continuation of the present BPA expansion trends without limits, technical corrections and more aggressive stewardship advances of multiple kinds will menace society with an ever increasing oestrogenization of the entire ecosphere.

Sources and More Information
  • BPA breakthrough: New treatment takes controversial chemical out of water, EHN, August 2, 2017.
  • Science: Pay attention to two other messages in the breakthrough BPA water treatment paper, EHN, August 8, 2017.
  • A multidisciplinary investigation of the technical and environmental performances of TAML/peroxide elimination of Bisphenol A compounds from water, pubs, 19th July 2017.
  • Feature image credit Leland Francisco.

Bisphenol A becomes officially recognised as an endocrine disruptor

Bisphenol A is recognised by ECHA for its endocrine-disrupting properties, based on a proposal by France

Member State Committee unanimously agrees that Bisphenol A is an endocrine disruptor

ECHA/PR/17/12 – The Member State Committee (MSC) supported the French proposal to additionally identify Bisphenol A as a substance of very high concern because of its endocrine disrupting properties which cause probable serious effects to human health. The committee also agreed to identify the substance PFHxS as an SVHC.

Helsinki, 16 June 2017 – The Member State Committee (MSC) unanimously agreed on the identification as substances of very high concern (SVHCs) of:

  • 4,4′-isopropylidenediphenol (bisphenol A, BPA) (EC 201-245-8, CAS 80-05-7), proposed by France, due to its endocrine disrupting properties for human health;
  • Perfluorohexane-1-sulphonic acid and its salts (PFHxS), proposed by Sweden, due to their very persistent and very bioaccumulative (vPvB) properties.

Bisphenol A is already listed in the Candidate List due to its toxic for reproduction properties. At the MSC meeting earlier this week, MSC unanimously agreed on its additional identification as an SVHC because of its endocrine disrupting properties which cause probable serious effects to human health which give rise to an equivalent level of concern to carcinogenic, mutagenic, toxic to reproduction (CMRs category 1A or 1B) substances.

ECHA will include PFHxS in the Candidate List and will update the current entry for BPA accordingly by the end of June 2017. Companies may have legal obligations with respect to these substances upon publication of the updated Candidate List.

Bisphenol A is recognised by ECHA for its endocrine-disrupting properties, based on a proposal by France

In February 2017, ANSES submitted a proposal to the European Chemicals Agency (ECHA) to classify bisphenol A (BPA) as a substance of very high concern (SVHC) within the framework of the European REACh regulation, based on its “endocrine-disrupting” properties which cause probable serious effects to human health. This proposal has just been adopted by ECHA’s Member State Committee. The decision means that industry players must notify ECHA of the presence of bisphenol A in all imported or manufactured items and must also inform buyers when items contain the substance. The inclusion of BPA on ECHA’s list of substances of very high concern also means that it may be submitted to authorisation as a substance, with its uses subject to the granting of a temporary, renewable authorisation.

Bisphenol A is a synthetic chemical which has been used for over 50 years, mainly in the plastics industry. ANSES has identified close to sixty business sectors that are potential users of the substance in France. Studies by ANSES on the uses and health effects of bisphenol A, conducted as part of the National Endocrine Disruptor Strategy, led the Agency to recommend, as of September 2011, a reduction in population exposure to the substance through its substitution in food contact materials in particular. Therefore since 1 January 2015 bisphenol A has been banned in food containers in France, and has led to a significant reduction in exposure levels.

Furthermore, in 2012, in the framework of implementation of the European regulation on the labelling of chemical substances (CLP regulation), ANSES submitted a proposal to ECHA for amending the classification of bisphenol A in order to include it in category 1B – substances toxic to reproduction (fertility). This proposal was adopted by the European Commission in July 2016.

Following this, a measure restricting BPA use in certain widely available items such as receipts made of thermal paper, was also adopted by the European Commission in December 2016, based on a dossier filed by ANSES with ECHA as part of the REACh regulation.

Identification of bisphenol A as a substance of very high concern

The REACh regulation specifies that substances that may have serious and often irreversible effects on human health and the environment can be identified as substances of very high concern (SVHC). In February 2017, ANSES submitted a proposal to ECHA for identifying BPA as an SVHC based on its “endocrine disrupting” properties which cause probable serious effects to human health.

This proposal has just been adopted by the Member State Committee of ECHA. As a direct result of BPA’s identification as an SVHC, industry players will now have to notify ECHA of the presence of bisphenol A in all imported or manufactured items and must also inform buyers, upon request, when items contain the substance.

BPA’s inclusion on the list of substances of very high concern means that its uses may be limited and subject to the granting of a temporary, renewable authorisation.

