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. Author manuscript; available in PMC: 2026 Feb 18.
Published in final edited form as: Neurotoxicology. 2025 Dec 27;112:103376. doi: 10.1016/j.neuro.2025.103376

Cadmium exposure at low environmental levels induces cognitive decline in aged male mice

Gahyun Lim a,b, Ho Young Lee a, Zachery R Jarrell a, Seong Su Kang c, Dean P Jones a,b,*, Young-Mi Go a,b,*
PMCID: PMC12865804  NIHMSID: NIHMS2134007  PMID: 41461297

Abstract

Cadmium (Cd) is a neurotoxic metal that accumulates via dietary, environmental, and occupational sources and is closely linked to oxidative stress and neuroinflammation. Little is known about the mechanistic effects of low-dose environmental Cd as found in the human diet on cognition in aged mice.

Male aged mice (C57BL/6J, 20 months old) received water with or without 3.3 mg/L Cd for 12 weeks. Cognitive function was assessed using the Y-maze, thiol/disulfide redox states were analyzed by high-performance liquid chromatography, brain Cd levels were determined by inductively coupled plasma mass spectrometry, hippocampal morphology was examined by histological analysis, and metabolomics was analyzed by high-resolution mass spectrometry.

Low-dose environmental Cd exposure led to brain Cd accumulation and impaired cognitive function in aged male mice, accompanied by reduced hippocampal neuronal density in the cornu ammonis 1 region. Cd shifted the plasma redox toward a more oxidizing state, along with elevated hydroxytetradecanoic acid and decreased N-oleoylethanolamine in the brain. Cd decreased bioactive signaling lipids (lysophosphatidic acid, oleamide, sphingomyelin, sphingosine) and selectively acylcarnitine levels in the brain. Increased pyridoxal phosphate and lipoamide and decreased glutamine brain levels suggest potential compensatory responses.

Exposure to low environmental levels of Cd in aged male mice disrupts redox homeostasis and systemic lipid metabolism, leading to cognitive decline, accompanied by compensatory responses. The results suggest that environmental Cd at levels found in the human diet could contribute to cognitive decline.

Keywords: Cadmium, Aging, Environmental Exposure, Acylcarnitine, Signaling Lipids

Graphical Abstract

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1. Introduction

Cadmium (Cd) is a naturally occurring toxic heavy metal in the environment, with diet being a primary source of exposure for the general population. Cd concentrations in human tissues gradually increase with age, reaching a peak in individuals aged 40–60 years (Satarug, 2018). Accumulating evidence demonstrated sex-specific differences in susceptibility to metals, including Cd, and their associated adverse health outcomes (Kim et al., 2014; Llop et al., 2013; Nishijo et al., 2004; Yimthiang et al., 2023). While cellular Cd levels in organs such as the lung, liver, and kidney are higher in females (Nishijo et al., 2004), dietary Cd intake is greater in males (Kim et al., 2018). These findings suggest that Cd-related health issues increase with age and that males may be more susceptible due to higher Cd exposure levels.

Our previous mouse studies demonstrate that low-dose Cd exposure promotes fibrosis, lipid accumulation, and mitochondrial dysfunction in the lung (Hu et al., 2019; Hu et al., 2017), and aggravates hepatic steatosis (Go et al., 2015b). In the brain, Cd burden increases with age due to gradual brain mass loss (Peters, 2006) and age-related breakdown of the blood-brain barrier (BBB) (Knox et al., 2022), while Cd progressively accumulates in neural tissue due to its long biological half-life (Lech and Sadlik, 2017; Ruiz et al., 2010). Accumulating mouse studies demonstrate that Cd negatively impacts cognitive function (Alam et al., 2021; Ali et al., 2021; Fan et al., 2021; Shu et al., 2022). In humans, a cross-sectional study of adults in the United States found that Cd accumulates in the brain (Al-Saleh and Shinwari, 2001; Panayi et al., 2002), systematic reviews reported associations between Cd exposure and cognitive performance (Chatterjee and Kortenkamp, 2022; Yang et al., 2023), and higher cumulative Cd levels are associated with neurocognitive decline, even at exposure levels considered non-adverse and common in the general population (Ciesielski et al., 2013).

Previous studies demonstrate that Cd exposure in young mice induces cognitive impairment mechanistically through oxidative stress and neuroinflammation (Ali et al., 2021; Fan et al., 2021). Intraperitoneal Cd exposure (1 mg/kg, 8 weeks) induced cognitive dysfunction via neuronal ferroptosis and lipid peroxidation in young mice (Wang et al., 2024). Oral Cd exposure (3 mg/L in drinking water) adversely affected multiple cognitive domains in young mice; 5-month exposure impaired olfactory learning and memory (Wang et al., 2018), and 7-month exposure disrupted hippocampal neurogenesis, leading to deficits in short-term spatial memory (Wang et al., 2022). Long-term, low-dose, and oral Cd exposure (1  mg/L via drinking water, 6 months) led to spatial working memory deficits, increased BBB permeability, and elevated amyloid beta (Aβ) and inflammation levels in young mice (Liu et al., 2023).

A comprehensive understanding of the mechanisms underlying Cd-induced cognitive decline, particularly in the context of aging, is still lacking. The prevalent use of young mice lacks focus on aged populations, in which cognitive decline is a pressing issue. Moreover, short-term or high-dose Cd exposure and intraperitoneal Cd administration, which bypasses the gastrointestinal tract, do not reflect real-world low-dose environmental Cd exposure. Furthermore, implementing systemic untargeted approaches helps in understanding the complex and multifaceted aspects of diseases. Considering that dietary exposure largely drives Cd accumulation, this study employed a low-level Cd exposure via drinking water (3.3 mg CdCl2/L) in 20-month-old male mice for 12 weeks, relevant to environmental Cd exposure in humans, and applied untargeted and unbiased high-resolution metabolomics to examine potential underlying mechanisms.

