Cloning of AwCAT from Anodonta woodiana and the Effect of PBDE on Its Transcription

Polybrominated diphenyl ether (PBDE) flame retardants are endocrine disruptors and suspected neurodevelopmental toxicants. While the direct mechanisms of neurodevelopmental toxicity have not been fully elucidated, it is conceivable that alterations in thyroid hormone levels in the developing brain may contribute to these effects. Cells within the brain locally convert thyroxine (T4) to the biologically active triiodothyronine (T3) through the action of the selenodeiodinase type 2 iodothyronine deiodinase (DIO2). Previous studies have demonstrated that PBDEs can alter hepatic deiodinase activity both in vitro and in vivo; however, the effects of PBDEs on the deiodinase isoforms expressed in the brain are not well understood. Here, we studied the effects of several individual PBDEs and hydroxylated metabolites (OH-BDEs) on DIO2 activity in astrocytes, a specialized glial cell responsible for production of more than 50% of the T3 required by the brain. Primary human astrocytes and H4 glioma cells were exposed to individual PBDEs or OH-BDEs at concentrations up to 5 μM. BDE-99 decreased DIO2 activity by 50% in primary astrocyte cells and by up to 80% in the H4 cells at doses of ≥500 nM. 3-OH-BDE-47, 6-OH-BDE-47, and 5'-OH-BDE-99 also decreased DIO2 activity in cultured H4 glioma cells by 45-80% at doses of approximately 1-5 μM. Multiple mechanisms appear to contribute to the decreased DIO2 activity, including weakened expression of DIO2 mRNA, competitive inhibition of DIO2, and enhanced post-translational degradation of DIO2. We conclude that decreases in DIO2 activity caused by exposure to PBDEs may play a role in the neurodevelopmental deficits caused by these toxicants.

Effects of individual polybrominated diphenyl ether (PBDE) congeners on harbour seal immune cells in vitro

Chapter 45 - Flame Retardants in Wild Bird Eggs and in Relation to Eggs in the Human Food Supply

No one wants their bed, couch, chair, computer, or TV to catch on fire. “If an ordinary upholstered chair in your home gets ignited, it can essentially take your whole house down,” says Richard Gann, a senior research scientist at the U.S. National Institute of Standards and Technology’s (NIST) Building and Fire Research Laboratory. The most flammable part of a mattress or couch is its plastic polyurethane foam cushioning, he explains. Once a fire gets through a chair or mattress’s fabric covering and into this cushioning, it can start a catastrophic reaction that quickly leads to “flashover,” in which nearly everything combustible inside a room ignites simultaneously. Until very recently, brominated flame retardants, especially polybrominated diphenyl ethers (PBDEs), were one of the main materials used to reduce the speed with which the plastic components of consumer goods including beds, couches, chairs, and electronics could be consumed by fire. However, growing evidence shows that PBDE compounds are escaping from the products they protect and making their way into the products’ users. Moreover, the chemicals may disrupt human thyroid hormone functioning and cause other health effects, prompting many nations to ban or suspend their use in new consumer goods. [For more information on the health effects of PBDEs, see “Unwelcome Guest: PBDEs in Indoor Dust, p. A202 this issue.] Although bromine- and chlorine-containing flame retardants are still used in some products, the need for new alternatives is being driven by a confluence of policy, standards, and pressure from environmental groups. Europe banned the use of two formulations, PBDE pentaBDE and octaBDE, in 2004, the same year they were withdrawn from the North American market. A third compound, decaBDE, was banned 1 April 2008 by the European Court of Justice. Stateside, Maine has banned the use of decaBDE, the only PBDE still on the market in North America, in mattresses and residential upholstered furniture produced and sold in that state, and will extend the ban to electronics in 2010. Washington prohibits the use of decaBDE in mattresses and sets a process for a future ban in furniture and electronics if the state can identify a safer and feasible alternative that meets fire safety standards. Asian countries and other U.S. states have similar legislation in the works. “Instead of adding new fire retardant chemicals that ultimately may be shown to cause health problems, we should be asking whether we need to use these chemicals or if there are other ways to achieve equivalent fire safety,” contends Arlene Blum, a biophysical chemist and visiting scholar at the University of California, Berkeley. “So many of the chemicals we have banned in the past were flame retardants—think about asbestos, polychlorinated biphenyls, polybrominated biphenyls, tris(2,3-dibromopropyl) phosphate, PBDEs—[and] they all ended up in the environment and in people,” she points out. “We need to think carefully about adding these sorts of chemicals to consumer products before there is adequate health information.”

