Meta-analysis of studies finds higher fluoride exposure may affect child IQ

On January 6, 2025, JAMA Pediatrics published a research manuscript titled “Fluoride exposure and children’s IQ: A systematic review and meta-analysis,” authored by scientists at the National Institute of Environmental Health Sciences (NIEHS) Division of Translational Toxicology. The meta-analysis is an in-depth statistical analysis of 74 epidemiological studies specifically on children’s IQ and fluoride exposure from the more broadly focused and recently published NTP Monograph: a Systematic Review of Fluoride Exposure and Neurodevelopment and Cognition conducted by the same scientists.

Fluoridated water has been used for decades to reduce dental cavities and improve general oral health. However, there is concern that pregnant women and children are now getting fluoride from many sources including drinking water, water-added foods and beverages, teas, toothpaste, floss, and mouthwash, and if their total fluoride exposure is too high, it may affect fetal, infant, and child neurodevelopment.

Of the 74 studies analyzed, 22 were rated as high quality (low risk of bias) and 52 were rated as low quality (high risk of bias). Studies were conducted in 10 countries outside the United States, including Canada, China, Denmark, India, Iran, Mexico, Pakistan, New Zealand, Spain, and Taiwan. These studies measured fluoride in drinking water or in urine. The measurement of fluoride in urine is an estimate of total fluoride exposure.

The meta-analysis found a statistically significant association between higher fluoride exposure and lower children’s IQ scores, indicating that the more fluoride a child is exposed to, the more likely that child’s IQ will be lower than if they were not exposed to fluoride.

The meta-analysis found that for every 1 mg/L increase in urinary fluoride, there is a decrease of 1.63 IQ points in children.

The U.S. Public Health Service recommends a fluoride concentration of 0.7 mg/L of drinking water. The World Health Organization has established the upper safe limit of fluoride in drinking water of 1.5 mg/L. Fluoride levels above 1.5 mg/L are found in wells and community water systems that serve over 2.9 million people in the United States. Using data from the high-quality studies, the analyses found that fluoride exposure was associated with lower IQ scores at levels below 1.5 mg/L fluoride measured in urine or drinking water. However, there were few studies, and therefore uncertainty, in the relationship below 1.5 mg/L when fluoride was measured only in drinking water. Furthermore, there were not enough data to determine if 0.7 mg/L of fluoride currently recommended for U.S. drinking water affected children’s IQ.

“To reduce total fluoride exposure, pregnant people and parents of young children should be mindful of TOTAL fluoride intake,” said Kyla W. Taylor, Ph.D., first author, corresponding author. “If their water is fluoridated, they may wish to replace tap water with low-fluoride bottled water, like purified water, and limit exposure from other sources such as dental products or black tea. Parents can use low fluoride bottled water to mix with powdered infant formula and limit use of fluoridated toothpaste by young children.”

This comprehensive meta-analysis may inform future risk-benefit assessments of the use of fluoride in community drinking water and children’s oral health products, according to the authors. (DM)

Citation: Taylor KW, Eftim SE, Sibrizzi CA, Blain RB, Magnuson K, Hartman PA, Rooney AA, Bucher JR. 2025. Fluoride Exposure and Children’s IQ Scores: A Systematic Review and Meta-Analysis. JAMA Pediatr; doi:10.1001/jamapediatrics.2024.5542. [Online ahead of print 6 Jan 2025].

Special cells play key role in preventing common birth defect

NIEHS researchers and their collaborators have uncovered a key role for certain cells in preventing a common birth defect of male genitalia known as hypospadias. Although one of the most common birth defects worldwide, the exact causes of hypospadias, where the urethra does not close properly at the tip of the penis and opens along the shaft instead, remain largely unknown.

To fill this knowledge gap, the researchers used mouse models, single-cell sequencing, and culture systems to investigate how different cell types in the penis work together to close the urethra properly. They discovered that a specific group of cells, which originate from outside of the embryonic penis, contributes to penis development. These cells migrate into the developing penis, interact with adjacent cells via the epidermal growth factor pathway, and secrete special signaling molecules called paracrine factors.

These findings could lead to a better understanding of the genetic and environmental factors that cause hypospadias, ultimately enabling the development of improved treatments for this common birth defect. (JW) [See related article.]

Citation: Amato CM, Xu X, Yao HH. 2024. An extragenital cell population contributes to urethra closure during mouse penis development. Sci Adv 10(49):eadp0673.

