Exploring How Endocrine Disrupting Chemicals Impact the Developing Brain and Behavior

Heather Patisaul, Ph.D.

September 13, 2018

NIEHS grantee Heather Patisaul, Ph.D., studies how prenatal or early life exposure to endocrine disrupting chemicals (EDCs) impact brain development and behavior. Interestingly, her research shows that the effects of these chemicals on behavior could differ between sexes.

EDCs are natural or man-made substances that may interfere with hormone signals within the body, thereby altering the normal function of tissues and organs. Bisphenol A (BPA) and flame retardants are two examples of chemicals that may act as EDCs and are found in everyday consumer products like plastics, houseware, and furniture.

A zoologist by training, Patisaul attributes her research interests to the late Louis J. Guillette, Jr., who was one of her undergraduate professors at the University of Florida. “In one conversation, I remember asking Dr. Guillette if anyone was looking at the impacts of EDCs on the brain,” Patisaul said. “At that time, no one was looking at neurological endpoints – that sparked my interest in studying the brain.”

Patisaul’s extensive graduate and post-doctoral research in behavioral neuroscience and toxicology paved the way for her successful research career. Now, she is a professor in the Department of Biological Sciences at North Carolina State University where she runs her own laboratory.

Exploring the Impact of BPA on Social Behaviors

While rats and mice are both commonly used rodent models to study how EDCs impact the brain, Patisaul’s laboratory is unique in its use of the prairie vole.

“The animal model that we use for our studies depends on the research question of interest,” Patisaul said. “The prairie vole is a great model for exploring chemical impacts on the social brain because the vole is naturally monogamous, and its social behaviors are more similar to humans than rat and mice behaviors are.”

Patisaul and her team are using the prairie vole to investigate how exposure to BPA may alter social behaviors and the neurological pathways that control them. In one study, they noted sex-specific differences in behaviors associated with anxiety, activity, and sociality in juvenile and adult prairie voles. They found that some doses of BPA exposure during early life increased hyperactivity and anxiety-related behaviors in females, but not males. Certain levels of BPA exposure also slightly lowered the females’ preference for their partner over a stranger. Females also had altered numbers of oxytocin and vasopressin-specific neurons. Oxytocin and vasopressin, special proteins used by neurons to communicate with one another and coordinate social behaviors, act similarly in voles and humans. According to the authors, their results suggest that developmental exposure to BPA, even at low doses, can significantly impact social behaviors and their underlying neurological pathways.

Patisaul and her team are continuing to use the prairie vole to further examine the sex-specific impacts of EDCs on social outcomes. New studies involve looking at the impact of EDCs on social behavior in males, as well as understanding the electrical properties of specific neurons that control these behaviors.

Examining How Flame Retardants Impact the Developing Brain

In addition to studying the impacts of BPA on the developing brain, Patisaul and her team are also examining the impact of flame retardants, particularly new ones that are entering the market to replace older chemicals with known neurotoxicity.

“Very little is known about the potential health effects of these new flame retardants,” Patisaul said. “However, our studies will help us better understand how these chemicals might impact neurodevelopment.”

Patisaul is collaborating with Heather Stapleton, Ph.D., and other colleagues to determine how Firemaster 550 (FM 550), a commercially used flame retardant mixture, impacts brain development and behavior. Their research is focusing on the critical role of the placenta in regulating brain development, and the adverse impacts that flame retardants can impose on this process. “The placenta provides lots of critical neurotransmitters and growth factors for the developing fetal brain,” said Patisaul. “Given this critical role, the placenta is an important target for understanding the potential neurotoxicity of EDCs.”

Research findings from Patisaul and her colleagues demonstrate the impact that developmental exposure to FM 550 can have on the placenta and developing brain. In one rat study, they found that FM 550 compounds accumulated in the placenta , and in some cases, these levels were higher in placentas associated with male fetuses. Results showed that prenatal exposure to FM 550 compounds led to increased anxiety-related behaviors in adult males and hyperactivity in females. The authors suggest that EDCs may accumulate differently in the placenta of male and female fetuses, which may be associated with sex-specific changes in behavior.

In another rat study, Patisaul and her colleagues noted similar differences in accumulation of FM 550 in placental tissue and evidence of disrupted endocrine, inflammatory, and neurotransmitter signaling pathways in the placenta. They also noted that the levels of serotonin, a key neurotransmitter involved in mood regulation and behavior, was reduced in placental tissue and the fetal forebrain. According to the authors, these results suggest that FM 550 and similar chemicals have the potential to impact the developing brain by disrupting normal placental functions.

Investigating Epigenetic Marks and Reprogramming in the Brain

Research has shown that the prenatal period and puberty are two critical windows of susceptibility, where EDCs may cause harmful impacts to the developing brain. Exposure to EDCs during these critical windows could alter epigenetic marks, or heritable changes that affect gene expression without changing the DNA sequence. Researchers suspect that these epigenetic changes could reprogram critical functions of the brain, thereby leading to adverse neurological outcomes later in life.

To further investigate this, Patisaul is now involved with new projects led by David Aylor, Ph.D., and other colleagues in the NIEHS Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription (TaRGET) II Consortium. Moving forward, Patisaul will continue working with TaRGET II researchers by examining the impact of chemical exposures across the prenatal, postnatal, and pubertal stages in rodents. This will include extraction of mouse brain tissues, such as the hypothalamus. One goal of this work is to better understand how epigenetic marks, such as DNA methylation, may relate to specific neurological outcomes.

“It is really exciting to be a part of the TaRGET II Consortium studies and get to work with scientists outside of my specific area of expertise,” said Patisaul. “It’s a natural fit for us, and we are eager to learn more about how epigenetics may play a role in shaping different neurological and behavioral outcomes.”