A mechanistic view of polybrominated diphenyl ether (PBDE) developmental neurotoxicity

Polybrominated Diphenyl Ethers (PBDEs)

The notion that some substances in the environment can damage the nervous system has an ancient history. The neurotoxicity of lead was recognized more than 2,000 years ago by the Greek physician Dioscerides, who wrote, “Lead makes the mind give way.” In the intervening millennia many other substances have been added to the list of known or suspected neurotoxicants. Despite this accumulation of knowledge, there is still much that isn’t understood about how neurotoxicants affect the developing brain, especially the effects of low-dose exposures. Today researchers are taking a hard look at low-dose exposures in utero and during childhood to unravel some of the mysteries of impaired neurodevelopment. About 17% of school-age children in the United States suffer from a disability that affects their behavior, memory, or ability to learn, according to a study published in the March 1994 issue of Pediatrics by a team from the Centers for Disease Control and Prevention (CDC). The list of maladies includes attention deficit/hyperactivity disorder (ADHD), autistic spectrum disorders, epilepsy, Tourette syndrome, and less specific conditions such as mental retardation and cerebral palsy. All are believed to be the outcome of some abnormal process that unfolded as the brain was developing in utero or in the young child. These disorders have an enormous impact on families and society. According to the 1996 book Learning Disabilities: Lifelong Issues, children with these disorders have higher rates of mental illness and suicide, and are more likely to engage in substance abuse and to commit crimes as adults. The overall economic cost of neurodevelopmental disorders in the United States is estimated to be $81.5–167 billion per year, according to a report published in the December 2001 issue of EHP Supplements. Potentially even more disturbing is that a number of epidemiologic studies suggest that the incidence of certain disorders is on the rise. In the United States, the diagnosis of autistic spectrum disorders increased from 4–5 per 10,000 children in the 1980s to 30–60 per 10,000 children in the 1990s, according to a report in the August 2003 Journal of Autism and Developmental Disorders. Similarly, notes a report in the February 2002 issue of CNS Drugs, the diagnosis of ADHD grew 250% between 1990 and 1998. The number of children in special education programs classified with learning disabilities increased 191% between 1977 and 1994, according to an article in Advances in Learning and Behavioral Disabilities, Volume 12, published in 1998. So what is going on? The short answer is that no one really knows. There’s not even consensus on what the soaring rates actually mean. Heightened public awareness could account for the surge in the numbers, or it may be that physicians are getting better at diagnosing the conditions. Some autism researchers believe the rise in that condition’s prevalence simply reflects changes in diagnostic criteria over the last 25 years. On the other hand, some scientists believe that the rates of neurodevelopmental disease are truly increasing, and that the growing burden of chemicals in the environment may play a role. With that in mind, investigators are considering the effects of gene–environment interactions. A child with a mild genetic tendency toward a neurodevelopmental disorder might develop without clinically measurable abnormalities in the absence of environmental “hits.” However, children in industrialized nations develop and grow up in a veritable sea of xenobiotic chemicals, says Isaac Pessah, director of the University of California, Davis, Center for Children’s Environmental Health and Disease Prevention. “Fortunately,” he says, “most of us have a host of defense mechanisms that protect us from adverse outcomes. However, genetic polymorphisms, complex epistasis, and cytogenetic abnormalities could weaken these defenses and amplify chemical damage, initiating a freefall into a clinical syndrome.” Pessah cites the example of autism. He says susceptibility for autism is likely conferred by several defective genes, no one of which can account for all the core symptoms of social disinterest, repetitive and overly focused behaviors, and problems in communication. Could multiple genetic liabilities and exposure to a chemically complex environment act in concert to increase the incidence and severity of the condition? Despite the uncertainties, many scientists believe it would be wise to err on the side of caution when it comes to a research agenda. As Martha Herbert, a pediatric neurologist at Harvard Medical School, puts it, “Even though we may have neither consensus nor certainty about an autism epidemic, there are enough studies coming in with higher numbers that we should take it seriously. Environmental hypotheses ought to be central to research now. The physiological systems that have been harmed by environmental factors may also point to treatment targets, and this might be a great way to help the children.”