2. Materials and Methods

2.1. Animals and Cd Exposure

Experimental protocols were approved by the Emory University Institutional Animal Care and Use Committee (IACUC), and experiments were performed following relevant guidelines and regulations. Male mice, aged 20 months (C57BL/6J), provided by the National Institute on Aging (NIA), had ad libitum access to a standard mouse diet (LabDiet Rodent Diet, Irradiated, 5053) with deionized drinking water with (Cd group, N=10) 3.3 mg CdCl2/L (Sigma-Aldrich, MA, USA) or vehicle control (Cont group, N=15) for 12 weeks. This study focused on aged male mice only because of the logistical complexity of obtaining a sufficient number of both sexes from the NIA within the available time. CdCl2 is fully ionized at this concentration and yields free Cd2+; for simplicity, ‘Cd’ dose refers to CdCl2. A Cd dose of 3.3 mg was administered to establish an aged mouse model comparable to non-occupationally exposed, non-smoking aged humans with low environmental Cd exposure (Jarrell et al., 2023; Jarrell et al., 2022; Liu et al., 2023). Cd contents in a standard rodent diet (65.5–68.8 ng/g) and drinking water (50 ng/L) were negligible relative to the added Cd, and body weight and water intake were measured weekly. Mice were housed in groups of up to five per cage under controlled environmental conditions (68–72°F, 40–50% relative humidity, 12 h light/dark cycle), and the bedding was changed weekly. General health and weight loss were monitored to ensure they did not reach IACUC endpoints for euthanasia prior to the designated end of study. Mice were euthanized via CO2 asphyxiation followed by cervical dislocation. This study utilized aged male mice to address the potential for increased risk in males, as well as the practical limitation in the availability of age-matched female mice.

2.2. Y-maze test

Cognitive function was assessed using a Y-maze (Stoelting Co, IL, USA) with three arms intersecting at 120° (35 cm length × 10 cm height × 5 cm width), assessed at baseline and after 12 weeks of intervention. Y-maze tests were conducted only at baseline and at the end of the intervention to reduce the risk of added stress and metabolic alterations caused by repeated testing in significantly aged mice. Before testing, mice were acclimated to the testing room for at least 30 minutes to minimize stress, and the testing was performed under consistent environmental conditions and time. To minimize the influence of olfactory cues between trials, the maze was thoroughly cleaned with 70% ethanol and dried with paper towels after each animal. Each mouse was placed at the end of one of three arms and freely moved for 8 minutes. An arm entry was recorded when all four limbs of the mouse fully entered the arm. The total arm entries and the percentage (%) of spontaneous alternations were calculated using the following formula: [(number of spontaneous alternations) / (total number of entries − 2)] × 100. Spontaneous alternation behavior was defined as successive entries into all three arms (e.g., ABC, BCA, CAB, etc.) without repetition.

2.3. Cadmium quantification

As previously described (Jarrell et al., 2023), brain 114Cd levels were quantified and normalized to brain tissue mass. Approximately 50–60 mg of brain tissue was digested with 70% nitric acid and 30% hydrogen peroxide. Indium (In) was added to samples as an internal standard before digestion for a final concentration of 16 ppb at analysis. Samples were digested in a random sequence in sealed vessels using a MARS 6 microwave digestion system (CEM Corporation, NC, USA). After digestion, each sample was diluted with 2% nitric acid to 10 ml and analyzed in triplicate following the same random sequence using inductively coupled plasma mass spectrometry (ICP-MS) (Thermo Scientific iCAP Q ICP-MS, Bremen, Germany) in collision cell mode using kinetic energy discrimination (KED) with helium as the collision gas (30 psi) and argon as the plasma gas. A linear calibration curve ranging from 0.0156 to 64 ppb was established within the same run as the samples. Additionally, two reference urine samples (NIST SRM 2668 levels 1 and 2) were used to assess the quality control of digests and analyses. The attained limit of detection for Cd was 1.3 ppt.

2.5. Hippocampal histology

Freshly isolated whole brains were fixed in 4% paraformaldehyde, processed, and embedded in paraffin following the standard procedures. For histological analysis, paraffin-embedded brains were stained with hematoxylin and eosin (H&E) and digitally imaged by the Cancer Tissue and Pathology Core at Emory University. Neuronal density in the hippocampal cornu ammonis 1 (CA1) region was quantified using ImageJ. Digital images of brain sections were calibrated using the scale bar, neurons within the CA1 region were manually counted, and neuronal density was expressed as neurons per mm2.

2.6. Measurement of plasma redox states

Plasma concentrations of individual thiols [glutathione (GSH) and cysteine (Cys)] and disulfides [glutathione disulfide (GSSG) and cystine (CySS)] were measured using high-performance liquid chromatography (HPLC), as previously described (Iyer et al., 2010; Jones and Liang, 2009). Blood was collected into a heparin-coated tube to inhibit coagulation. To stabilize thiols, samples were mixed with 10% perchloric acid containing γ-glutamylglutamate as an internal standard. Thiols were alkylated using iodoacetic acid and derivatized using dansyl chloride. The derivatized samples were subjected to HPLC analysis (Waters Alliance 2659, MA, USA) with Empower software. Redox potentials (Eh) for the redox couples GSSG/GSH (E0 = −264mV) and CySS/Cys (E0 = −250mV) in plasma were calculated using the Nernst Equation.

