Mothers exposed to PBDE flame retardants while pregnancy increase children’s risk of developing reading disorders

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A new study from researchers at Columbia University Vagelos College of Physicians and Surgeons suggests that prenatal exposure to flame retardants may increase the risk of reading problems.

The study was published in the January 2020 print edition of Environmental International.

An estimated 2 million children have learning disorders; of these, about 80% have a reading disorder. Genetics account for many, but not all, instances of reading disorders.

In the current study, the researchers hypothesized that in utero exposure to polybrominated diphenyl ethers (PBDEs)–a type of flame retardant that is known to have adverse effects on brain development–might alter the brain processes involved in reading.

(While use of PBDEs has been banned, exposure to the compounds is still widespread because they do not degrade easily in the environment.)

The research team analyzed neuro-imaging data from 33 5-year-old children–all novice readers–who were first given a reading assessment to identify reading problems.

They also used maternal blood samples, taken during pregnancy, to estimate prenatal exposure to PDBEs.

The researchers found that children with a better-functioning reading network had fewer reading problems. The also showed that children with greater exposure to PDBEs had a less efficient reading network.

However, greater exposure did not appear to affect the function of another brain network involved in social processing that has been associated with psychiatric disorders such as autism spectrum disorder.

“Since social processing problems are not a common aspect of reading disorders, our findings suggest that exposure to PDBEs doesn’t affect the whole brain–just the regions associated with reading,” says Amy Margolis, PhD, assistant professor of medical psychology in the Department of Psychiatry at Columbia University Vagelos College of Physicians and Surgeons.

The researchers found that children with a better-functioning reading network had fewer reading problems.

Although exposure to PDBEs affected reading network function in the 5-year-olds, it did not have an impact on word recognition in this group.

The finding is consistent with a previous study, in which the effects of exposure to the compounds on reading were seen in older children but not in emergent readers. “Our findings suggest that the effects of exposure are present in the brain before we can detect changes in behavior,” says Margolis.

“Future studies should examine whether behavioral interventions at early ages can reduce the impact of these exposures on later emerging reading problems.”

Additional authors are Sarah Banker (Columbia University Irving Medical Center, New York, NY), David Pagliaccio (CUIMC), Erik De Water (Icahn School of Medicine at Mount Sinai, New York, NY), Paul Curtin (Icahn School of Medicine), Anny Bonilla (Icahn School of Medicine), Julie B. Herbstman (CUIMC), Robin Whyatt (CUIMC), Ravi Bansal (University of Southern California, Los Angeles, CA), Andreas Sjödin (Center for Disease Control and Prevention, Atlanta, GA), Michael P. Milham (Child Mind Institute, New York, NY), Bradley S. Peterson (USC), Pam Factor-Litvak (CUIMC), Megan K. Horton (Icahn School of Medicine).

Funding: This work was supported by funding from the National Institute for Environmental Health Sciences (K23ES026239 to A.E.M., R00 ES020364 to M.K.H; R21 ES016610-01 to R.W.)

The authors report no financial or other conflicts of interest.


Across the world, humans face exposure to a vast number of industrial chemicals, whose potential for negatively impacting human health has long been a concern [1,2,3]. In early 2018, the United States Environmental Protection Agency (EPA) reported 30,972 active chemicals in industry out of a total of 86,071 registered in the agency’s Toxic Substances Control Act (TSCA) Chemical Substance Inventory.

The European Chemicals Agency’s (ECHA) most recently updated figure from their relatively new Regulation for Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) initiative reports 21,403 unique substances.

China has also established a program recently – similar to Europe’s REACH regulations – that mandates new updating of China’s chemical inventory, the Inventory of Existing Chemical Substances (IECSC), which lists 45,612 substances as of 2013. As world governments attempt to define what chemicals have been produced and are in use, efficient methods to identify and evaluate compounds for safety screening are still being debated and formed.

Progress is slow, with few chemicals actually being heavily regulated. In the US, the history of chemical regulation is long and convoluted, and is well reviewed elsewhere [4]. Presently, the EPA is in the midst of a three-tiered evaluation program designed to assess the safety of existing chemicals, with only the most dangerous chemicals likely to ever reach the eventual ‘Risk Management’ phase.

It is questionable whether this type of approach is practical at all, yet meaningful change may not come soon, as it is unlikely that the country will shift the burden of proof regarding chemical safety from regulatory agencies to manufacturers (as with Europe’s REACH program).

In the meantime, the vast volume and diversity of industrial chemicals we expose ourselves to continues to pose a potentially serious risk to human health. There are numerous avenues by which hazardous compounds may impact human health, perhaps the most widely recognized of which are potential for carcinogenicity, adverse effects on reproductive health, and disruption of hormonal signaling.

Another exceedingly concerning endpoint for human health is nervous system toxicity, particularly during development of the brain. The developing brain is an especially vulnerable target due to the complex nature of its formation and refinement that spans prenatal and years of postnatal development.

