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Plastics are disrupting our health and day-to-day lives. Nanoplastics have been found in bottles of drinking water. Per- and polyfluoroalkyl substances (PFAS) are in our cookware and clothing. And phthalates are in nearly everything.
Some premature births have been linked to phthalates — one of the many reasons why Stephanie Engel has spent the past 20 years studying the effects of these chemicals on babies and children.
Phthalates, sometimes known as “everywhere chemicals,” are used to make plastics more durable. They are found in a wide range of consumer goods, including personal care products, vinyl flooring, and some medical tubing. They’re also added to food packaging and shopping bags to make them more flexible.
“Phthalates can migrate out of whatever they’re in,” Engel says. “From a container of lotion or your shampoo or cosmetics, it can absorb into your skin. You can ingest it from water bottles. Or it could be in food with plastic wrap around it. All routes lead to phthalate exposure.”
Engel, a professor in the UNC Gillings School of Global Public Health, began studying the effects of phthalate exposure on children’s neurodevelopment in the early 2000s. Her research has found an association between exposure in the womb and clinically diagnosed ADHD.
Now, she and Carolina neuroimaging scientist Weili Lin are leading a study that uses magnetic resonance imaging (MRI) to scan children’s brains. They hope to gain a better understanding of how phthalate exposure in early life affects brain growth and development, continuing a line of inquiry Engel started two decades ago to learn what these chemicals are doing to our most vulnerable populations.
Pesticides to phthalates
In 2003, after graduating from UNC-Chapel Hill with a PhD in epidemiology, Engel moved to New York City for a postdoctoral position at the Mount Sinai Medical Center, where she eventually became a faculty member.
While there, she worked with colleagues in the Children’s Environmental Health Center on a project examining how the effects of low-level exposure to some insecticides used within New York City public housing communities might affect brain development in children.
Stephanie Engel (photo by Megan Mendenhall)
During this same time, the Centers for Disease Control and Prevention released their National Human Biomonitoring Report on about 200 high-production-volume chemicals and their exposure concentrations to the U.S. public.
This report showed that women of reproductive age and people of color had the highest exposure to some phthalates across all of the subpopulations examined — but little was known about their health impacts in humans. Some research did suggest that DEHP, a specific phthalate, was carcinogenic in animals, and it was associated with reproductive toxicity in rats.
Scientists suspected that certain phthalates might be interfering with hormones that regulate the reproductive system, which would explain abnormalities found in the reproductive tracts of male rats exposed to these chemicals. Called endocrine disruptors, these chemicals may interfere with other hormones as well.
“Hormones play an important role in brain development,” Engel says. “And we started asking: If there was significant exposure, and that exposure was interfering with hormones that are critical for brain development, was it possible that there might be an association between prenatal phthalate concentrations and some of the developmental endpoints that we had been measuring in our children for the last eight years?”
With these new questions in mind, Engel and her colleagues measured prenatal phthalate exposure by testing urine samples collected from mothers during their pregnancy. Then, they compared this information with assessments of the children’s behavior.
“I think we were the first study to examine associations between prenatal exposure to phthalates and effects immediately after birth on neonatal orientation, motor development, and quality of alertness — and also on ADHD-like behaviors in children between 4 and 8 years,” she says.
A link to ADHD
While Engel’s work with the Mount Sinai study established a possible link between prenatal phthalate exposures and ADHD-like behaviors in children, the cohort was relatively small and behavioral assessments of the children were solely based on parental reports.
“We were really interested in the idea that these behaviors looked a lot like ADHD, but we didn’t have a clinical assessment of the children,” Engel explains.
To learn more, she needed a larger cohort. After some searching, she found the Norwegian Mother, Father, and Child Cohort Study (MoBa), comprised of a large population of people in Norway who enrolled between 1998 and 2008.
MoBa was created to improve understanding of how conditions in early life can influence health in later life. Researchers enrolled over 114,000 pregnant mothers, followed the women and their children from the womb into puberty, and collected questionnaire health data and stored biological samples like urine for future analysis.
