How Forever Chemicals Harm Human Health

Forever Chemicals and Human Health: What PFAS Do to the Body

Physiologists investigate the mechanisms behind the harm per- and polyfluoroalkyl substances cause.
By Diana Kightlinger

World War II was raging and the race to build the first atomic bomb was on. Scientists working on the Manhattan Project were desperate to create materials that could withstand the corrosive and volatile chemicals used in uranium enrichment. They succeeded—spectacularly.

The resulting compounds—now known as per- and polyfluoroalkyl substances (PFAS)—featured a nearly unbreakable bond between carbon and the chemical wild child fluorine, making them impervious to oil, water, heat and degradation. But as early as 1947, studies revealed that these fluorocarbons were toxic and accumulated in human blood. 

Still, their advantages were too beguiling to ignore. 3M acquired the patents on PFAS in the 1950s and hired some of the original chemists to turn them into products, such as Scotchgard and firefighting foams. Yet, an Environmental Working Group timeline of 3M and DuPont memos, studies and reports from 1950 to 2000 also shows growing awareness of PFAS health risks.

“PFAS manufacturers documented the health effects, including high cholesterol; liver disease; kidney, liver, breast and reproductive cancer; and immune dysregulation, but those reports were kept confidential,” says Margarita Curras-Collazo, PhD, FAPS, a professor of neuroscience in the Department of Molecular, Cell and Systems Biology at University of California, Riverside.

The Environmental Protection Agency (EPA) finally became aware of PFAS health impacts in the late 1990s, but the harm was done—these “forever chemicals” had accumulated worldwide in water, soil, wildlife and the blood of 99% of humans. 

Not everyone exposed to PFAS becomes ill, but their long serum half-lives allow them to accumulate in the body and interfere with normal functions even after low-level exposure. 

Physiologists are now unraveling the mechanisms that determine who is vulnerable and why.

Elimination Leaves Kidneys Susceptible

Exposure to PFAS occurs primarily by drinking water, eating food and breathing contaminated air. However, some of the highest serum PFAS levels occur in workers involved in firefighting and chemical manufacturing. Once forever chemicals enter the body, they can circulate through the bloodstream for years until excreted.

“The kidneys and intestines are the primary routes of PFAS elimination,” says Jing (Jason) Wu, PhD, an assistant professor in the Department of Physiology at the University of Arizona and associate editor of the American Journal of Physiology-Renal Physiology. “Shorter-chain PFAS are primarily excreted in the urine, while longer-chain PFAS rely more heavily on biliary excretion and elimination through the gut epithelium.” 

The repeated encounters between the kidney’s proximal tubule—a key site of renal organic anion transport—with concentrated PFAS during elimination may make it uniquely vulnerable. Although the link between forever chemicals and kidney disease was recognized more than a decade ago, the mechanisms remain unclear. In vitro studies in cell models show that PFAS can cause oxidative stress and activate inflammatory pathways. They might also trigger epithelial-to-mesenchymal transition, a process implicated in fibrosis—scar tissue buildup that drives chronic kidney disease (CKD). But researchers have conducted few in vivo studies.

To address that gap, Wu and his colleagues studied PFAS exposure in mice using models of hypertensive kidney disease and CKD that were induced by removing 5/6 of the kidney. The researchers tested both models with a mixture of the four forever chemicals most common in human plasma. 

The group reported that PFAS induced salt-sensitive hypertension, renal fibrosis and reduced glomerular filtration rate, providing the first experimental evidence that PFAS exposure can cause hypertensive kidney disease. PFAS increased expression of the epithelial sodium channel, or ENaC, promoting sodium and water reabsorption in the kidney and raising blood pressure.

In addition, the researchers found that PFAS exposure promotes contraction and limits dilation of kidney blood vessels, elevating blood pressure by reducing renal blood flow. Together, the findings suggested that forever chemicals raise blood pressure by affecting the kidney’s epithelial compartment and vascular system. In CKD mice, they found that PFAS exposure both decreased glomerular filtration rate and increased scarring, albumin in urine and, ultimately, mortality. 

To investigate the pathways, the group used single-cell sequencing. Their studies showed greater expression of genes involved in lipid uptake and biogenesis in the proximal and other kidney tubule segments. Wu notes that previous studies link lipotoxicity to fibrosis in diabetic kidney disease and CKD. 

Some mechanisms may be organ-specific, but evidence is strongest for one that recurs throughout the body: the peroxisome proliferator-activated receptors PPAR-α and PPAR-γ, which control how the body burns and stores fat.

“Activation of this pathway has been linked to fatty liver disease and other chronic liver conditions,” Wu says. “We found that PFAS exposure dramatically increased expression of PPAR-α target genes in the kidney, suggesting activation of the same pathway.” 

Specialization Defines Pancreas’ Response

The PPAR mechanism doesn’t appear to carry over to the pancreas, however. “In β-cells or islets, we’re not really seeing evidence of PPAR-α activity in PFAS-exposed cells,” says Jenny Bruin, PhD, an associate professor in the Department of Biology at Carleton University in Ottawa. 

β-cells produce insulin and keep blood sugar within a tight range, but forever chemicals could change that. Bruin and colleagues authored a comprehensive review published in the American Journal of Physiology-Endocrinology and Metabolism covering persistent organic pollutants and β-cell toxicity. They looked at three tiers of evidence: human, animal and cellular.

Epidemiological studies showed a consistent link between PFAS concentration in human blood and incidence of type 2 diabetes and between exposure to forever chemicals and the elevated blood glucose and insulin levels that can precede prediabetes. In addition, PFAS levels are associated with a higher ratio of proinsulin to mature insulin, which suggests greater demands on β-cells. 