Some polybrominated diphenyl ether (PBDE) flame retardants with wide environmental distribution inhibit TCDD-induced EROD activity in primary cultured carp ( Cyprinus carpio) hepatocytes

In vitro immune toxicity of polybrominated diphenyl ethers on murine peritoneal macrophages: Apoptosis and immune cell dysfunction

Physiological effects of polybrominated diphenyl ether (PBDE-47) on pregnant gartersnakes and resulting offspring

In recent years, polybrominated diphenyl ethers (PBDEs) have been detected at increasing levels in the environment due to their widespread use as flame retardants. PBDEs can affect thyroid hormone homeostasis and the cholinergic neurotransmitter system. In this study, several PBDE congeners were detected in whole brain samples and neuronal cells of herring gulls (Larus argentatus). A herring gull neuronal cell culture method was used to determine the effects of PBDEs on cytotoxicity and mRNA expression. Real-time RT-PCR assays were developed for genes associated with the thyroid hormone pathway (thyroid hormone receptors [TR alpha and beta], transthyretin [TTR]), and the cholinergic system (neuronal nicotinic acetylcholine receptor alpha-7 [nAChR alpha-7]). Administration of T3 resulted in a significant up-regulation of the two TRs and a significant down-regulation of TTR. TTR was also down-regulated by the commercial penta-BDE mixture, DE-71. In contrast, neither DE-71, nor BDE-47, -99, or -100 altered the mRNA levels of the TRs or nAChR alpha-7. The in vitro approach was a relevant model system for assessing the effects of PBDEs on cytotoxicity and mRNA expression. Herring gull neuronal cells were responsive to both T3 and PBDEs although, receptors associated with two predicted mechanisms of PBDE action were not effective molecular biomarkers of exposure.

Objective To discuss the effects of polybrominated diphenyl ethers （PBDEs） exposure in e-waste dismantling region on the human body and provide data support for the identification of environmental health damage to residents in the e-waste dismantling region. Methods Adults in an e-waste dismantling region （exposed group, 54 participants） and a control region （control group, 58 participants） were selected, questionnaires were carried out and blood and urine samples were collected. Blood PBDEs, blood lipids, blood routine, blood lead, urine cadmium, urine chromium and urine nickel were detected. T-test was utilized to compare the differences of PBDEs between the two groups. Multivariate analysis were utilized to compare the differences between the two groups in blood routine indexes. Linear regression was used to analyze the relationship between PBDEs and blood routine. Results Exposure levels of PBDEs were significantly higher in the exposed group （240.00 ng/g, adjusted mass fraction of blood lipids, thereafter） than in the control group （93.00 ng/g, P<0.05）. There was no statistical significance in the differences in most blood routine indexes of the two groups （ P>0.05）, and their reference values were all within normal ranges. Mean platelet volume, plateletcrit, basophils percentage, absolute value of basophils, and mean corpuscular hemoglobin concentration were higher in the exposed group than in the control group （P<0.05）. Platelet distribution widths were lower in the exposed group than in the control group and below the normal reference range （P<0.05）. Conclusion PBDEs exposure in e-waste dismantling region tend to change platelet morphology, the number of basophils, and mean corpuscular hemoglobin concentration, and may pose potential health hazards to local residents.

Involvement of reactive oxygen species in brominated diphenyl ether-47-induced inflammatory cytokine release from human extravillous trophoblasts in vitro

PBDEs are flame retardants found in furniture, carpets and electronics. These organic pollutants are highly lipophilic and accumulate in the adipose tissue of animals and humans. However, the effects of PBDEs on adipocyte metabolism are unknown. The purpose of this study was to determine the effects of penta-PBDE on lipolysis and glucose oxidation in rat adipocytes in vitro and in vivo. In vitro, adipocytes from 12 male Sprague-Dawley rats were isolated and incubated for 90 minutes with either 0, 15 or 30ug/ml PBDEs (4 rats/group.) In vivo, male Sprague-Dawley rats weighing 120g were gavaged daily for 4 weeks with either 18mg/kg PBDEs or corn oil (12 rats/group). Adipocytes from in vivo and in vitro treatments were tested for lipolytic response to epinephrine and [U-14C] glucose oxidation response to insulin. Rat weight gain was similar in all groups throughout the study. In vitro data show that incubation with PBDEs for 90 minutes had no effect on lipolysis or glucose oxidation in rat adipocytes. In vivo data show that after 4 weeks, basal lipolysis was increased by 58% and maximal lipolysis was increased by 22%, compared to control. There was a 41% decrease in maximal glucose oxidation in rats treated with PBDEs for 4 weeks, compared to controls. In summary, although incubation of adipocytes with PBDEs does not change adipocyte functionality, a low daily dose of PBDEs to rats increased basal and maximal lipolysis and decreased maximal glucose oxidation in freshly isolated rat adipocytes. Whether these changes persist and contribute to permanently altered adipocyte function remains to be determined. Supported by Agr. Exp. Stn. Grant NH00432.

Higher HDL-C levels attenuated the association of plasma polybrominated diphenyl ethers with prediabetes and type 2 diabetes mellitus in rural Chinese adults