Summary: A University of Illinois study found that rats exposed to a mixture of phthalates during pregnancy and lactation developed fewer neurons and synapses in the medial prefrontal cortex and showed lasting deficits in cognitive flexibility compared with unexposed peers.

Source: University of Illinois.

Perinatal Phthalate Exposure Reduces Neurons and Synapses and Impairs Cognitive Flexibility in Rats

Researchers report that male and female rats exposed to an environmentally relevant mixture of phthalates during gestation and lactation had significantly fewer neurons and synapses in the medial prefrontal cortex (mPFC) and exhibited measurable deficits in cognitive flexibility compared with control animals.

Janice Juraska, a psychology professor at the University of Illinois who led the research, emphasized that the mixture and doses used in the study were chosen to reflect levels humans might encounter in daily life. “Phthalates are used as plasticizers in a variety of consumer goods, including plastics, personal care products, fragrances, pharmaceuticals, clothing and building materials,” Juraska said. “Contact with these products can lead to exposure through the skin, ingestion or inhalation.”

Background: Widespread Exposure and Developmental Concerns

Phthalates are ubiquitous in modern environments and are known endocrine-disrupting chemicals. Prior studies have demonstrated that phthalates cross the placenta and can reach offspring through breast milk, raising concerns about prenatal and early postnatal exposure. Because hormonal signaling guides many aspects of brain development, disruption during critical developmental windows can have lasting consequences for brain structure and behavior.

Human epidemiological research has suggested links between prenatal phthalate exposure and altered behavior, problems with self-regulation, and higher rates of neuropsychiatric conditions. The current study uses a rat model to investigate long-term structural and behavioral effects on the medial prefrontal cortex, a brain region centrally involved in executive functions and behavioral flexibility.

Study Design and Methods

Pregnant rats were assigned to one of three groups: a control group receiving no phthalates and two exposure groups receiving an environmentally relevant mixture of phthalates orally at either 200 μg/kg/day or 1000 μg/kg/day. Exposure continued through pregnancy and for 10 days during lactation. Offspring were raised to adulthood and then assessed on behavioral tests and brain anatomy.

Behaviorally, adult offspring were tested using an attentional set-shifting task to measure cognitive flexibility—the ability to shift attention and adjust strategies when task rules change. Anatomically, researchers performed stereological quantification of neurons, glial cells, and synapses within the medial prefrontal cortex to determine long-term structural effects of perinatal phthalate exposure.

Key Findings

• Independent of sex, rats exposed perinatally to either dose of the phthalate mixture exhibited a significant reduction in the number of neurons in the medial prefrontal cortex compared with controls.
• Synapse number within the mPFC was also lower in exposed animals, and the overall size of the mPFC was reduced.
• Phthalate-exposed rats showed impaired cognitive flexibility on the attentional set-shifting task, making significantly more errors during rule shifts than unexposed rats.
• The study found a correlation between synapse number and cognitive flexibility: animals with fewer synapses demonstrated less flexibility in the behavioral assay.

The researchers emphasize that negative outcomes were observed at both exposure levels examined, which the team describes as likely within the range of estimated daily human intakes for some phthalates.

Implications

These results suggest that perinatal exposure to common endocrine-disrupting phthalates can produce lasting reductions in cortical neuron and synapse number and can impair executive functions related to the medial prefrontal cortex in adulthood. Given the mPFC’s role in executive control and its implication in many neuropsychiatric disorders, the findings raise concerns about possible human health consequences of early-life phthalate exposure.

While this study uses a rodent model and direct translation to humans requires caution, the combination of structural brain changes and corresponding behavioral deficits strengthens the case for further investigation into human developmental exposures and the potential long-term cognitive and psychiatric effects.

Funding: Janice Juraska is affiliated with the Beckman Institute for Advanced Science and Technology at the University of Illinois. This research was supported by the National Institute of Environmental Health Sciences and the U.S. Environmental Protection Agency.

Source: Diana Yates, University of Illinois. Publisher organized by NeuroscienceNews.com. Image credit: NeuroscienceNews.com image is in the public domain.

Original research: Kougias, D. G.; Sellinger, E. P.; Willing, J.; Juraska, J. M. “Perinatal exposure to an environmentally relevant mixture of phthalates results in a lower number of neurons and synapses in the medial prefrontal cortex and decreased cognitive flexibility in adult male and female rats.” Journal of Neuroscience. Published July 16, 2018. doi: 10.1523/JNEUROSCI.0607-18.2018

Suggested citation: University of Illinois. Perinatal Exposure to Phthalates Impairs Brain Structure and Function: Rat Study. NeuroscienceNews. July 19, 2018.

Abstract

The growth and organization of the developing brain are guided by hormones, but little is known about whether disruption of hormonal signals affects cortical regions like the medial prefrontal cortex (mPFC). This study examined long-term effects of perinatal exposure to phthalates—endocrine-disrupting compounds—on the mPFC and related behavior. Pregnant dams received an environmentally relevant mixture of phthalates at 0, 200, or 1000 μg/kg/day orally through pregnancy and for 10 days during lactation. As adults, offspring were assessed on an attentional set-shifting task to measure cognitive flexibility, and the mPFC was analyzed stereologically for numbers of neurons, glia, and synapses. Perinatal phthalate exposure at either dose led to reductions in neuron number, synapse number, and mPFC size and produced deficits in cognitive flexibility in both male and female rats. Synapse number correlated with cognitive flexibility: rats with fewer synapses were less flexible. These results indicate that perinatal phthalate exposure can have lasting effects on cortical structure and behavior.