Wednesday, April 16, 2025

First study reveals neurotoxic potential of rose-scented citronellol at high exposure levels

Cross-species study using zebrafish, mice, brain organoids, and BBB-on-chip models reveals neurotoxic potential of high-dose citronellol exposure through behavioral and metabolomic analysis

National Research Council of Science & Technology

[1] Graphical Abstract — image:
The research team identified the neurotoxic potential of citronellol, a fragrance compound widely used in cosmetics and air fresheners, through a cross-species investigation using zebrafish, mice, human brain organoids, and a blood-brain barrier (BBB) organ-on-chip system.
#1. Neurotoxic Effects: Citronellol exposure led to increased ROS generation, neuroinflammation, and behavioral impairments, including anxiety-like behaviors and altered locomotion, particularly in zebrafish models.
#2. Blood-Brain Barrier Penetration: The study confirmed that citronellol is BBB-permeable, allowing it to accumulate in brain tissue across zebrafish, mice, and organ-on-chip models.
#. Neurochemical Alteration: Metabolomic profiling revealed that citronellol shifts kynurenine metabolism toward the production of 3-hydroxykynurenine (3-HK), a neurotoxic compound, while also affecting key neurosteroids such as progesterone and cortisol.
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Credit: Korea Research Institute of Chemical Technology(KRICT)

Citronellol, a rose-scented compound commonly found in cosmetics and household products, has long been considered safe. However, a Korean research team has, for the first time, identified its potential to cause neurotoxicity when excessively exposed.

A collaborative research team led by Dr. Myung Ae Bae at the Korea Research Institute of Chemical Technology (KRICT) and Professors Hae-Chul Park and Suhyun Kim at Korea University has discovered that high concentrations of citronellol can trigger neurological and behavioral toxicity. The study, published in the Journal of Hazardous Materials (Impact Factor: 12.2), employed multiple experimental models across species and used advanced metabolomic profiling to reveal this novel toxicity mechanism.

Citronellol is a naturally occurring fragrance compound derived from plants such as rose, geranium, and citronella. While it has been widely used in products for its floral scent and calming effect, this study revealed that excessive exposure can negatively affect the nervous system.

To ensure the reliability of their findings, the researchers employed four distinct biological models: zebrafish, mice, human brain organoids, and a blood-brain barrier (BBB) organ-on-chip system. The neurotoxic effects of citronellol were evaluated across these systems to confirm cross-species relevance.

In animal models, the team observed that citronellol could penetrate the BBB and accumulate in the brain. This accumulation led to increased generation of reactive oxygen species (ROS) and activation of inflammatory signaling pathways. Both phenomena are known contributors to impaired neurological and behavioral function. The researchers also noted damage to the BBB and the infiltration of immune cells into brain tissue, further exacerbating neuroinflammation.

A key discovery of the study was the alteration of kynurenine metabolism. Kynurenine, a metabolite derived from tryptophan, can be converted into either kynurenic acid, a neuroprotective compound, or 3-hydroxykynurenine (3-HK), which is neurotoxic. The researchers found that citronellol exposure shifted this balance toward the production of 3-HK, thereby enhancing neurotoxic risk.

Notably, zebrafish behavioral tests revealed signs of anxiety and abnormal locomotor activity following exposure to citronellol (2, 4, and 8 mg/L). This included reduced phototactic behavior and increased thigmotaxis, common indicators of stress or neurobehavioral disorders in aquatic models.

Beyond animal testing, the study confirmed similar toxicity mechanisms in human-relevant models. Brain organoids derived from human stem cells and BBB chips both showed evidence of citronellol-induced neurotoxicity and inflammation, suggesting potential risks in humans.

Currently, citronellol is listed by the Korea Ministry of Food and Drug Safety as a potential allergen that must be labeled on cosmetics exceeding certain concentrations, in line with EU regulations. However, its potential neurotoxic effects under high-exposure conditions have not been previously studied.

“This is a representative success case demonstrating the utility of next-generation human-mimicking platforms such as zebrafish and organoids,” the researchers said. Dr. Lee Young-Kuk, President of KRICT, commented, “Through follow-up studies, we plan to use this biomimetic platform to advance human safety assessments and contribute to public health.”