Brain waves during sleep are distinct for diabetes patients

People with type 2 diabetes mellitus have fewer sleep spindles — a hallmark of restful non-rapid eye movement sleep — than people without the disease, according to NIEHS researchers and their collaborators.

Diabetes mellitus is a major public health issue in the U.S. and elsewhere. The disease affects all organs because of high blood sugar levels and can lead to serious complications, including coronary heart disease, chronic kidney disease, retinopathy, and stroke. Diabetes affects the brain by damaging cells and blood vessels, although the full impact on brain function is not entirely clear. Moreover, little is known about how sleep and the characteristics of brain waves during sleep change in patients with diabetes mellitus.

To address this question, the researchers compared electroencephalogram (EEG) oscillations, specifically spindle waves, in 952 patients with type 2 diabetes mellitus and 952 healthy individuals matched by age, sex, and body mass index. They found that people with type 2 diabetes mellitus had significantly lower spindle density compared to the healthy controls. As noted by the researchers, these results suggest that long-term blood sugar imbalances in diabetes may contribute to a loss of sleep spindles, potentially worsening the brain's ability to regulate blood sugar levels. (JW)

Citation: Yeung D, Talukder A, Shi M, Umbach DM, Li Y, Motsinger-Reif A, Hwang JJ, Fan Z, Li L. 2025. Differences in brain spindle density during sleep between patients with and without type 2 diabetes. Comput Biol Med 184:109484.

Lipid profiling reveals new disease-predictive features of high-density lipoprotein

NIEHS researchers and their collaborators have identified a new way to categorize high-density lipoprotein (HDL), often referred to as “good cholesterol,” which could help predict heart disease risk.

HDL is a group of small particles in the bloodstream originally studied for its role in transporting lipids — various types of fats, fat-soluble vitamins, and other water-insoluble compounds. HDL is now known to have broader biological functions, several of which become impaired during disease. To explore this further, the researchers analyzed HDL isolated from 101 patients who had undergone coronary computed tomography (CT) imaging.

The identity of the lipids composing the patients’ HDL was profiled using a mass spectrometry-based method called “lipidomics.” The authors then used software to cluster patients based on the likeness of their HDL lipid composition. The results showed that the patients fell into one of two discrete groups, which the authors referred to as HDL metabotypes. Patients in metabotype 1 were more likely to be female and tended to have healthier cholesterol profiles, better heart-protective function of their HDL, and less plaque buildup in their arteries on CT imaging compared to those in metabotype 2.

These findings suggest that HDL characteristics beyond just cholesterol content could be useful for predicting coronary disease, according to the authors. Future studies will be required to determine whether these metabotypes hold true across different patient groups and disease conditions, and whether they are stable over time. (JW)

Citation: Karmaus PWF, Gordon SM, Chen MY, Motsinger-Reif AA, Snyder RW, Fennell TR, Waidyanatha S, Fernando RA, Remaley AT, Fessler MB. 2024. Untargeted lipidomics reveals novel HDL metabotypes and lipid-clinical correlates. J Lipid Res 65(12):100678.

Employment industry and occupation may affect heart health

Marginalized adults working in laborer positions tend to have worse cardiovascular health (CVH) than those working in professional or managerial positions, according to NIEHS researchers.

Cardiovascular disease, the leading cause of death affecting millions of adults each year in the U.S alone, is a collection of disorders affecting the heart and blood vessels. Although a decrease in cardiovascular disease mortality has been observed in recent decades, socially disadvantaged groups continue to have higher rates. Relatedly, workplace factors likely contribute to disparities, although it remains understudied.

In the current study, the researchers used data from the 2004-2018 National Health Interview Survey to determine associations between industry of employment and occupational status in relation to a modified “ideal” cardiovascular health (mICVH) metric that includes sleep as a newly recognized indicator of cardiovascular disease risk. The study included a nationally representative set of 230,196 adults. The findings showed that working in laborer instead of professional or managerial positions was associated with a lower mICVH prevalence, especially in adults over the age of 50 and those with an annual household income less than $75,000.

According to the authors, social risk factors related to industry of employment and occupational class should be included in future studies focusing on CVH. In addition, the results provide evidence to help support efforts that promote CVH and mitigate cardiovascular disease risk. (SS)

Citation: Murkey JA, Gaston SA, Alhasan DM, Jackson WB 2nd, Jackson CL. 2024. Industry of employment and occupational class in relation to cardiovascular health by race/ethnicity, sex/gender, age and income among adults in the USA: a cross-sectional study. BMJ Public Health 2(1):e000726.

