Study Links PFAS ‘Safe Substitute’ to Lasting Male Brain Effects

A chemical touted as a safer alternative to banned “forever chemicals” may still pose risks to the developing male brain, according to new research from the University of Rochester.

The study found that early exposure to perfluorohexanoic acid (PFHxA) — a shorter-chain PFAS compound — caused lasting anxiety and memory problems in male mice, even after the chemical cleared from their systems.

The findings challenge assumptions about short-chain PFAS safety. While industries have replaced legacy PFAS with compounds like PFHxA, believing shorter molecular chains would reduce health impacts, this study suggests the male brain remains vulnerable during critical developmental windows.

Male-Only Effects Mirror Human Disorders

Researchers exposed pregnant mice to PFHxA through treated food during pregnancy and nursing. Male offspring showed decreased activity, increased anxiety-like behaviors, and memory deficits when tested as adults. Female mice exposed to identical doses showed no behavioral changes.

“Although these effects were mild, finding behavioral effects only in males was reminiscent of the many neurodevelopmental disorders that are male-biased,” said Ania Majewska, the study’s senior author and professor of neuroscience at the University of Rochester. Males are diagnosed with autism and ADHD at much higher rates than females.

The research team tested multiple behavioral domains in adult mice, including open-field exploration, elevated maze performance, and novel object recognition. What’s particularly striking is that these effects persisted long after PFHxA levels in the brain returned to normal — by 90 days of age, exposed mice had the same brain concentrations as unexposed controls.

Key Study Findings

• Dose-dependent brain accumulation: Higher PFHxA doses led to elevated brain levels at birth, with both dose groups showing increases at 21 days
• Targeted brain regions: Previous human studies found PFHxA concentrates particularly in the cerebellum, a region critical for motor function
• Long-term behavioral changes: Effects lasted into adulthood despite chemical clearance from the brain
• Sex-specific vulnerability: Only males showed behavioral alterations, mirroring human neurodevelopmental disorder patterns

Challenging “Safer” Chemical Assumptions

The timing of this research is particularly relevant. The European Union restricted PFHxA in 2024, following years of bans on longer-chain PFAS. Yet this compound has been found in pregnant women’s blood and breast milk, raising concerns about fetal and infant exposure.

“Finding that developmental exposure to PFHxA has long-term behavioral consequences in a mammalian model is concerning when considering short-chain PFAS are thought to be safer alternatives,” said Elizabeth Plunk, the study’s lead author and recent University of Rochester toxicology graduate.

The research methodology was carefully designed to mirror real-world exposure patterns. Rather than injecting chemicals directly, researchers used a more natural exposure route — giving pregnant mice PFHxA through mealworm treats, allowing the chemical to pass through the placenta and into breast milk.

Implications for Human Health

This study represents the first evaluation of PFHxA’s developmental neurotoxicity in a mammalian model. The researchers acknowledge their findings are preliminary but argue they highlight critical knowledge gaps in PFAS regulation.

The work comes as the EPA recently set its first national drinking water standards for PFAS, aiming to reduce exposure for millions of Americans. These persistent chemicals, which resist breakdown in the environment, have been linked to kidney cancer and developmental issues in babies.

Future research will need to examine the cellular and molecular mechanisms behind PFHxA’s effects, particularly in brain regions controlling motor function, emotion, and memory. The researchers emphasized that understanding these pathways is crucial for developing appropriate regulations around this chemical.

For now, the study serves as a reminder that shorter doesn’t necessarily mean safer when it comes to industrial chemicals and the developing brain.