DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Flame Retardant Exposure During Early Development and Autism Spectrum Disorder

Posted April 26, 2022

Heather Patisaul, Ph.D., North Carolina State University

Heather Patisaul, Ph.D., North Carolina State University
Dr. Heather Patisaul

Currently 1 in 44 children are identified as having Autism Spectrum Disorder (ASD), a developmental disability that causes social, communication, and behavioral challenges. The exact cause of ASD is unknown, though is likely due to environmental, biological, and genetic risk factors. Evidence suggests that the period during gestation and immediately following birth may be a critical timeframe for the development of ASD. The prevalence rate of ASD has increased steadily over the past two decades, indicating a need to better understand the cause.1 The impact of environmental chemical exposures is among the areas where current research is focused.

Dr. Heather Patisaul, with North Carolina University, has been interested in environmental factors that may play a role in the increased prevalence of ASD. Using funding from a Fiscal Year 2016 Autism Research Program Idea Development Award, Dr. Patisaul and her team have been investigating a potential link between ASD and the widespread use of flame-retardants (FRs). FireMaster® 550 (FM 550) is one of the most widely used mixtures of FR, but little is known about its safety. This mixture and its components can be found in numerous products such as electronics, building materials, foam-based furniture, and infant products. Studies indicate that FM 550 easily leaches from products and has been found in household dust, air, and food. Evidence indicates that its components may be neurotoxic, disrupt hormone signaling, and have structural similarities to insecticides that are known to adversely affect neurodevelopment. For these reasons, FM 550 exposure is speculated to be a potential contributing factor for the increase of ASD.

Dr. Patisaul’s unique study utilizes prairie voles as an animal model of ASD in place of traditional mice and rats, which do not represent ASD well in humans. Prairie voles have been used for previous ASD studies due to their social behaviors of pair bonding, attachment, paternal care, and sibling care. However, Dr. Patisaul’s work is the first to use voles in toxicology studies, particularly to assess the effects of FM 550 exposure during early development. To assess this effect, vole mothers were dosed with one of three concentrations of FM 550 from gestational day one to birth. After birth, offspring were dosed at the same concentration as their mother from post-natal day (PDN) 1 to PND 21. A series of experiments were then conducted to assess the behavioral, cell, and molecular changes associated with FM 550 exposure, which led to several key findings.

Prairie vole offspring were put through a battery of behavioral tests, including an open field test to assess animal anxiety; a sociability test to assess social and exploratory motivation; a social preference test to assess preference for familiar versus stranger animals; and a partner preference test to assess pair bonding. This series of tests indicated that, compared to controls, FM 550-exposed females displayed impaired sociality and heightened anxiety, as well as a stronger partner preference (likely due to increased anxiety). Anxiety is a common co-morbidity with ASD and is more common in females. In comparison, exposed males did not display increased anxiety; however, compared to control males, they failed to pair-bond, which suggests impaired attachment, a common trait in humans with ASD.

The effect of FM 550 exposure on microglial cells, an important immune cell type in the central nervous system, was assessed due to previous studies indicating their potential role in ASD. Microglial cells were quantified and mapped in several brain regions that are either sensitive to disruption during early development, vary based on sex, or govern anxiety. Results indicated that FM 550 exposure decreased microglial cells in all of the brain regions tested but especially the pre-frontal cortex. In addition, the microglial structural assays that were performed indicated increased reactivity in males. Additional work is needed to fully understand the consequences of these results; however, this phenotype has been previously reported in the brain of humans with ASD.

Potential molecular targets of FM 550 were also assessed. Sections of vole brain were stained for arginine vasopressin (AVP), a molecule known to play a role in social and emotional behaviors. Results indicated a decrease in AVP in the paraventricular nucleus (PNV) of exposed female voles. The PNV is known to coordinate sex-specific social and anxiety-related behaviors. In addition, the expression of estrogen receptor alpha (ESR1) RNA was examined due to sex-related expression differences in the bed nucleus of the stria terminalis (BnST) brain region, which is also instrumental for social behaviors. Preliminary data from this study indicated potential exposure-related effects in the BnST; this finding is currently being confirmed.

The work that Dr. Patisaul and her team have completed indicates that FM 550 exposure can have negative effects on social behaviors in both sexes and provides initial elucidation regarding the methods of action of these effects. In addition, the use of prairie voles was unique and could pave the way for future use of this animal model and additional toxicology studies assessing behavior. Overall, these studies indicate a strong need to better understand the effects of chemical agents wildly used in our environment and the potential impact they can have on human development.


References:

1 U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. 2020. What is Autism Spectrum Disorder? March 25.
    https://www.cdc.gov/ncbddd/autism/facts.html/.


Links:

Public and Technical Abstracts: Environmental Contaminants and Autism Risk


Publications:

Gillera SEA, Marinello WP, Horman B, Phillips AL, Ruis MT, Stapleton HM, Reif DM, and Patisaul HB. 2019. Sex-specific effects of perinatal FireMaster® 550 (FM 550) exposure on socioemotional behavior in prairie voles. Neurotoxicology and Teratology 106840. doi:10.1016/j.ntt.2019.106840.

Gillera SGA, Marinello WP, Cao K, Horman BM, Stapleton HM, and Patisaul HB. 2021. Sex- specific disruption of the prairie vole hypothalamus by developmental exposure to a flame-retardant mixture. Endocrinology 162(8). doi.org/10.1210/endocr/bqab100.

Krentzel AA, Kimble LC, Dorris DM, Horman BM, Meitzen J, and Patisaul HB. 2021. FireMaster ® 550 (FM 550) exposure during the perinatal period impacts partner preference behavior and nucleus accumbens core medium spiny neuron electrophysiology in adult male and female prairie voles, Microtus ochrogaster. Hormones and Behavior 134:105019. doi:10.1016/j.yhbeh.2021.105019.



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