About

Pamela J. Lein is a Professor and Department Chair in the Department of Molecular Biosciences at the School of Veterinary Medicine. Her research focuses on the cellular and molecular mechanisms of neurotoxicology, gene x environment interactions in neurodevelopmental disorders and neurodegenerative diseases, and the development of medical countermeasures for acute intoxication with seizurogenic compounds. She has a background that includes a BS from Cornell University, an MS from East Tennessee State University, a PhD from the State University of New York at Buffalo, and postdoctoral training at the Roswell Park Cancer Institute. Her work investigates how environmental neurotoxicants such as polychlorinated biphenyls (PCBs) and air pollution impact brain development and function, with particular attention to neuroinflammatory mechanisms and receptor-dependent pathways. She has contributed to understanding the role of ryanodine receptor-dependent mechanisms in PCB developmental neurotoxicity and has explored gene-environment interactions relevant to autism and other neurodevelopmental disorders. Her research has been recognized through awards such as the Zoetis Award for Veterinary Research Excellence and has been published extensively, including chapters in scientific books and articles highlighted as editor’s choices. Dr. Lein's work aims to elucidate neurotoxic processes and develop strategies to mitigate their effects.

Research topics

• Neuroscience
• Biochemistry
• Biology
• Chemistry
• Immunology
• Cell biology
• Pharmacology
• Psychology
• Medicine

Selected publications

• Additional file 2 of Sex and tissue resolved co-expression networks reveal a female placental–brain axis protective against prenatal PCB exposure

  Figshare · 2026-04-07

  articleOpen access

  Additional file 2: Supplementary Figures S1-S12. Fig. S1. Sample-to-Sample Spearman Correlation Heatmap of gene expression, annotated by tissue, sex, PCB dose, litter, and uterine horn position. Fig. S2. Analysis of variance by experimental variable an PCA analysis of litter effects. Fig. S3. Examples of select PCB dose responsive DEGs. Fig. S4. PCB sex-consensus networks for brain. Fig. S5. PCB sex-consensus network for placenta. Fig. S6. PCB tissue-consensus networks for males. Fig. S7. PCB tissue-consensus networks for females. Fig. S8. Folic Acid sex-consensus network for brains. Fig. S9. Folic Acid sex-consensus networks for placenta. Fig. S10. Folic Acid tissue-consensus networks for males. Fig. S11. Folic Acid tissue-consensus networks for females. Fig. S12. Additional pairwise comparisons for sex-consensus folic acid networks. This is an expanded version of Fig. 6 but with all the pairwise comparisons. Fig. S13. Additional pairwise comparisons for tissue-consensus folic acid networks. This is an expanded version of Fig. 7 but with all the pairwise comparisons.

  PublisherDOI

• Are micro- and nanoplastics accumulating in the brain promoting neurological dysfunction and disease?

  Open Access Government · 2026-04-16

  articleOpen access1st authorCorresponding

  Are micro- and nanoplastics accumulating in the brain promoting neurological dysfunction and disease? Pamela J. Lein considers whether micro- and nanoplastics are accumulating in the brain and the question of whether they are promoting neurological dysfunction and disease. In February 2025, Nature Medicine published a startling report by a team of researchers at the University of New Mexico that estimated the human brain was 0.5% plastic by weight. This finding was based on their analysis of micro- and nanoplastics (MNPs) in autopsied human brains. Comparative analyses of the MNP levels in human brain, liver, and kidney samples collected in 2016 or 2024 revealed that not only were these tiny plastic particles accessing the brain, but they were actually accumulating in the brain. Specifically, brain samples contained up to 30 times more MNPs than samples from the same person’s liver or kidney.

  PublisherDOI

• Additional file 1 of Sex and tissue resolved co-expression networks reveal a female placental–brain axis protective against prenatal PCB exposure

  Figshare · 2026-04-07

  articleOpen access

  Additional file 1. RNA-seq quality control reports for each sample.