Studies in rodents focused mainly on legacy PFAS chemicals, PFOS and PFOA, and showed evidence of metabolic and β-cell dysfunction in males exposed to very high doses. Bruin says further studies should use newer replacement PFAS and physiologically relevant lower PFAS doses in females as well. 

In cell models, PFAS rapidly produced a burst of calcium activity and insulin secretion. But the studies were done in immortalized β-cells—insulin-secreting cancerous cells. Bruin’s group followed up with studies of primary cells isolated from islets.

“When we expose mouse islets to PFAS in a dish, we see hypersecretion of insulin, but only under high glucose conditions,” Bruin says. “So, if you consume PFAS in a meal, your β-cells may be stimulated to make more insulin than they’re supposed to.” That could happen if the meal came in packaging that contains forever chemicals, for example.

“We’ve always thought of insulin resistance as the central driving cause of type 2 diabetes,” Bruin says. “But too much insulin can also lead to insulin resistance and—because insulin is a growth factor—obesity.”

Bruin’s lab is working to identify molecular targets for PFAS in islets. One area of promise is glucagon-like peptide-1 receptor activation, which appears to mediate the overstimulation of insulin secretion. 

“Potentially there’s an indirect effect of PFAS on some of the other endocrine cells in the islet,” Bruin says. “They could then be indirectly stimulating GLP-1 receptors in β-cells.” Bruin suspects islet endocrine cells react differently than liver cells because they’re highly specialized to produce specific hormones.

β-cells differ in another way. The liver can regenerate throughout life, but β-cells cannot. During fetal development, β-cells rapidly differentiate and replicate to build the initial β-cell mass. Any disruption during this critical window might not surface until later periods of metabolic stress, such as puberty, pregnancy or aging. 

Brain Impacts Emerge Early and Last a Lifetime

In the developing brain, timing is everything. Unlike diseases in other organs that may unfold over years, the consequences of PFAS exposure may be especially profound in unborn children, altering function and behavior for life. Research is also limited. Findings demonstrating the association between forever chemicals and harmful physiological effects on the brain and nervous system weren’t publicly available until the 2000s.

“It’s well-established in the neurotox field that developmental exposure produces the most intense neurotoxic outcomes, many of which endure into adulthood,” Curras-Collazo says. “The immature systems of developing organisms are less able to degrade toxicants. Their rapid growth rate also makes them more susceptible because of the need for nutrients and oxygen and the fast pace of neurodevelopment.”

PFAS readily cross the placenta and penetrate and accumulate in the developing fetal brain. Curras-Collazo says that, in pregnancy, disrupting placental cells’ ability to protect against infectious and toxic substances and regulate immune responses may result in harmful neuroinflammation and long-lasting neurological reprogramming or damage.

In addition, studies show that acute PFOS and PFOA exposure significantly alter signaling via gamma-aminobutyric acid, a key neurotransmitter during neurodevelopment. Some epidemiological studies align with experimental findings, linking early-life PFAS exposure to birth defects, lower birth weight, behavioral abnormalities and slightly lower IQ scores.

Among the conditions attracting attention is autism spectrum disorder (ASD), which now affects an estimated 1 in 31 U.S. children, according to the Centers for Disease Control and Prevention. Yet genetics account for only 30% to 40% of ASD heritability.

Supported by a recent National Institute of Environmental Health Sciences grant, Curras-Collazo’s lab is studying the link between prenatal PFAS exposure and traits relevant to ASD. The researchers treat pregnant mice with PFOS- or PFOA-infused snacks until they give birth. They then run behavioral tests on the pups to assess social recognition and repetitive behavior. At the 2026 American Physiology Summit, the group reported that prenatal exposure to forever chemicals in mice is linked to ASD-like deficits similar to those seen in humans.

“Epigenetic mechanisms—changes in how genes are regulated rather than changes to the DNA sequence itself—may be involved,” Curras-Collazo says. 

Another possible mechanism is PFAS disruption of the thyroid hormone system. During pregnancy, a mother’s hormones cross the placenta and fetal blood-brain barrier. “This may be critical in shaping PFAS actions on the developing brain and subsequent behavior,” Curras-Collazo says. But she is not ready to single out one driver.

“The human and animal studies point to several possible mechanisms running in parallel,” she says. “Severe neurotoxicity could also result in death of certain populations of neurons that can’t be replaced after critical neurodevelopment windows close.” 

Mechanisms Shape Action

Despite stringent controls on some long-chain forever chemicals, such as PFOS and PFOA, most legacy PFAS and newer alternatives lack comprehensive safety evaluations. And real-world exposure involves mixtures of PFAS, not individual chemicals. “It’s important to study exposure to PFAS mixtures in vitro and in vivo, through different lenses and across different organisms and cell types,” Wu says. 

But with tens of thousands of PFAS found worldwide, “forever” could describe the research as aptly as the chemicals. Instead, Bruin says, “We should be trying to regulate these chemicals as a class because it’s too hard to do it one by one.” The EPA enforces strict drinking water limits for only two specific compounds—PFOA and PFOS—but individual states are filling the gap by banning all PFAS from consumer goods.

For now, physiologists continue to uncover how PFAS alter processes, building the mechanistic framework needed to understand risk and susceptibility. “We need not just find mechanisms but also interventions that can help prevent, reverse or mitigate the harm they cause,” Curras-Collazo says. “We need every possible defense to protect ourselves against these chemicals. There’s no end in sight.” 

This article was originally published in the September 2026 issue of The Physiologist Magazine. Copyright © 2026 by the American Physiological Society. Send questions or comments to tphysmag@physiology.org.