2.8. High-resolution metabolomics

Brain tissue and plasma samples were analyzed for high-resolution metabolomics using liquid chromatography-high-resolution mass spectrometry (LC-HRMS), conducted at the Emory University Clinical Biomarkers Laboratory, following an established protocol (Go et al., 2015a; Hu et al., 2018). Samples were randomized into analytical batches of 40 samples before processing. For metabolite extractions, brain tissues (20–30 mg) were processed using a three-cycle freeze-thaw method in a 2:1 ratio of acetonitrile and water mixture at a 15 μL/mg tissue ratio. Plasma samples were mixed with two parts acetonitrile per volume of plasma. Isotope-labeled internal standards were included in all metabolite extractions to ensure the quality of LC-HRMS analyses. Samples were analyzed in triplicate using a Q Exactive HF Hybrid Quadrupole-Orbitrap mass spectrometer (Thermo Fisher Scientific, MA, USA) at 120,000 resolutions with a mass-to-charge ratio (m/z) scan range of 85–1275. To increase coverage in metabolite detection, a dual LC-MS method was used: hydrophilic interaction chromatography (HILIC) with positive electrospray ionization (ESI) and C18 reverse phase chromatography with negative ESI. For quality control and assurance, two reference samples were used: standard reference material available from the National Institute of Technology (NIST SRM1950) at the beginning and end, and a pooled human plasma sample (Qstd3) at the beginning, middle, and end of each batch of 40 samples.

apLCMS(Yu et al., 2009) and xMSanalyzer(Uppal et al., 2013) were used for peak extraction, noise filtering, retention time (RT) adjustment, ion intensity (abundance) quantification, and feature alignment. Features exhibiting a median coefficient of variation (CV) > 0.75 among technical replicates and samples with a mean pairwise Pearson correlation < 0.7 across replicates were excluded. Batch effects were corrected using ComBat.(Johnson et al., 2007) After data filtering, 13,499 brain metabolic features from HILIC (+) and 7,316 from C18 (−) were included in the analysis.

2.9. Metabolite annotation and identification

Features were annotated using xMSannotator version 1.3.2 (Uppal et al., 2017), which employs a global correlation-based clustering approach and a multi-step method. It provides annotation scores based on mass matching, coelution of multiple adducts and isotopic forms, and network and pathway associations, categorizing annotations into high, medium, or low confidence levels. A feature with a high confidence level receives an annotation score of 3, a medium confidence level feature scores a 2, and a low confidence level feature scores a 1. Features with an annotation score of 0, corresponding to identification level 5 in Schymanski criteria (Schymanski et al., 2014), were excluded from the analysis as they lack unequivocal structural or formulaic information. Level 1 identifications using Schymanski criteria (Schymanski et al., 2014) were achieved using reference standardization (Liu et al., 2020). Features categorized as ‘Unique’ with annotation scores of 2 and 3 were assigned to Schymanski identification level 3, while those classified as ‘Multiple’ with annotation scores of 2 and 3 were assigned to Schymanski identification level 4. All features were annotated or identified against the Human Metabolome Database (HMDB) with an accuracy of < 5 ppm. Previous research, including the metabolome atlas of the aging mouse brain (Ding et al., 2021) and the lipidome profile of the mouse brain (Fitzner et al., 2020), was referenced.

2.10. Bioinformatics and statistics

Before statistical analysis, technical replicates were median summarized using non-zero values, and metabolomic features detected in at least two technical replicates were retained. To increase confidence in selecting differentially abundant and discriminatory metabolites, metabolomic features present in more than 50% of all samples and 80% in each group were retained. Metabolomic data were quantile-normalized, log2-transformed, and non-detects were imputed using the value of half the lowest detected value.

Differential analysis was performed using the limma package (Ritchie et al., 2015) in R Studio (version 4.0.3), which identifies differentially abundant metabolites between groups using an empirical Bayes approach, improving statistical power in high-dimensional datasets. Partial least squares discriminant analysis (PLS-DA) was also performed to identify features with high variable importance in projection (VIP) scores. VIP scores were used to assess the significance of each metabolite in discriminating between the groups. Metabolic pathway analysis using differentially abundant metabolites was performed using Mummichog version 2.0 (Li et al., 2013). For statistical analysis of non-metabolomics data, descriptive statistics (mean ± standard error of the mean, SEM) were calculated, and either a paired t-test or an unpaired t-test was performed to compare the groups.

3. Results

3.1. Brain Cd accumulation

Brain Cd concentrations were measured after 12 weeks of low-dose environmental Cd exposure. The Cd-exposed group showed significantly higher Cd accumulation in the brain compared with the Cont group (Cont: 0.3 ± 0.04 vs. Cd: 1.8 ± 0.4 pg/mg tissue, Figure 1). Cd levels in Cd-exposed mice were approximately 10-fold lower than the 20 pg/mg wet weight (range, 0 to 120) value for Polish people aged from 1 to 80 years were (Lech and Sadlik, 2017), suggesting that the Cd dose and exposure duration in this study are relevant to human exposure levels. Throughout the 12-week Cd exposure period, mice consumed approximately 3–4 mL of water per day regardless of treatment. Therefore, the Cd-exposed mice ingested an estimated 10–13 μg of Cd daily. Final body weight was analyzed by analysis of covariance adjusting for baseline body weight, and there was no significant difference between the Cont and Cd groups (P=0.951).

Fig. 1.

Fig. 1.

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Cd Accumulation in the brain. Low-dose environmental Cd exposure (3.3 mg CdCl2/L, 12 weeks) increased Cd accumulation in the brain of aged male mice (C57BL/6J, 20-month-old). Cd concentrations in brain tissues were measured by ICP-MS (N = 13 (Cont) and 9 (Cd)). Results are presented as mean ± SEM. Statistical comparison was performed using an unpaired t-test. *** P value<0.001. Abbreviation: ICP-MS, Inductively Coupled Plasma Mass Spectrometry.

3.2. Cognitive function

To assess cognitive function, we conducted the Y-maze test before and after the Cd exposure and applied a paired t-test to observe the changes. The percentage (%) of spontaneous alternation reflects spatial working memory, with lower values indicating poorer working memory, and vice versa (Kraeuter et al., 2019). The Cont group did not show a significant change in the % alternation after the intervention (Baseline: 66.1 ± 3.4 vs. Final: 65.8 ± 2.9 %). In contrast, the Cd group showed a significant decline in % alternation (Baseline: 62.9 ± 3.2 vs. Final: 49.2 ± 4.0 %), indicating Cd-induced cognitive impairment (Figure 2A). The total number of arm entries decreased in both Cont and Cd groups (Figure 2B), consistent with age-related declines in motor activity (Tran et al., 2021). A comparable number of arm entries between groups indicates that motor activity did not confound spontaneous alternation performance. The Cd group showed a significantly lower % of spontaneous alternation than the Cont group, suggesting a working memory deficit (Kraeuter et al., 2019) in addition to the age-related declines in motor activity observed in both groups.