“What’s really unique about this study is that those pregnancies represented about half of all pregnancies in Norway at the time,” Engel explains. “It was really population-based, but also large enough to get a frank clinical diagnosis of ADHD linked with a clinical patient registry.”
Because Engel had access to the children’s diagnoses and biological samples collected during pregnancy, she could compare exposure concentrations between children with and without an ADHD diagnosis.
“We could do this very elegant, nested case-control study where you select the ADHD cases and a random sample of the cohort,” Engel says. “You go back to their stored urine, you measure the phthalate metabolites, and you ask whether the phthalate concentrations were higher among children who ultimately developed ADHD.”
She found that children with higher prenatal exposures to certain phthalates had almost three times the odds of being diagnosed with ADHD.
Brain pictures
By the 2010s, there was mounting evidence across the world that prenatal exposure to phthalates could be problematic for a child’s brain development, and that young children were being exposed to certain kinds of phthalates more than adults. But these reports only measured exposure in people as young as 3 years old, and little information was available for infants and toddlers.
Engel was concerned about the impact of high exposure during the first two years of a child’s life because of the massive growth and development that takes place in the brain during this time.
In 2016, she was introduced to Weili Lin, who was overseeing the Baby Connectome Project (BCP), which focused on characterizing early brain development during the first five years of life. The study used MRIs — a noninvasive imaging technique used to capture detailed images of soft tissue and organs — to map the development of the human brain from birth through early childhood.
Using these scans, scientists like Lin and his team can identify and analyze gray and white matter within specific regions of the brain during early development. MRI also allows for the assessment of white matter microstructure, providing insights into connectivity patterns crucial for cognitive development. Additionally, it enables scientists to map the maturation processes of functional brain networks.
“These unique features collectively position MRI as a perfect and unique imaging modality in elucidating the complex interplay between brain structure and functional development during early infancy,” Lin explains. “It offers invaluable insights into neurodevelopmental trajectories and potential biomarkers for early intervention in disorders.”
When Engel learned of the BCP project, she was eager to partner with Lin.
“By taking a picture of the brain at different points during development, we can see how that child’s brain compares to other children with higher or lower exposure to phthalates,” Engel says. “It’s similar to how we monitor growth curves for height and weight in children.”
Clinicians commonly use developmental inventories — which often take the form of questionnaires — to determine if children are meeting certain milestones, like smiling or sitting up on their own. They can be useful in identifying behavior that could be symptomatic of some neurodevelopmental delays.
“But inventories are not great about telling us about the mechanisms,” she says. “Lots of different problems in your brain can actually result in the same behavioral symptom out in the world.”
Using brain scans, Engel could start to piece together how phthalate exposures in early life might change the structural and functional development of the brain.
Challenging datasets
In 2016, she and Lin collaborated on a pilot study leveraging the ongoing BCP project to collect urine samples from subjects between 2 weeks and 5 years old.
“We’ll be able to make that connection between what we’re seeing in the brain scans and how it’s manifesting out in the world,” Engel says.
Engel is still analyzing this information and admits it’s one of the trickiest datasets she’s ever worked with.
For starters, working with infants and toddlers can be touch-and-go. They need to fall asleep during the MRI session to get a usable scan and often couldn’t fall asleep or would wake up in the middle. At other times, Engel’s team could get a scan but not a urine sample.
Additionally, the data analysis is very challenging, and it’s taken time for Engel and her team to figure out the best approach.
“It’s really complicated because what we’re trying to look at is not just the relationship of exposure at one point in time with brain development at a single age, but how exposure over time influences the arc of brain development,” she explains. “And both things are changing — a child’s exposure changes, and their brain changes.”
Engel hopes to illuminate the direct effects of phthalates on children’s brains and is in the process of sharing early findings with the broader scientific community.
“I do think a picture is worth a thousand words. And the fact that we have pictures of the brain can be very influential from a policy perspective,” she says. “I want my research to help inform sensible environmental policy that can protect the development of children’s brains.”