Ancient lead exposure shaped evolution of human brain
A groundbreaking international study changes the view that exposure to the toxic metal lead is largely a post-industrial phenomenon. Instead, the findings reveal our human ancestors were periodically exposed to lead for over two million years.
Southern Cross University
image:
Infographic shows:
* lead exposure to humans in modern times versus our ancestors
* how teeth fossil and brain tissue were analysed for this study
* how the modern NOVA1 gene may have protected modern humans against undesirable effects of lead
view moreCredit: J Gregory @2025 Mount Sinai Health System
A groundbreaking international study changes the view that exposure to the toxic metal lead is largely a post-industrial phenomenon. The research reveals that our human ancestors were periodically exposed to lead for over two million years, and that the toxic metal may have influenced the evolution of hominid brains, behaviour, and even the development of language.
Moreover, the study – published in Science Advances – adds a piece to the puzzle of how humans outcompeted their cousins, the Neanderthals. Brain organoid models with Neanderthal genetics were more susceptible to the impacts of lead than human brains, suggesting that lead exposure was more harmful to Neanderthals.
Led by researchers from the Geoarchaeology and Archaeometry Research Group (GARG) at Southern Cross University (Australia), the Department of Environmental Medicine at the Icahn School of Medicine at Mount Sinai Hospital (New York, USA), and the School of Medicine at the University of California San Diego (UCSD, USA), the research combined novel fossil geochemistry, cutting-edge brain organoid experiments, and pioneer evolutionary genetics to uncover a surprising story about lead’s role in human history.
A toxic thread through human evolution
Until now, scientists believed lead exposure was largely a modern phenomenon, linked to human activities such as mining, smelting, and the use of leaded petrol and paint. By analysing 51 fossil teeth from hominid and great ape species, including Australopithecus africanus, Paranthropus robustus, early Homo, Neanderthals, and Homo sapiens, the team discovered clear chemical signatures of intermittent lead exposure stretching back almost two million years.
Using high-precision laser-ablation geochemistry at Southern Cross University’s GARG Facility (located in Lismore, NSW) and Mount Sinai’s Exposomics state-of-the-art facilities, the researchers found distinctive ‘lead bands’ in the teeth, formed during childhood as the enamel and dentine grew. These bands reveal repeated episodes of lead uptake from both environmental sources (such as contaminated water, soil, or volcanic activity) and from the body’s own bone stores, released during stress or illness.
“Our data show that lead exposure wasn’t just a product of the Industrial Revolution – it was part of our evolutionary landscape,” said Professor Renaud Joannes-Boyau, Head of the GARG research group at Southern Cross University.
“This means that the brains of our ancestors developed under the influence of a potent toxic metal, which may have shaped their social behaviour and cognitive abilities over millennia.”
From fossils to function: lead and the language gene
The team also turned to the lab to explore how this ancient exposure might have affected brain development. Using human brain organoids, miniature, lab-grown models of the brain, they compared the effects of lead on two versions of a key developmental gene called NOVA1, a gene known to orchestrate gene expression upon lead exposure during neurodevelopment. The modern human version of NOVA1 is different from that found in Neanderthals and other extinct hominids, but until now, scientists did not know why this change evolved.
When organoids carrying the archaic NOVA1 variant were exposed to lead, they showed marked disruptions in the activity of FOXP2 – expressing neurons in the cortex and thalamus – brain regions that are critical for the development of speech and language. This effect was far less pronounced in organoids with the modern NOVA1 variant.
“These results suggest that our NOVA1 variant may have offered protection against the harmful neurological effects of lead,” said Professor Alysson Muotri, Professor of Pediatrics/Cellular & Molecular Medicine and Director of the UC San Diego Sanford Stem Cell Institute Integrated Space Stem Cell Orbital Research Center.
“It’s an extraordinary example of how an environmental pressure, in this case, lead toxicity, could have driven genetic changes that improved survival and our ability to communicate using language, but which now also influence our vulnerability to modern lead exposure.”
Genetics, neurotoxins, and the making of modern humans
Genetic and proteomic analyses in this study revealed that lead exposure in archaic-variant organoids disrupted pathways involved in neurodevelopment, social behaviour, and communication. The altered FOXP2 activity in particular points to a possible link between ancient lead exposure and the evolutionary refinement of language abilities in modern humans.
“This study shows how our environmental exposures shaped our evolution,” said Professor Manish Arora, Professor and Vice Chairman of Environmental Medicine.
“From the perspective of inter-species competition, the observation that toxic exposures can offer an overall survival advantage offers a fresh paradigm for environmental medicine to examine the evolutionary roots of disorders linked to environmental exposures.”