Fig. 2.

Fig. 2.

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Cd accumulation induced cognitive impairment and decreased hippocampal neuronal density. Low-dose environmental Cd exposure (3.3 mg CdCl2/L, 12 weeks) impaired the cognitive function and decreased the hippocampal neuronal density in aged male mice (C57BL/6J, 20-month-old). The Y-maze was conducted at baseline and at the final time point. (A) The percentage (%) of spontaneous alternation and (B) the number of total arm entries were calculated ((A) Cont, N=8 (B) Cd, N=9). (C) Hippocampal morphology was evaluated using hematoxylin and eosin (H&E) staining (Fig. 2C left and middle). The scale bar represents 20 μm. Neuronal counts in the CA1 region from the Cont and Cd groups are shown as a bar graph quantifying neuronal density on the images from both groups (Fig. 2C right, N=3). Results are presented as mean ± SEM. Statistical comparisons were performed using an unpaired t-test. * P value<0.05, ** P value<0.01. Abbreviations: H&E, Hematoxylin and Eosin; CA1, Cornu Ammonis 1.

3.3. Hippocampal neuronal density

The hippocampus plays a critical role in spatial navigation, learning, and memory. The CA1 region, critical for memory formation and consolidation, is highly vulnerable to metabolic and cytotoxic insults, and damage to it can lead to neurological deficits (Bartsch et al., 2015; Chauhan et al., 2021). Neuronal density has been widely used as a marker of hippocampal integrity and cognitive function (Rozhkova et al., 2022; Wilson et al., 2013; Yamamoto et al., 2021). Neuronal density of the CA1 region in the hippocampus was calculated to assess whether the reduction of neuronal density accompanied the Cd-induced cognitive decline observed in the Y-maze test. As shown in the representative images and quantification in Fig. 2C, Cd exposure significantly decreased neuronal density in the hippocampal CA1 region compared with the Cont group (Cont: 447.0 ± 31.0, Cd: 325.3 ± 2.4).

3.4. Redox States

Cd exposure increases oxidative stress, promotes inflammation, and contributes to neurodegeneration (Alam et al., 2021; Ali et al., 2021; Fan et al., 2021; Shu et al., 2022). Therefore, we examined whether Cd burden was associated with elevated oxidative stress by measuring major thiol/disulfide redox couples, including glutathione (GSH) and its disulfide form glutathione disulfide (GSSG), as well as cysteine (Cys) and its disulfide form cystine (CySS). A more negative redox potential (Eh) indicates a more reducing environment; whereas, a more positive Eh reflects a more oxidizing state. In plasma, elevated systemic oxidative stress was observed in the Cd group compared to the Cont group, as indicated by the Eh of GSSG/GSH (Cont: −157.7 ± 6.8 vs. Cd: −108.8 ± 13.7 mV, Figure 3A). The Eh of CySS/Cys did not differ between the groups (Supplementary Figure 1). Hydroxytetradecanoic acid (HTA) is a long-chain hydroxy fatty acid previously associated with lipid peroxidation, protein oxidation, and GSH depletion in the rat brain (Tonin et al., 2010). Consistently, Cd exposure increased brain levels of HTA, consistent with the oxidized plasma redox potential, indicating that Cd heightened the oxidative stress (Figure 3B). Furthermore, N-oleoylethanolamine (OEA) is an oleic acid-derived bioactive lipid with antioxidant and anti-inflammatory functions, reflecting the status of redox balance and cellular homeostasis (Giudetti et al., 2021; Hu et al., 2020; Mock et al., 2023). The brain levels of OEA were significantly decreased in the Cd group compared with the Cont group (Figure 3C), indicating that Cd exposure enhanced oxidative stress and inflammatory responses.

Fig. 3.

Fig. 3.

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Low-dose Cd stimulated oxidative stress. Low-dose environmental Cd exposure (3.3 mg CdCl2/L, 12 weeks) induced an oxidizing environment in aged male mice (C57BL/6J, 20-month-old). (A) Plasma redox potential (Eh) of the GSSG/GSH couple measured by HPLC (N = 14 (Cont) and 8 (Cd)). Eh was calculated from the Nernst equation. (B) HTA and (C) OEA levels in the brain measured by LC-HRMS (N = 14 (Cont) and 9 (Cd)). Data are presented as mean ± SEM. Statistical comparisons were performed using an unpaired t-test. * P value<0.05, ** P value<0.01, *** P value<0.001. Abbreviations: HTA, Hydroxytetradecanoic acid; GSSG, Glutathione disulfide; GSH, Glutathione; OEA, N-Oleoylethanolamine; HPLC, High-Performance Liquid Chromatography; LC-HRMS, Liquid Chromatography-High-Resolution Mass Spectrometry.

3.5. Discriminant and pathway analyses of brain metabolomics

After applying data filtering criteria, a total of 10,699 features from the HILIC (+) and 6,325 features from the C18 (−) were retained for downstream analysis. Differential analysis using limma identified 387 significantly altered features in the HILIC (+) and 287 features in the C18 (−), based on a P value threshold of < 0.05. A volcano plot of the significantly altered features obtained from HILIC (+) mode (Figure 4A) illustrated the distribution of differentially expressed features, and two-way hierarchical clustering analysis (HCA) of those features (Figure 4B) revealed clear group separation, with a greater number of features decreasing in intensity in response to Cd exposure. Similarly, two-way HCA of differentially abundant C18 (−) features altered by Cd exposure is shown in Supplementary Figure 2A and B. Pathway analysis was conducted using differentially abundant metabolic features. The carnitine shuttle and pyridoxine metabolism pathways were significantly enriched (Figure 4C).

Fig. 4.

Fig. 4.