Sources
  • MSC unanimously agrees that Bisphenol A is an endocrine disruptor, ECHA, 16 June 2017.
  • Bisphenol A is recognised by ECHA for its endocrine-disrupting properties, based on a proposal by France, ANSES, 16/06/2017.
  • Image credit Percy.

60 MiNueTs : Toxic Bodies

UCSF Program on Reproductive Health and the Environment, 2017

The University of California San Francisco (UCSF) Program on Reproductive Health and the Environment (PRHE)’s mission is to create a healthier environment for human reproduction and development through advancing scientific inquiry, clinical care and health policies that prevent exposures to harmful chemicals in our environment.

PRHE is housed within the Department of Obstetrics, Gynecology and Reproductive Sciences, in the UCSF School of Medicine, one of the nation’s most prestigious medical schools. The Department is renowned for promoting cutting-edge reproductive science research, extending the frontiers of multidisciplinary women’s health care and professional education, advocating for women’s health at local, state and national levels, and engaging community involvement.

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Time Bomb: a Journey into Old Exposures, Gametic Glitches, and the Autism Explosion

Slides from Society for Neuroscience Wonder, February 2017

This presentation to a student-run chapter of SFN explained the history and science behind the “Time Bomb” hypothesis of autism.

DES DiEthylStilbestrol Resources

Evidence that bisphenol S crosses the human placenta

Common BPA alternative, BPS, crosses into placenta

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

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

2017 Study Abstract

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

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

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

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

Prenatal BPA exposure alters our natural ability to control appetite

Mouse study sheds light on how endocrine-disrupting chemical increases obesity risk

Washington, DC – An expectant mother’s exposure to the endocrine-disrupting chemical bisphenol A (BPA) can raise her offspring’s risk of obesity by reducing sensitivity to a hormone responsible for controlling appetite, according to a mouse study published in the Endocrine Society’s journal Endocrinology.

BPA is a chemical found in a variety of food containers, including polycarbonate plastic water bottles and can linings. BPA can interfere with the endocrine system by mimicking estrogen, one of the main sex hormones found in women. Research indicates BPA exposure is nearly universal. More than 90 percent of people tested in population studies had detectable levels of BPA and compounds produced when it is metabolized by the body in their urine.

As of 2014, nearly 100 epidemiological studies had been published tying BPA to various health problems, according to the Society and IPEN’s Introduction to Endocrine-Disrupting Chemicals.

Prenatal bisphenol A exposure weakens body’s fullness cues, The Endocrine Society News Room, February 07, 2017.

Image credit Owen and Aki.

The new study – Perinatal Exposure to Bisphenol-A (BPA) Delays the Postnatal Leptin Surge in Male and Female CD-1 Mice – found mice born to mothers exposed to BPA were less responsive to the hormone leptin, which is sometimes called the satiety hormone. Leptin helps inhibit the appetite by reducing hunger pangs when the body does not need energy. The hormone sends signals to the hypothalamus region of the brain to suppress the appetite.

“Our findings show that bisphenol A can promote obesity in mice by altering the hypothalamic circuits in the brain that regulate feeding behavior and energy balance.
Low level prenatal exposure to BPA delays a surge of leptin after birth that allows mice to develop the proper response to the hormone. BPA exposure permanently alters the neurobiology in the affected mice, making them prone to obesity as adults.”

said the study’s senior author, Alfonso Abizaid, Ph.D., of the Department of Neuroscience at Carleton University in Ottawa, Canada.

To examine how BPA can encourage the development of obesity, the researchers fed pregnant mice BPA in their food. The mice were exposed to doses of BPA that are lower than levels deemed safe by the U.S. Food and Drug Administration and Health Canada. Once the mice gave birth, the researchers gave their offspring injections of leptin at various intervals and then examined their brain tissue and analyzed their blood to gauge the response to the hormone.

Other pregnant mice were not exposed to any chemicals or were exposed to an estrogen chemical called diethylstilbestrol (DES), so their young could be compared to those born to mice that were exposed to BPA. All the mice were fed a control diet to eliminate differences in food intake.

Newborn mice typically exhibit a surge of leptin when they are eight days old that programs the hypothalamus circuits to respond to fullness cues. The study found that animals exposed to BPA experienced this surge two days late, and mice exposed to DES never had a surge of leptin. When they were treated with leptin over the course of two days, control animals that weren’t exposed to either chemical lost more weight than BPA- or DES-exposed mice.

In addition, researchers found that mice exposed to BPA before birth had reduced fiber density and brain activity in the hypothalamus circuits involved in regulating energy expenditure.

“This study improves our understanding of how BPA can disrupt the endocrine system in a manner that raises the risk of obesity in animals.
Since BPA has also been linked to obesity in humans, people need to be aware that environmental factors can lead to increased susceptibility to obesity and cardio-metabolic disorders.”

Abizaid said.

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