Modern lessons from an ancient problem
While lead exposure today is mostly due to human industry, it remains a serious global health issue, particularly for children. The findings underscore how deeply intertwined environmental toxins and human biology have been and warn that our vulnerability to lead may be an inherited legacy of our past.
“Our work not only rewrites the history of lead exposure,” added Professor Joannes-Boyau, “it also reminds us that the interaction between our genes and the environment has been shaping our species for millions of years, and continues to do so.”
About the research
The study analysed fossil teeth from Africa, Asia, Europe, and Oceania, using advanced geochemical mapping to identify patterns of childhood lead exposure. Laboratory experiments with brain organoids carrying either modern or archaic NOVA1 genes examined the effects of lead on brain development, with a focus on FOXP2, a gene central to speech and language. Genetic, transcriptomic, and proteomic data were integrated to build a comprehensive picture of how lead may have influenced the evolution of hominid social behaviour and cognition.
Journal
Science Advances
Method of Research
Experimental study
Subject of Research
Human tissue samples
Article Title
Impact of intermittent lead exposure on hominid brain evolution
Article Publication Date
15-Oct-2025
COI Statement
A.R.M. is the cofounder of and has an equity interest in TISMOO, a company dedicated to genetic analysis and human brain organogenesis, focusing on therapeutic applications customized to autism spectrum disorders and other neurological diseases. A.R.M. has several patents on stem cells and brain organoid models. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of- interest policies. C.A. and M.A. are founders of Linus Biotechnology Inc. The terms of this arrangement have been reviewed and approved by the Mount Sinai Health System in accordance with its conflict-of-interest policies. The company was not involved with any component of this study. Other authors declare that they have no competing interests. B.L.T. and C.A.B. were used by NGeneBioAI, a for-profit entity, at the time of their contribution to this work.
Did lead limit brain and language development in Neanderthals and other extinct hominids?
Ancient human relatives were exposed to lead up to two million years ago, according to a new study. However, a gene mutation may have protected modern human brains, allowing language to flourish.
image:
UC San Diego researchers have found high levels of lead in the teeth of both Neanderthals (left) and modern humans (right). However, a gene mutation may have protected modern human brains, allowing language to flourish.
view moreCredit: Kyle Dykes/UC San Diego Health Sciences
What set the modern human brain apart from our now extinct relatives like Neanderthals? A new study by University of California San Diego School of Medicine and an international team of researchers reveals that ancient hominids — including early humans and great apes — were exposed to lead earlier than previously thought, up to two million years before modern humans began mining the metal. This exposure may have shaped the evolution of hominid brains, limiting language and social development in all but modern humans due to a protective genetic variant that only we carry. The study was published in Science Advances on October 15, 2025.
The researchers analyzed fossilized teeth from 51 hominids across Africa, Asia and Europe, including modern and archaic humans such as Neanderthals, ancient human ancestors like Australopithecus africanus, and extinct great apes such as Gigantopithecus blacki.
They detected lead in 73% of the specimens, including 71% of modern and archaic humans. Notably, G. blacki fossils dating back 1.8 million years showed the most frequent acute lead exposure.
It’s long been assumed that humans have been exposed to harmful amounts of lead since antiquity — when the Romans used lead pipes to transport water — and that lead contamination increased significantly during the Industrial Revolution, only to be curtailed during the late twentieth century.
“We stopped using lead in our daily lives when we realized how toxic it is, but nobody had ever studied lead in prehistory,” said corresponding author Alysson Muotri, Ph.D., professor of pediatrics and cellular & molecular medicine at UC San Diego School of Medicine, associate director of the Archealization Center and director of the Sanford Integrated Space Stem Cell Orbital Research Center.
Surprisingly, teeth from people born between the 1940s and 1970s — when children were exposed to leaded gasoline and paint — showed similar patterns of lead exposure to fossilized human teeth.
The team hypothesizes that, like the Romans, ancient humans and other hominids may have been exposed to lead because of their need for water.
“One possibility is that they were looking for caves with running water inside,” Muotri said. “Caves contain lead, so they were all contaminated. Based on the tooth enamel studies, it started very early in infancy.”
Lead exposure impedes brain development, leading to deficits in intelligence and difficulties with emotional regulation.
Given these findings, Muotri and his team wondered how the modern human brain had flourished despite exposure to lead during our evolution.
A tiny genetic change
A gene called neuro-oncological ventral antigen 1 (NOVA1) plays a central role in human brain development and synapse formation. Considered the master regulator of neurodevelopment, NOVA1 controls how neural progenitor cells respond to lead. Disruption of NOVA1 activity is linked to several neurological disorders.