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Volcano plot and two-way HCA of differentially abundant metabolites affected by Cd exposure. (A) Volcano plot of log2 fold change versus −log10 P value showing differentially abundant metabolites detected from HILIC (+) column by LC-HRMS. Red color denotes metabolites with higher abundance in the Cont group (N=14) compared to the Cd group (N=9); blue color represents metabolites with lower abundance in the Cont group compared to the Cd group. (B) Two-way HCA plot of 387 metabolites versus Cont (N=14, blue) and Cd (N=9, yellow) groups from LC-HRMS. (C) Enriched metabolic pathways of differentially abundant metabolites detected from HILIC (+) and C18 (−) columns by LC-HRMS. Abbreviation: HCA, Hierarchical Clustering Analysis; HILIC, Hydrophilic Interaction Liquid Chromatography; LC-HRMS, Liquid Chromatography-High-Resolution Mass Spectrometry.

PLS-DA identified 423 features in HILIC (+) and 241 features in C18(−) as discriminatory by groups at VIP > 2.0. HCA of selected HILIC (+) and C18 (−) features showed clear separation between the groups (data not shown).

3.6. Classification of differentially abundant metabolites

Out of the differentially abundant 387 features in HILIC (+) and 287 features in C18 (−), 28 (Table 1) and 24 (Table 2), respectively, were annotated or identified. Total 52 features were categorized into superclass according to HMDB; 26 features (50%) were lipids and lipid-like molecules, 14 features (27%) were organic acids and derivatives, 5 features (10%) were organoheterocyclic compounds, 3 features (6%) were benzenoids, 2 features (4%) were organic oxygen compounds, and 2 features (4%) were organic nitrogen compounds (Supplementary Figure 3). Lipids and lipid-like molecules accounted for the largest proportion. Interestingly, 39 out of 52 differentially abundant features had a VIP score above 2, indicating that these features strongly contribute to the group separation.

Table 1.

Differentially Abundant Metabolites (HILIC (+)).

m/z RT(s) Metabolite Identification Level Database Adduct VIP
218.1865 274 Deoxyhypusine 4 HMDB11150 M+H 2.01
279.1591 27 Alpha-CEHC 4 HMDB01518 M+H 2.01
341.3046 29 MG (18:0) 3 HMDB11131 M+H-H2O 2.06
272.2221 31 Tridecanoylglycine 3 HMDB13317 M+H 2.10
305.0977 232 N-Acetylaspartyl glutamic acid 3 HMDB01067 M+H 2.11
109.0284 273 Quinone 4 HMDB03364 M+H 2.12
300.2896 29 Sphingosine 1 HMDB00252 M+H 2.13
226.1801 32 N-Undecanoylglycine 3 HMDB13286 M+H-H2O 2.18
541.2623 35 Tetrahydroaldosterone glucuronide 3 HMDB10357 M+H 2.19
360.2742 32 Hydroxy lauroylcarnitine 3 HMDB13164 M+H 2.28
206.0668 264 Lipoamide 4 HMDB00962 M+H 2.29
326.3052 30 N-Oleoylethanolamine 3 HMDB02088 M+H 2.30
950.2934 287 Lauroyl-CoA 3 HMDB03571 M+H 2.31
860.6156 31 PC (42:7) 4 HMDB08321 M+H 2.34
550.3869 35 PC (18:1/2:0) 4 HMDB11148 M+H 2.36
246.1698 43 Isovalerylcarnitine 4 HMDB00688 M+H 2.37
247.1732 44 Isovalerylcarnitine 4 HMDB00688 M+H [+1] 2.38
255.1086 83 Galactosylglycerol 4 HMDB06790 M+H 2.48
276.1553 185 Glutamyl-Lysine 3 HMDB04207 M+H 2.58
551.3914 33 PC (18:1/2:0) 4 HMDB11148 M+H [+1] 2.63
442.3525 31 Hydroxy octadecenoylcarnitine 3 HMDB13339 M+H 3.04
282.2790 29 Oleamide 3 HMDB02117 M+H 3.05
217.1547 199 Valyl-Valine 3 HMDB29140 M+H 3.22
173.0806 88 Octenedioic acid 4 HMDB00341 M+H --
357.2996 30 MG (18:1) 4 HMDB11536 M+H --
542.3239 38 LysoPC (18:2) 3 HMDB10386 M+Na --
188.1281 35 N-Heptanoylglycine 4 HMDB13010 M+H --
357.0821 123 Amino-phosphoribitylaminouracil 4 HMDB03841 M+H --
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Differential abundance was determined using limma, with significance based on P value < 0.05. Identification levels were assigned using Schymanski criteria (Schymanski et al., 2014) and reference standardization (Liu et al., 2020). Adduct forms refer to the ionized forms of molecules (M), generated during LC-HRMS, reflecting their charge states and interactions with ions. Abbreviations: CEHC, Carboxyethyl hydroxy chroman; LysoPC, Lysophosphatidylcholine; MG, Monoacylglycerol; PC, Phosphatidylcholine; HMDB, Human Metabolome Database; VIP, Variable Importance in Projection.

Table 2.

Differentially Abundant Metabolites (C18 (-)).