How human liver tissue models enable translational toxicology for PFAS

A study led by Division of Translational Toxicology researchers provides new mechanistic and human health data for firefighting foams that contain a group of chemicals known as PFAS. The researchers used human liver tissue models, in combination with transcriptomics and cellular imaging, as a scalable platform to predict the health effects of aqueous film-forming foams (AFFFs) and per- and poly fluorinated alkyl substances (PFAS).

AFFFs are used to rapidly extinguish hydrocarbon-based fuel fires and protect fire fighters. AFFF products often contain PFAS, which provide superior fire protection to firefighters but are environmentally persistent. Widespread production and use of PFAS, including AFFFs, has led to contamination of rivers, drinking water, surface waters, groundwater, air, house dust, and food. Some PFAS are known to bioaccumulate in mammals from environmental exposures, which can increase their potential for adverse health effects.

To address critical data gaps in environmental health related to PFAS and AFFF, the researchers investigated 30 substances to estimate the threshold, or potency ranges, for human liver injury with PFAS and AFFF products. They prioritized substances by molecular hazard pathways related to liver cancer, unraveled biological response similarities, and translationally predicted the potency ranges of in vivo liver weight change from PFAS exposures.

According to the authors, the study revealed biological response similarities for PFAS and AFFF and represents a promising extension of emerging science into toxicological applications for greener chemistries and next-generation risk assessments. In addition, the novel approach to predict in vivo liver weight change potencies from molecular initiating events, together with the finding that vitamin D receptor prominently interacted with PFAS, may shed new light on the role of PFAS in endocrine disruption and fatty liver disease progression. (JW)

Citation: Mauge-Lewis KA, Ramaiahgari SC, Auerbach SS, Roberts GK, Waidyanatha S, Fenton SE, Phadke DP, Balik-Meisner MR, Tandon A, Mav D, Howard B, Shah R, Sparrow B, Gorospe J, Ferguson SS. 2025. Unraveling human hepatocellular responses to PFAS and aqueous film-forming foams (AFFFs) for molecular hazard prioritization and in vivo translation. Environ Sci Technol 59(5):2423-2435.

PUF proteins regulate stem cells through higher order protein-RNA complexes

New findings from NIEHS researchers and their collaborators shed light on how PUF RNA regulatory proteins regulate stem cells.

PUF proteins bind to RNA molecules and regulate the activity of genes, relying on extensive collaborations with protein partners. Although many PUF partners are known, most are poorly understood. A key challenge is to learn how these partnerships affect PUF function.

In the new study, the researchers used a model organism called nematodes (a type of worm) to explore interactions between a PUF protein called FBF-2 and a partner called LST-1. Biochemical, structural, and biological evidence indicated that one LST-1 molecule engages two FBF-2 proteins through specific regions called PUF interacting motifs (PIMs). Based on this finding, the researchers propose that LST-1 helps link two FBF-2 molecules to bind to adjacent RNA elements.

The results also showed that adjacent FBF-binding elements (FBEs) are required to repress or activate germline stem cells, which are the cells that eventually develop into eggs and sperm. The scientists found a complex made of FBF-2 and LST-1 on RNA with these adjacent FBEs and used cryo-electron microscopy to model the structure of this complex.

According to the authors, the study opens the door to investigating the existence, regulation, and function of similar PUF complexes, both in nematodes and more broadly in higher organisms, including humans. (JW)

Citation: Qiu C, Crittenden SL, Carrick BH, Dillard LB, Costa Dos Santos SJ, Dandey VP, Dutcher RC, Viverette EG, Wine RN, Woodworth J, Campbell ZT, Wickens M, Borgnia MJ, Kimble J, Hall TMT. 2025. A higher order PUF complex is central to regulation of C. elegans germline stem cells. Nat Commun 16(1):123.

Targeting Nsp15 actions may hold promise for treating coronavirus

Coronaviruses like SARS-Cov-2 encode special proteins called nonstructural proteins (Nsps) that help the virus make more copies of itself and avoid the body’s immune defenses. A new study by NIEHS researchers highlights the role of one Nsp in regulating coronavirus infections.

Among the 16 Nsps encoded by coronaviruses, one known as Nsp15 has been shown to significantly influence the severity and duration of viral infection in animal models. Nsp15 helps to eliminate signs of viral replication during infection by cutting viral RNA into pieces at a certain uridine base. This step essentially prevents the accumulation of double-stranded RNA (dsRNA) intermediates that would otherwise stimulate the host immune response.

