Environmental exposures can elicit distinctive responses in the brain that, in turn, influence health and disease over a person’s lifetime. These exposures and their effects — known collectively as the neuroexposome — have been difficult to study, particularly during pregnancy and after birth when the developing brain is most vulnerable.

But as Megan Horton, Ph.D., explained during her June 25 Keystone Science Lecture, new tools are now enabling exciting advances in the understanding of the neuroexposome and children’s brain development.

“Hopefully, we can use this data to impact public policies protecting vulnerable windows of development and improving adolescent brain outcomes and behavioral outcomes,” said Horton, a professor of environmental medicine and climate science at the Icahn School of Medicine at Mount Sinai.

“This is an exciting time for neuroepidemiology with the use of MRI [magnetic resonance imaging] data to look at early life exposures and impact on brain structure and function,” said Kimberly Gray, Ph.D., from the NIEHS Population Health Branch, who hosted the lecture.

Gray added that whether these early life, low-dose chemical exposures sensitize the brain to exposures later in life, and what will these developmental alterations look like later in life, are questions that remain to be answered.

Making sense of exposure data

Horton leads the NIEHS-funded Programming Research in Obesity, Growth, Environment, and Social Stress (PROGRESS) magnetic resonance imaging (MRI) study, an offshoot of the larger PROGRESS study that was launched in 2006. PROGRESS is a longitudinal birth cohort study that enrolled more than 1,000 pregnant women to assess the effects of chemical exposures, as well as nonchemical stressors, on their children. For the PROGRESS-MRI study, Horton and her colleagues enrolled 215 children from the original cohort.

The team has used exposure science, neuroimaging, and advanced statistical approaches to investigate how the environment affects children’s health.

“Our challenge is to link the growingly high-dimensional exposure data, particularly mixtures over time, with the equally dynamic and high-dimensional outcome data,” said Horton. “Thinking about neurodevelopmental outcomes, both behavioral and cognitive assessments as well as structural and functional brain changes, we want to understand how these brain-behavior relationships are impacted by environmental exposures.”

Linking chemical exposures to neuroimaging and behavior

The Horton lab uses deciduous (baby) teeth as a noninvasive way to reconstruct early-life exposures to environmental chemicals. Teeth, like trees, form rings as they grow. As Horton explained, teeth form a distinct ring on the day of a child’s birth known as the “neonatal line.” She and her team use these rings to measure various chemical exposures over time during prenatal and postnatal periods before and after a child’s birth.

To measure outcomes, they use neuroimaging methods, particularly MRIs, and neurobehavioral evaluation tools, such as the Behavioral Assessment System for Children.

“Since we’ve moved from looking at a single chemical at a single time point, our statistical methods no longer work,” said Horton.

She worked closely with biostatistics researchers at Mount Sinai to combine two statistical methods — the weighted quantile sum (WQS) and the distributed lag model — to create a new statistical tool called Lagged WQS that can analyze the effect of various mixtures over time.

Effects of metal mixtures, maternal stress

Using these new tools, together with support from the Public Health Impact of Metals Exposure (PHIME) study, Horton’s lab has made the following discoveries.

• Critical windows of metal mixture exposure occurred in early prenatal and late postnatal months (six to nine months).
• Higher levels of metal mixtures were associated with behavioral problems, risk-taking, and structural and functional brain changes. 
• Associations between exposure and negative outcomes were mainly driven by the metals manganese, lead, tin, zinc, and copper.

Given that environmental exposures are closely tied to racial and social inequities, Horton is also interested in exploring associations between nonchemical stressors and adolescent brain health.

“One of the great things about PROGRESS is it was designed to look at not just chemical mixtures but also the impact of maternal stress, anxiety, and depression,” said Horton. “We have the data to combine maternal stress with chemical exposures and see how that impacts risk-taking.”