m/z RT(s) Metabolite Identification Level Database Adduct VIP
88.9880 16 Oxalic acid 3 HMDB02329 M-H 2.00
714.5082 205 PE (34:2) 4 HMDB08835 M-H 2.03
152.0716 136 Dopamine 1 HMDB00073 M-H 2.04
125.0468 109 Aminoimidazole-carboxamide 4 HMDB03192 M-H 2.07
773.5319 285 PG (36:2) 3 HMDB10605 M-H 2.10
393.2410 162 LysoPA(P-16:0/0:0) 3 HMDB11154 M-H 2.12
251.0533 290 Cysteinyl-methionine 4 HMDB28781 M-H 2.13
417.2855 208 Palmitoylglucuronide 3 HMDB10331 M-H 2.16
411.3481 293 MG (22:1) 4 HMDB11552 M-H 2.16
675.5422 252 SM (d18:0/14:0) 3 HMDB12085 M-H 2.18
418.2888 204 Palmitoylglucuronide 3 HMDB10331 [M-H]+1 2.28
673.5265 233 SM (d18:1/14:0) 3 HMDB12085 M-H 2.31
168.0431 28 Phosphodimethyl ethanolamine 3 HMDB60244 M-H 2.31
299.2588 258 Hydroxy octadecanoic acid 4 HMDB37396 M-H 2.40
246.0171 97 Pyridoxal phosphate 3 HMDB01491 M-H 2.55
243.1964 211 Hydroxy tetradecanoic acid 4 HMDB10731 M-H 2.60
153.0557 138 Hydroxy-methoxybenzenemethanol 4 HMDB32012 M-H --
138.0561 164 Dihydroxy benzylamine 4 HMDB12153 M-H --
780.5896 295 PE (22:2/P-18:1) 4 HMDB09578 M-H --
740.5236 206 PC (15:0/18:3) 4 HMDB07941 M-H --
119.0170 206 3-Methylthio propionic acid 4 HMDB01527 M-H --
312.2545 155 Palmitoylglycine 3 HMDB13034 M-H --
116.0353 24 Amino-oxobutanoic acid 4 HMDB06454 M-H --
146.0822 28 Amino-hydroxy-methylpentanoic acid 4 HMDB29449 M-H --
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Differential abundance was determined using limma, with significance based on P value < 0.05. Identification levels were assigned using Schymanski criteria (Schymanski et al., 2014) and reference standardization (Liu et al., 2020). Adduct forms refer to the ionized forms of molecules (M), generated during LC-HRMS, reflecting their charge states and interactions with ions. Abbreviations: LysoPA, Lysophosphatidic acid; MG, Monoacylglycerol; PC, Phosphatidylcholine; PE, Phosphatidylethanolamine; PG, Phosphatidylglycerol; SM, Sphingomyelin; HMDB, Human Metabolome Database; VIP, Variable Importance in Projection.

3.7. Effects of Cd exposure on brain lipids

Low-dose environmental Cd exposure reduced the abundance of multiple classes of bioactive lipids in the male aged mouse brain, potentially affecting neuronal signaling and lipid-mediated functions (Figure 5). The brain levels of lysophosphatidic acid (LysoPA) (P-16:0/0:0) (Figure 5A), the fatty acid amides oleamide (Figure 5B), and OEA (Figure 3C), were significantly reduced in the Cd group compared to the Cont group in the aged male mice. The Cd-exposed group had lower brain sphingolipid levels, sphingosine, and sphingomyelin (SMs) (d18:0/14:0), compared to the Cont group (Figure 5C and D). All these lipids had VIP scores greater than 2, indicating their strong contribution to group separation.

Fig. 5.

Fig. 5.

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Cd-induced disruption of signaling lipids in the brain.

The abundance of bioactive signaling lipids in the brain decreased in response to low-dose environmental Cd exposure (3.3 mg CdCl2/L, 12 weeks) in aged male mice (C57BL/6J, 20-month-old), measured by LC-HRMS; (A) LysoPA(P-16:0/0:0), (B) Oleamide, (C) Sphingosine, and (D) SM(d18:0/14:0) (N = 14 (Cont) and 9 (Cd)). Data are presented as mean ± SEM. Statistical comparisons were performed using an unpaired t-test. * P value<0.05, ** P value<0.01. Abbreviations: LysoPA, Lysophosphatidic Acid; SM, Sphingomyelin; LC-HRMS, Liquid Chromatography-High-Resolution Mass Spectrometry.

Cd exposure decreased levels of several, but not all, acylcarnitines in the aged mouse brain (Figure 6A). Those changes included isovalerylcarnitine (C5:0), hydroxylauroylcarnitine (C12:0-OH), and hydroxyoctadecenoylcarnitine (C18:1-OH), with palmitoylcarnitine (C16:0) also exhibiting a trend (P value: 0.051) (Figure 6A). Brain levels of free carnitine (C0) and acetylcarnitine (C2:0) were not altered by Cd. Plasma carnitine (C0) and isovalerylcarnitine (C5:0) were lower in the Cd group, and acetylcarnitine (C2:0) showed a decreasing trend (P value: 0.07) (Figure 6B) while plasma levels of C12:0-OH, C16:0, and C18:1-OH were not different between the groups.

Fig. 6.

Fig. 6.

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Cd-induced alterations in acylcarntines in the brain and plasma.

Relative intensities of acylcarnitine levels in the (A) brain and (B) plasma of aged male mice (C57BL/6J, 20-month-old) after low-dose environmental Cd exposure (3.3 mg CdCl2/L, 12 weeks) measured by LC-HRMS (Brain: N = 14 (Cont) and 9 (Cd), Plasma: N = 10 (Cont) and 9 (Cd)). All acylcarnitines are adduct forms of ‘M+H’ and the Schymanski identification level of 1. Data are presented as mean ± SEM. Statistical comparisons were performed using an unpaired t-test. * P value<0.05, ** P value<0.01. Abbreviations: ns, non significance; LC-HRMS, Liquid Chromatography-High-Resolution Mass Spectrometry; C0, Free Carnitine (Brain: m/z 162.1125, 73s / Plasma: m/z 162.1125, 59s); C2:0, Acetylcarnitine (Brain: m/z 204.1231, 57s / Plasma: m/z 204.1230, 48s); C5:0, Isovalerylcarnitine (Brain: m/z 246.1698, 43s / Plasma: m/z 246.1700, 35s); C12:0-OH, Hydroxylauroylcarnitine (Brain: m/z 360.2742, 32s / Plasma: m/z 360.2743, 30s); C16:0, Palmitoylcarnitine (Brain: m/z 400.3413, 33s / Plasma: m/z 400.3421, RT 28s); C18:1-OH, Hydroxyoctadecenoylcarnitine (Brain: m/z 442.3525, 31s / Plasma: m/z 442.3529, 29s).