As such, neurodevelopmental toxicity induced by chemical exposures has been heavily studied [5], but much remains unclear. Here, we will focus on a class of industrial chemicals that has been under heavy scrutiny for suspected neurodevelopmental toxicity: polybrominated diphenyl ethers (PBDEs).

PBDEs are a group of environmentally persistent chemicals that have been widely used as flame retardants on household consumer products since 1970s. Due to their environmental stability and propensity for bioaccumulation, PBDE concentrations have ubiquitously and cumulatively built up in our environment and in our bodies around the globe.

Intriguingly, PBDEs enter the environment from both anthropogenic and natural sources. Historically, these compounds were first described in the biomedical literature as early as the 1960s – a decade before their anthropogenic production – when they were isolated from Australian marine sponges (Dysidea sp.) and found to have antimicrobial properties [6,7,8].

They have also been isolated from various red algae [9,10]. Recently, in the case of sponges, it was demonstrated that PBDEs are actually produced by symbiotic cyanobacteria and are theorized to confer some level of microbial resistance to the host sponges, although the mechanism(s) by which the compounds are toxic to other organisms remains unknown [11].

It is interesting to note, however, that these compounds are excreted by the cyanobacteria and subsequently accumulate in high concentrations, crystalizing in the sponge ectosomal tissues. This is perhaps how sponges avoid the compounds’ toxic effects and how they may be a defense mechanism against potential eukaryotic predators such as fish in addition to other prokaryotes [12].

In the context of human health, it is unfortunate that such a class of compounds, whose natural production was likely evolutionarily driven by their toxicity, ended up becoming a flame retardant of choice for consumer products. Understanding the natural origins of PBDEs may also inform our investigation of their biological effects in humans, which is of pressing importance given another unfortunate aspect of PBDE biology – the growing evidence for their epidemiological association with neurodevelopmental disorders (NDDs).

In this review, we will briefly discuss known biological mechanisms affected by PBDEs, focusing on epigenetic impairments and the impacts these disruptions may have on human health, especially in the context of neurodevelopmental disorders.

Conclusions

Considering this growing body of work documenting epigenetic dysregulation induced by PBDE exposure, there appear to be several central lines of evidence emerging from research done in various health contexts, including: adipocyte differentiation and obesity, reproductive health—of both sperm/testes and the placenta, carcinogenicity (especially thyroid related), and negative impacts on nervous system formation and function. It is becoming clear that many, if not all, of these various aspects of human health are impacted by PBDE-induced disruption of normal epigenetic states and mechanisms.

There are fairly consistent findings of a negative relationship between PBDE levels and DNA methylation from in vitro and non-human animal studies across varied cell/tissue types and methylation detection methods.

However, the data from human samples is more difficult to interpret. Studies reporting effects on global DNA methylation levels inferred from representative regions have incongruent results, and evidence of alterations to methylation in the placenta are, likewise, not in direct agreement.

However, this confoundment and the fact that human studies have so far been conducted across very different populations and models should only encourage further work on the topic, especially given indications from non-human animal and in vitro studies.

It will be of great value if these types of studies can build on the tentatively established negative impact of PBDEs on methylation and begin to focus on understanding the mechanisms underlying the alterations, while continuing to clarify effects in human studies.

Compared to DNA methylation, the literature is poorer regarding the effects of PBDEs on other epigenetic mechanisms such as chromatin dynamics and expression of non-coding RNAs. However, some interesting ideas are beginning to emerge.

While not yet well understood, PBDE-induced dysregulation of histones and chromatin regulators is an intriguing intersection for PBDEs and neurodevelopmental disorders, bolstered by the recent emergence of chromatin regulation as a major node of NDD risk [31,82].

Further, it is tempting to speculate that epigenetic effects of PBDE exposure may, generally, turn out to be a point of convergence for environmental and genetic factors that contribute to NDDs. If the effects of these compounds on targets such as DNA methylation, chromatin components and regulators, and non-coding RNA expression (all of which are mechanisms known to have roles in neurodevelopment and perhaps NDD etiology) can be further explored and resolved, one or more could very well turn out to be that link.

This is of pressing importance, especially for neurodevelopmental disorders considering their explosive increase in prevalence, growing evidence for the involvement of PBDEs in their etiology, and the long elusive role of environmental factors in these devastating conditions.

Going forward, a major challenge for epigenetic PBDE research will be to assimilate new findings into the existing framework of PBDE toxicity that has been established from insights into other major impacted biological mechanisms.

It will also be important to carefully consider nuanced aspects of exposures including tissue and sub-cellular localization, conduct more research on environmentally relevant doses and mixtures of PBDEs, further explore the prevalence and effects of their metabolites, and, to the extent that it is possible, integrate evidence generated across human and non-human studies (both in vitro and in vivo).

This will be necessary in order to construct a more wholistic understanding of how these compounds impact cellular states and, ultimately, phenotypic outcomes. Hopefully, with continued research, we may eventually be able to explain how and to what extent these pervasive environmental pollutants are related to the numerous human health conditions that they appear to be contributing to.


Source:
Columbia University

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