Schematic illustration of neurotoxic mechanism of citronellol.

Credit

Korea Research Institute of Chemical Technology(KRICT)

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KRICT is a non-profit research institute funded by the Korean government. Since its foundation in 1976, KRICT has played a leading role in advancing national chemical technologies in the fields of chemistry, material science, environmental science, and chemical engineering. Now, KRICT is moving forward to become a globally leading research institute tackling the most challenging issues in the field of Chemistry and Engineering and will continue to fulfill its role in developing chemical technologies that benefit the entire world and contribute to maintaining a healthy planet. More detailed information on KRICT can be found at https://www.krict.re.kr/eng/

The study was conducted with support from KRICT’s basic research fund and the Ministry of Environment’s program on the safety management of household chemical products.

Journal

Journal of Hazardous Materials

DOI

10.1016/j.jhazmat.2024.136965

Article Title

Neurotoxic effects of citronellol induced by the conversion of kynurenine to 3-hydroxykynurenine

For a while, crocodile

The ancestors of today’s crocodylians survived two mass extinction events. A new study uncovered a secret to their longevity, which could help conservationists better protect our planet’s most vulnerable species

University of Utah

Hemiprotosuchus and Chaliminia — image:
Some 215 million years ago in what is now northwestern Argentina, the terrestrial crocodylomorph Hemiprotosuchus leali prepares to devour the early mammal relative Chaliminia musteloides.
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Credit: Jorge Gonzalez

Most people think of crocodylians as living fossils— stubbornly unchanged, prehistoric relics that have ruled the world’s swampiest corners for millions of years. But their evolutionary history tells a different story, according to new research led by the University of Central Oklahoma (UCO) and the University of Utah.

Crocodylians are surviving members of a 230-million-year lineage called crocodylomorphs, a group that includes living crocodylians (i.e. crocodiles, alligators and gharials) and their many extinct relatives. Crocodylian ancestors persisted through two mass extinction events, a feat requiring evolutionary agility to adapt to a rapidly changed world. The study’s authors discovered that one secret to crocodylian longevity is their remarkably flexible lifestyles, both in what they eat and the habitat in which they get it.

“Lots of groups closely related to crocodylians were more diverse, more abundant, and exhibited different ecologies, yet they all disappeared except these few generalist crocodylians alive today,” said Keegan Melstrom, lead author and assistant professor at UCO, who began the research as a doctoral student at the U. “Extinction and survivorship are two sides of the same coin. Through all mass extinctions, some groups manage to persist and diversify. What can we learn by studying the deeper evolutionary patterns imparted by these events?”

Earth has experienced five mass extinctions in its history. Experts argue that we’re living through a sixth, driven by habitat destruction, invasive species and changing climates. Identifying traits that boost survivorship during planetary upheaval may help scientists and conservationists better protect vulnerable species today.

Historically, the field has regarded mammals as the poster children for understanding mass extinction survival, lauding their generalist diet and ability to thrive in different ecological niches. Despite their resilience, research has largely ignored the crocodylomorph clade. The paper, published on April 16 in the journal Palaeontology, is the first to reconstruct the dietary ecology of crocodylomorphs to identify characteristics that helped some groups persist and thrive through two mass extinctions—the end-Triassic, about 201.4 million years ago (Ma), and the end-Cretaceous, about 66 Ma.

“There’s a danger of trying to draw conclusions from millions of years ago and directly apply it to conservation. We have to be cautious,” said co-author Randy Irmis, curator of paleontology at Natural History Museum of Utah and professor in the U’s Department of Geology & Geophysics. “If people study mammals and reptiles and find the same patterns with respect to extinction survival, then we might predict that species with a generalist diet may do better. That information helps us make predictions, but it’s unlikely we’ll ever be able to pick out which individual species will survive.”