3.8. Possible compensatory mechanisms in response to Cd exposure

After 12 weeks of low-dose environmental Cd exposure, the brain levels of pyridoxal phosphate (PLP) and lipoamide, key coenzymes for neurotransmission and mitochondrial function, were elevated (Figure 7A and B). Glutamine (Gln), a major amino acid in the brain that serves as a precursor for neurotransmitters and supports energy metabolism, was significantly reduced following the Cd exposure (Figure 7C). The increased PLP and lipoamide and decreased Gln levels in the brain may represent potential compensatory responses to Cd exposure in the brain of aged male mice.

Fig. 7.

Fig. 7.

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Potential compensatory responses to low-dose Cd exposure.

The abundance of metabolites that are potentially involved in compensatory response to low-dose environmental Cd exposure (3.3 mg CdCl2/L, 12 weeks) in aged male mice (C57BL/6J, 20-month-old) was measured by LC-HRMS: (A) Pyridoxal phosphate, (B) Lipoamide, and (C) Glutamine (N = 14 (Cont) and 9 (Cd)). Data are presented as mean ± SEM. Statistical comparisons were performed using an unpaired t-test. * P value<0.05, ** P value<0.01. Abbreviation: LC-HRMS, Liquid Chromatography-High-Resolution Mass Spectrometry.

4. Discussion

This study adds to knowledge about Cd and dementia by demonstrating that in aged male mice, Cd exposure at low dose alters brain lipids, increases oxidative stress, and causes cognitive impairment. Disruptions of brain lipid metabolism are highly relevant, as the brain contains high lipid content (~50% by dry weight) (Hornemann, 2021) and its fatty acid oxidation capacity declines with age (Li et al., 2023). The brain Cd concentration in our Cd-exposed mice (1.8 pg/mg tissue) falls within the lower range of reported human brain concentrations (0–120 pg/mg tissue) (Lech and Sadlik, 2017). This suggests that the current Cd-exposed mouse model is comparable to those observed in humans with low environmental Cd exposure, such as non-smokers and individuals without occupational exposure. This finding highlights that the brain is highly sensitive to Cd exposure, even at low levels. Moreover, a previous study using ICP-MS reported that aged individuals with Alzheimer’s disease (26.7 pg/mg tissue, range: 5–145) have higher Cd brain concentrations than aged individuals (32.1 pg/mg tissue, range: 4–104) (Panayi et al., 2002). Overall, environmentally relevant dietary Cd levels could contribute to cognitive impairment, underscoring the importance of monitoring Cd burden and regulating dietary Cd intake to minimize accumulation in the brain.

Plasma GSH/GSSG and Cys/CySS redox couples become increasingly oxidized with age in humans, indicating that the redox potential (Eh) progressively changes as individuals respond to environmental and physiological challenges (Go and Jones, 2017). The balance of GSH and GSSG reflects oxidative stress and redox signaling, influencing cellular regulation, growth, proliferation, and apoptosis by modulating the activity of redox-sensitive proteins and transcription factors (Jones, 2002). A previous mouse study showed that the brain is more susceptible to Cd-induced oxidative stress than other metabolic organs, including the liver, kidney, and spleen (Agnihotri et al., 2015). In our study, the altered GSH/GSSG redox couple suggests that chronic, low-dose Cd exposure causes dysregulation in systemic redox homeostasis and impairs brain metabolism in aging, contributing to cognitive decline in aged male mice.

The hippocampus is essential for learning, memory, spatial navigation, and emotional regulation (Anand and Dhikav, 2012), with the CA1 region playing a pivotal role in memory formation and consolidation (Bartsch et al., 2015; Chauhan et al., 2021). Notably, CA1 neurons in aged rodents exhibit reduced stability, which is associated with impairments in spatial learning (Woodruff-Pak, 2010). The observed decrease in neuronal density within the CA1 region following Cd exposure suggests that Cd may have disrupted the structural and functional integrity of the hippocampal network, potentially impairing synaptic connectivity and consequently affecting cognitive performance (Ivenshitz and Segal, 2010).

The Cd-induced increase in HTA and decrease in OEA suggest that the aged male mouse brain is under an oxidizing environment characterized by disrupted redox homeostasis and reduced resilience. HTA has been shown to elevate oxidative stress (Tonin et al., 2010), and OEA is involved in redox homeostasis (Giudetti et al., 2021; Hu et al., 2020; Mock et al., 2023), which also supports neurogenesis and neuroplasticity (Ren et al., 2019; Yang et al., 2015), cognitive and motor functions (Luo et al., 2019; Ren et al., 2019; Yang et al., 2015), and fatty acid β-oxidation (Tutunchi et al., 2020). Cd exposure may have promoted HTA and inhibited OEA synthesis in the brain, potentially inducing the cognitive decline observed in this study. Future mechanistic studies are needed to determine whether restoring OEA levels and inhibiting HTA accumulation in the brain could promote protective or therapeutic effects against Cd-associated neurodegenerative changes.

LysoPA is a signaling lipid that regulates cellular proliferation, myelination, synaptic transmission, and neuronal development (Geraldo et al., 2021; Yung et al., 2015). Previous studies demonstrate that oleamide enhances cognitive function by promoting hippocampal neurogenesis and improving synaptic plasticity (Sasaki et al., 2024; Tao et al., 2022). OEA is a signaling lipid with neuroprotective properties, promoting hippocampal neurogenesis and neuroplasticity (Ren et al., 2019; Yang et al., 2015), and facilitating recovery from neural injury (Luo et al., 2019). SMs and sphingosine are members of the sphingolipid family, a group of bioactive lipids that play key roles in membrane structure and lipid signaling related to cell survival and inflammation (Mei et al., 2023). SMs are among the most abundant sphingolipids in mammalian tissues, and sphingosine serves as a precursor to sphingosine-1-phosphate, a potent signaling molecule (Cartier and Hla, 2019). Collectively, the decline in these signaling lipids in the aged mouse brain following Cd exposure suggests a disruption of lipid-mediated communication in the brain, potentially contributing to cognitive dysfunction.

