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Brain Drain? PBDEs Alter Development of Human Brain Cells

Levels of polybrominated diphenyl ethers (PBDEs)—persistent and bioaccumulative flame retardants—have been increasing in human tissues over the last several years. Although developmental exposure to PBDEs has been shown to cause behavioral alterations in rodent models, there is little information on the effects of PBDE exposure on neurodevelopment in humans. Schreiber et al. studied the in vitro effects of two prominent congeners found in human tissues, tetrabrominated BDE-47 and pentabrominated BDE-99, on proliferation, migration, and differentiation in primary fetal human neural progenitor cells (hNPCs). They also studied the potential involvement of thyroid disruption in the neurodevelopmental effects of the PBDEs. Over a range of noncytotoxic concentrations, PBDEs did not affect nNPC proliferation, but they reduced hNPC migration and affected neural differentiation in a concentration-dependent manner. Other experiments indicated that BDE-47 and BDE-99 affected migration and differentiation in vitro by endocrine disruption of cellular thyroid hormone signaling. These studies provide biological plausibility for in vivo animal studies reporting behavioral effects after developmental exposures, and they raise concerns about potential developmental neurotoxicity in humans.

Brain Drain? PBDEs Alter Development of Human Brain Cells

A new laboratory study demonstrating that polybrominated diphenyl ethers (PBDEs) can alter human fetal brain cells may explain at least in part the neurotoxicity recently documented in epidemiologic studies of young children exposed to PBDEs and previously shown in animal models [EHP 118:572–578; Schreiber et al.]. The new study, the first to examine PBDE neurotoxicity in a human cell–based system, links the brain cell alterations to endocrine disruption.

A wealth of data demonstrates that babies can be exposed to significant amounts of PBDE flame retardants both in the womb and through breastfeeding. Although all 3 PBDE formulations—penta, octa, and deca—are banned in Europe, and the penta and octa formulations were discontinued in the United States (deca also is banned in some states), PBDEs may still be used in some new U.S. products and in wares manufactured elsewhere. They also are found in a wide variety of older plastic consumer goods that remain in use in many homes, businesses, and automobiles. The PBDEs are known to migrate into indoor dust, posing a particularly high exposure risk to infants and toddlers because of their characteristic hand-to-mouth behavior.

To investigate how PBDEs may impact the developing fetal brain, the team of scientists employed a method for evaluating human developmental neurotoxicity they had recently developed [EHP117:1131–1138] as an alternative to animal testing. This method uses primary fetal human neural progenitor cells (hNPCs) cultured to produce complex 3-dimensional cellular systems called neurospheres. Neurospheres undergo the same basic processes that occur during the early stages of normal human brain development: cell proliferation, differentiation, and migration. Tests conducted with neurospheres may help identify exogenous substances that disturb these basic processes in vivo.

The researchers focused on 2 of the PBDE compounds that accumulate the most in humans, BDE-47 and BDE-99. At concentrations below levels that cause cell death, they found these compounds could reduce the migration of the hNPCs—which suggests the possibility of adverse effects on brain development—and the effects increased with higher PBDE concentrations. At the highest tested concentration (10 μM), BDE-47 decreased the distance the cells migrated by more than 25% compared with unexposed cells, whereas the same concentration of BDE-99 decreased the distance by more than 30%. Additional testing established that both compounds also interfered with the differentiation of immature progenitor cells into neurons and oligodendrocytes.

Further tests suggested the PBDE compounds affected cell migration and differentiation by interfering with thyroid hormone signaling, an endocrine-disrupting effect that could be associated with additional impacts throughout a person’s life. Followup work to determine whether PBDEs cause the same effects in rodent neurospheres would facilitate extrapolation from animals to humans, the authors say.

Other work has shown the tendency of PBDEs to accumulate in brain and neuronal cells, and the researchers used radiolabeled BDE-47 to measure an accumulation in test cells of approximately 60-fold. Considered with available human exposure data, these data suggest current PBDE exposure levels are likely to be of concern for human health, the authors write. Two recent studies have linked PBDEs with subtle changes in childrens’ IQs and behavior [EHP 117:1953–1958 and EHPdoi:10.1289/ehp.0901340], and the authors say additional studies are needed to assess these associations.

By Kellyn S. Betts

Kellyn S. Betts has written about environmental contaminants, hazards, and technology for solving environmental problems for publications including EHPand Environmental Science & Technology for more than a dozen years.

Source: Betts KS 2010. Brain Drain? PBDEs Alter Development of Human Brain Cells. Environ Health Perspect 118:a173-a173. doi:10.1289/ehp.118-a173a

Originally published online on nih.gov: 01 April 2010