Previous studies have shown that Nsp15 attached to dsRNA may use a process called “base flipping” to cleave the RNA; however, mechanistic details remained elusive. To address this knowledge gap, the researchers used a sophisticated imaging technique known as cryo- electron microscopy to map the structure of Nsp15 bound to dsRNA containing an unpaired uridine base. Unpaired uridine bases are commonly found in viral genomes and help the virus interact with other molecules, including RNA and proteins.

By solving this structure and using various biochemical approaches, including nuclear magnetic resonance, the researchers discovered that Nsp15 works best at removing dsRNA with an unpaired uridine base that is already in a position, which makes it easy to flip. According to the authors, further research focused on the mechanism of Nsp15 could lead to novel therapies targeting this protein. (SS)

Citation: Wright ZM, Butay KJ, Krahn JM, Wilson IM, Gabel SA, DeRose EF, Hissein IS, Williams JG, Borgnia MJ, Frazier MN, Mueller GA, Stanley RE. 2025. Spontaneous base flipping helps drive Nsp15's preferences in double stranded RNA substrates. Nat Commun 16(1):391.

Hair straightener use during adolescence may increase risk of fibroids

Hair straightener use during adolescence may increase the risk of developing fibroids, according to a study by NIEHS researchers. The study is the first to investigate the risk of fibroids linked to using this common beauty product during adolescence and to consider women born in different time periods.

Hair straightening products contain endocrine-disrupting chemicals that may promote the growth or survival of fibroid cells. Differences in how various racial and ethnic groups use these products, as well as the specific chemicals in products marketed to different populations, may contribute to disparities in fibroid development.

Using self-reported data from the Sister Study, the researchers examined the link between hair straightener use during adolescence and fibroid development in women before age 36 and between ages 36 and 61. They found an elevated risk of fibroids during both age periods among Black and non-Hispanic White women who used hair straighteners between the ages of 10 and 13. The association was stronger among Black women born between 1928 and 1945 and 1965 and 1974 and reduced among Black women born between 1955 and 1964, whose teenage years coincided with increased popularity of Afro/natural hairstyles in the 1970s.

These findings provide further evidence of the potential health risks associated with hair straightener use, especially among older Black women, who were likely exposed to more chemically potent formulas, and younger Black women, who were more likely exposed to formaldehyde-containing products. The authors recommend future research to evaluate specific types of hair straighteners and their chemical components in relation to fibroids and other chronic diseases. (MD)

Citation: Ogunsina K, O’Brien KM, White AJ, Chang CJ, Gaston SA, Jackson CL, Sandler DP. 2025. Hair straightener use in relation to prevalent and incident fibroids in the Sister Study with a focus on Black women. Environ Health Perspect 133(1):17004.

Specialized brain structures support different types of memory

A specialized brain extracellular matrix called perineuronal nets (PNNs) contribute to different types of memory, according to NIEHS researchers and their collaborators.

PNNs wrap around distinct types of neurons and apparently limit plasticity of the brain. In the hippocampus, a brain region that plays a key role in storing and retrieving memories, PNNs surround excitatory CA2 pyramidal neurons, which contribute to social memory and behavior. Elsewhere in the brain and hippocampus, they surround inhibitory interneurons that express a protein called parvalbumin that helps with memory processing.

Using mice, the researchers found that PNNs on each cell type contribute to distinct forms of memory. To make this discovery, they generated mouse strains with the primary protein component of PNNs deleted from either CA2 pyramidal cells or parvalbumin cells. Their experiments revealed that CA2 PNNs are important for social and spatial learning, whereas parvalbumin-expressing PNNs are important for fear memory. Additional data suggested that impaired social memory may be due to reduced input to the hippocampus from another brain region called the supramammillary nucleus, which signals social novelty.

According to the authors, these findings clarify the specific role of PNNs on CA2 pyramidal cells and parvalbumin-expressing cells in different types of memory. The results also support the conclusion that PNNs are integral to the functioning of CA2 neurons, which are increasingly appreciated to be active contributors to hippocampal function. In addition, these findings offer a mechanistic link between the impaired social behavior seen in a mouse model of Rett syndrome and CA2 PNNs, which the authors had previously found to be abnormally elevated in CA2 of the Rett model. (JW)

Citation: Alexander GM, Nikolova VD, Stöber TM, Gruzdev A, Moy SS, Dudek SM. 2025. Perineuronal nets on CA2 pyramidal cells and parvalbumin-expressing cells differentially regulate hippocampal-dependent memory. J Neurosci 45(6):e1626242024.