A hidden past of alternative lifestyles

Living crocodylians are famous for being semi-aquatic generalists that thrive in environments like lakes, rivers or marshes, waiting to ambush unsuspecting prey. Picky eaters, they are not. Young ones will snack on anything from tadpoles, insects or crustaceans before graduating to bigger fare, such as fish, baby deer, or even fellow crocs. Yet the uniform lifestyle of today’s crocodylians masks a massive diversity of dietary ecologies in which past crocodylomorphsthrived.

During the Late Triassic Period (237–201.4 Ma) Pseudosuchia, a broader evolutionary group that includes early crocodylomorphs and many other extinct lineages, ruled the land. The earliest crocodylomorphs were small-to-medium-sized creatures that were rare in their ecosystems, and were carnivores that mostly ate small animals. In contrast, other pseudosuchian groups dominated on land, occupied a wide range of ecological roles and exhibited a dizzying diversity of body shapes and sizes.

Despite their dominance, once the end-Triassic extinction hit, no non-crocodylomorph pseudosuchians survived. Whereas hyper-carnivore crocodylomorphs appeared to also die off, the terrestrial generalists made it through. The authors hypothesize that this ability to eat almost anything allowed them to survive, while so many other groups went extinct.

“After that, it goes bananas,” said Melstrom. “Aquatic hypercarnivores, terrestrial generalists, terrestrial hypercarnivores, terrestrial herbivores—crocodylomorphs evolved a massive number of ecological roles throughout the time of the dinosaurs.”

Something happened during the Late Cretaceous Period that set crocodylomorphs on a decline. The lineages specialized for diverse ecologies began to disappear, even the terrestrial generalists. By the end-Cretaceous mass extinction event (punctuated by the meteor that killed the non-avian dinosaurs), most of the survivors are semiaquatic generalists and a group of aquatic carnivores. Today’s 26 species of living crocodylians are nearly all semiaquatic generalists.

Beyond the smile of a crocodile

How do scientists parse the food on multi-million-year-old menus? They analyze the shape of fossilized teeth and skulls to glean the basis of an animal’s diet. A jaw stacked with tiny knives was likely slicing and puncturing flesh. A mortar-and-pestle-like grill probably broke down plant tissue. Skull shape dictates how an animal moves its mouth, providing a clue to its eating habits. Deciphering ancient animal diets reveals where it would have hunted, which the authors call dietary ecology.

It was a massive undertaking. The authors visited zoological and paleontological museum collections across seven countries and four continents to get the fossil specimens they needed. They examined the skulls of 99 extinct crocodylomorph species and 20 living crocodylian species, creating a fossil dataset spanning 230 million years of evolutionary history. The researchers had previously built a database of living non-crocodylians to compare with, including 89 mammals and 47 lizard species. The specimens represented a range of dietary ecologies, from strict carnivores to obligate herbivores, and a wide variety of skull shapes.

As semiaquatic ambush predators, today’s crocodylians mostly occupy similar ecological roles in lots of different environments. They do continue to have remarkably flexible diets, perhaps a remnant of their deeply diverse evolutionary past. For critically endangered crocodylians like the Gharial of the Himalaya foothills or the Cuban Crocodile of the country’s Zapata Swamp, dietary flexibility may give them a chance to persist through our current sixth mass extinction. The biggest challenges facing these species are habitat loss and human hunting.

“When we see living crocodiles and alligators, rather than thinking of ferocious beasts or expensive handbags, I hope people appreciate their amazing 200+ million years of evolution, and how they’ve survived so many tumultuous events in Earth history,” said Irmis. “Crocodylians are equipped to survive many future changes—if we’re willing to help preserve their habitats.”

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Other co-authors include Kathleen Ritterbush of the University of Utah and Kenneth Angielczyk of the Field Museum of Natural History.

The results published in Palaeontology as “For a while, crocodile: crocodylomorph resilience to mass extinctions."

The research was supported by the U.S. National Science Foundation, the Northwest Federation of Mineralogical Societies, the National History Museum of Los Angeles County, the American Museum of Natural History, the Palaeontological Association, the Paleontological Society, the Geological Society of American and the University of Utah Department of Geology & Geophysics.

The teeth of this fossil Borealosuchus skull typify the toothy grin of semi-aquatic generalist predators that survived the end-Cretaceous mass extinction.