The lipids in the brain are enriched in polyunsaturated fatty acids (PUFAs), which are primarily esterified to phospholipids and contribute to membrane structure and function (Bazinet and Laye, 2014). Upon stimulation, these phospholipids are cleaved by phospholipases, releasing bioactive lipids that act as signaling messengers (Bazan, 2005). Accumulating evidence showed that Cd disrupts phospholipid metabolism and increases lipid saturation levels, limiting the availability of PUFA substrates necessary for signaling lipid synthesis (Olszowski et al., 2018; Sivaprakasam and Nachiappan, 2016; Sivaprakasam et al., 2016; Zhu et al., 2022). In the present study, Cd-induced alterations in phospholipid metabolism reduced the pool of PUFA. Additionally, altered neurotransmitter signaling and elevated oxidative stress (Arruebarrena et al., 2023), may have promoted the oxidation of PUFA-rich phospholipids, further limiting substrate availability and impairing lipid-mediated signaling pathways. Future studies are needed to investigate whether restoring signaling lipid levels can mitigate Cd-induced cognitive decline.

Cellular carnitines are in both free carnitine and acylcarnitine forms, which transport long-chain fatty acids into the mitochondria for β-oxidation (Jones et al., 2010). A growing number of studies examined acylcarnitine profiles in neurodegenerative disorders; however, the majority analyzed circulating levels, and their findings remain inconsistent (Dambrova et al., 2022). In this study, both brain and circulating acylcarnitine levels declined in response to Cd exposure. This decrease aligns with a previous lipidomics study reporting reduced levels of short-, medium-, and long-chain acylcarnitines in the cortex of AD mice (Puris et al., 2021). Elevated circulating long-chain acylcarnitines are known to be toxic, as they increase with aging and are higher in individuals with obesity and type 2 diabetes, reflecting incomplete β-oxidation (Jarrell et al., 2020; McCoin et al., 2015). The contrasting trends in acylcarnitine levels between tissues and plasma need further investigation to clarify their specific physiological and nutritional activities.

We previously demonstrated that Cd oxidizes Cys residues in proteins involved in carnitine metabolism in the liver, including carnitine acetyltransferase (CrAT), carnitine/acylcarnitine carrier (CAC), and carnitine palmitoyltransferases (CPTs). This redox modification was associated with altered levels of various acylcarnitine and acyl-CoA, indicating that Cd disrupts multiple mitochondrial metabolic pathways (Go et al., 2014). Mechanistically, previous research demonstrated that Cd impaired CrAT functions, likely by binding to the enzyme’s sulfhydryl groups (Shoaf et al., 1986). Building on our previous findings, this study proposes that Cd inhibits CrAT or CAC through thiol group modification, inducing a redox imbalance and the selective decrease of brain acylcarnitine levels. This inhibition likely impairs mitochondrial fatty acid β-oxidation and CoA recycling, contributing to neuronal metabolic dysfunction.

Studies on compensatory responses to Cd have focused on protective mechanisms against oxidative stress, including the induction of metallothionein-II in hepatocytes (Martinez Flores et al., 2013) and tissue-specific regulation of antioxidant enzymes and proinflammatory cytokines in zebrafish (Guo et al., 2017; Martinez Flores et al., 2013; Zhu et al., 2018). In this study, the observed increase in lipoamide and PLP, and decrease in Gln levels, may reflect compensatory metabolic adaptations to sustain neuronal and mitochondrial functions against a redox imbalance in the aged male mice brain following Cd exposure. PLP, the active form of vitamin B6, is a vital coenzyme in the brain involved in neurotransmitter synthesis and metabolism (Combs, 2012; Ebadi, 1981). Lipoamide is a key coenzyme for mitochondrial enzymes that possesses antioxidant and neuroprotective properties (Combs, 2012; Hou et al., 2019; Zhou et al., 2018). A previous in vitro study showed that Cd increased neuronal reliance on Gln, likely as a compensatory response to impaired mitochondrial respiration, leading to elevated mitochondrial Gln-dependent ATP production and lipid biosynthesis (Bovio et al., 2021). Cd-induced acylcarnitine deficiency could impair mitochondrial β-oxidation and shift metabolism toward increased Gln utilization to meet energy and biosynthetic demands, thereby contributing to decreased brain Gln.

5. Conclusion

A limitation of the current study is its focus on aged male mice, which reduces the generalizability of our findings across both sexes. Despite the limitation, our work provides the first evidence that Cd burden in the brain following exposure to environmentally relevant low levels comparable to those found in the human brain may contribute to cognitive impairment. These findings suggest that Cd accumulation in the elderly could represent a potential risk factor for dementia and Alzheimer’s disease. Future lipid-focused investigations, employing advanced analytical methodologies such as lipidomics, may offer greater resolution and broader lipid coverage, enabling a more comprehensive interpretation of Cd-induced neurotoxicity.

Supplementary Material

1

Highlights.

  • Environmental Cd exposure impairs cognitive function in aged male mice.

  • Accumulated Cd reduces hippocampal neuronal density and disrupts redox homeostasis.

  • Cd lowers bioactive signaling lipids and acylcarnitine levels in the aged mouse brain.

  • Cd triggers compensatory responses via pyridoxal phosphate, lipoamide, and glutamine.

Acknowledgments

We thank Jennifer Jeon, Choon-Myung Lee, Michael Orr, and ViLinh Tran. Drs. Young-Mi Go and Dean P. Jones share equal senior authorship in this collaborative research.

Funding Sources

This study was supported by National Institute of Environmental Health Science grants R01 ES031980 and P30 ES019776, and National Institute on Aging grant R21 AG080247.

Footnotes

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

CRediT authorship contribution statement

YMG and DPJ: designed the research. GL, HL, and ZRJ: performed experiments, analyzed data, and performed statistical analysis. GL, HL, ZRJ, SSK, DPJ, and YMG: wrote the paper. Research reported in this publication was supported in part by the Cancer Tissue and Pathology Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Data Availability

The data are available within the article, supplementary information, or available from the authors upon reasonable request.

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