Most modern humans have a variant of NOVA1 gene that differs by a single DNA base pair from the ancestral version that was present in Neanderthals. Previous work by Muotri and his colleagues showed that replacing the human NOVA1 variant with the archaic variant resulted in significant changes to the architecture and synaptic connectivity of tiny stem-cell-derived models of human brains called organoids.
“Everything about the organoids is identical except for that genetic variant, allowing us to ask whether that specific mutation between us and Neanderthals is giving us any advantage,” said Muotri. The archaic variant accelerated brain maturation but resulted in less complexity over time. “If all humans have this newer mutation in all corners of the world, very strong genetic pressure must have selected for it in our species.”
To explore whether environmental lead exposure influenced this selection, the team created brain organoids with both the human and archaic NOVA1 variants and exposed them to lead. They then compared the development of their cortical and thalamic neurons.
Lead exposure altered NOVA1 expression in both variants, affecting genes linked to neurodevelopmental disorders such as autism and epilepsy.
However, only the archaic NOVA1 variant changed the expression of FOXP2, a gene essential for language and speech development. People with certain FOXP2 mutations cannot produce sophisticated language.
“These type of neurons related to complex language are susceptible to death in the archaic version of NOVA1,” said Muotri. “ The FOXP2 gene is identical between us and the Neanderthals, but it's how the gene is regulated by NOVA1 that likely contributes to language differences.”
Evolutionary implications
The findings suggest that the acquisition of the modern NOVA1 variant may have protected us from the detrimental effects of lead, promoting complex language development and social cohesion. This could have given modern humans a significant evolutionary advantage over Neanderthals, even in the presence of lead contamination.
Muotri believes these results have important implications for understanding how environmental stressors shaped brain development during human evolution. He speculates that lead exposure may have contributed to the extinction of Neanderthals around 40,000 years ago.
“Language is such an important advantage, it’s transformational, it is our superpower,” said Muotri. “Because we have language, we are able to organize society and exchange ideas, allowing us to coordinate large movements. There is no evidence that Neanderthals could do that. They might have had abstract thinking, but they could not translate that to each other. And maybe the reason is because they never had a system to communicate that was as efficient as our complex language.”
Understanding how NOVA1 gene variants can affect FOXP2 expression helps elucidate the relationship between lead contamination and brain development and also sheds light on neurological conditions related to language, including speech apraxia — a condition that makes it difficult to produce speech sounds correctly — and autism.
The study's co-authors included Janaina Sena de Souza, Sandra M. Sanchez-Sanchez, Jose Oviedo, University of California San Diego; Marian Bailey and Matthew Tonge at Southern Cross University; Renaud Joannes-Boyau, Southern Cross University and University of Johannesburg; Justin W. Adams, University of Johannesburg and Monash University; Christine Austin, Manish Arora, Icahn School of Medicine at Mount Sinai, Kira Westaway, Macquarie University; Ian Moffat, Flinders University and University of Cambridge; Wei Wang and Wei Liao, Anthropology Museum of Guangxi; Yingqi Zhang, Institute of Vertebrate Paleontology and Paleoanthropology; Luca Fiorenza, Monash University and Johann Wolfgang Goethe University; Marie-Helene Moncel, Museum National d'Histoire Naturelle; Gary T. Schwartz, Arizona State University; Luiz Pedro Petroski and Roberto H. Herai, PontifÃcia Universidade Católica do Paraná; Jose Oviedo, University of Arizona; and Bernardo Lemos, Harvard T. H. Chan School of Public Health.
The study was funded, in part, by the National Institutes of Health (grants R01 ES027981, P30ES023515, R01ES026033), the Australian Research Council (grant DP170101597), the National Science Foundation (grant BCS 0962564), and the The Leakey Foundation.
Disclosures: Muotri is the co-founder of and has an equity interest in TISMOO, a company specializing in genetic analysis and human brain organogenesis. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict-of-interest policies.
More information, including a copy of the paper, can be found online at the Science Advances press package at https://www.eurekalert.org/press/vancepak/.
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Lead baindicates no lead exposure during tooth formation; red indicates high exposure.
Credit
UC San Diego Health Sciences
Human brain organoids derived from human pluripotent stem cells (left) and genetically modified with the Neanderthal variant of the NOVA1 gene (right).
Credit
UC San Diego Health Science
Alysson Muotri, Ph.D. with brain organoids
Credit
Erik Jepsen/UC San Diego
Alysson Muotri, Ph.D.
Credit
Kyle Dykes/UC San Diego Health Sciences
Journal
Science Advances
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