  PublisherDOI

• Additional file 1 of Sex and tissue resolved co-expression networks reveal a female placental–brain axis protective against prenatal PCB exposure

  Figshare · 2026-04-07

  articleOpen access

  Additional file 1. RNA-seq quality control reports for each sample.

  PublisherDOI

• Cytochrome P450-Mediated Xenobiotic Metabolism in the Brain, Effects of 3,3'-Dichlorobiphenyl (PCB-11) Exposure, and Contributions to Naphthalene-Induced DNA Adducts (Abstract ID: 225165)

  Journal of Pharmacology and Experimental Therapeutics · 2026-05-01

  article
  PublisherDOI

• Sex and tissue resolved co-expression networks reveal a female placental–brain axis protective against prenatal PCB exposure

  Genome biology · 2026-04-07

  articleOpen access

  BACKGROUND: Neurodevelopmental disorders have a strong male bias that is poorly understood. The placenta provides molecular information about environmental interactions with genetics (including biological sex) that shape developmental processes in the brain. We investigate placental-brain transcriptional responses in an established mouse model of prenatal exposure to a human-relevant mixture of polychlorinated biphenyls (PCBs). RESULTS: To understand sex, tissue, and dosage effects in embryonic (E18) brain and placenta RNAseq data, we use weighted gene correlation network analysis (WGCNA) to create gene networks that could be compared across sex or tissue. WGCNA reveals that expression within most correlated gene networks is significantly and strongly associated with PCB exposure, but frequently in opposite directions between male-female and placenta-brain comparisons. In WGCNA and differentially expressed gene analyses, more transcriptional changes are observed in male brain than placenta, but the reverse is seen in females. Furthermore, female X-inactive specific transcript (Xist) levels correlate with sex-specific and non-monotonic PCB dose response, suggesting an X-linked protective epigenetic mechanism. The transcriptomic effects of low-dose PCB exposure are significantly opposed by dietary folic acid supplementation across both sexes but are strongest in female placentas. PCB and folic acid interacting gene networks are enriched in metabolic pathways involved in energy usage and translation, with female-specific protective effects enriched in PPAR, thermogenesis, glycerolipid, and O-glycan biosynthesis, as opposed to toxicant responses in male brain. CONCLUSIONS: A female protective effect in response to prenatal PCB exposure appears to be mediated by dose-dependent sex differences in transcriptional modulation of placental metabolic pathways.

  PublisherDOI

• Spatial and spectral mapping of traffic-related nanoparticles in hippocampal subregions of an Alzheimer disease model

  Environmental Pollution · 2026-01-27

  articleOpen accessCorresponding

  Chronic exposure to traffic-related air pollution (TRAP) is linked to increased risk of neurodegenerative diseases, including Alzheimer disease (AD). Ultrafine particulate matter (UFPM) is a suspected driver of TRAP neurotoxicity, but its spatial interactions with AD pathology remain poorly defined. We investigated the distribution, composition, and pathological context of TRAP-derived UFPM in the hippocampus of TgF344-AD rats chronically exposed to TRAP or filtered air (FA) for 14 months. Using a multimodal imaging workflow that combines enhanced darkfield hyperspectral imaging (EDF-HSI) with confocal immunofluorescence for microglia (CD68/Iba1) and amyloid beta (Aβ) plaques (Thioflavin S), we mapped the localization and spectral properties of UFPM in situ. UFPM accumulation was elevated in TRAP-exposed females, suggesting sex-specific vulnerability in blood-brain barrier permeability or particle accumulation. Particles near plaques showed red-shifted spectral signatures, suggestive of biochemical transformation. Dimension reduction revealed clustering of particle spectra by TRAP exposure and plaque proximity. However, UFPM was rarely found within plaques or microglia, implying indirect neuroimmune modulation. These findings highlight a novel spatial and spectral imaging approach for characterizing environmental nanoparticle interactions in the brain and suggests chronic TRAP exposure may influence AD-related inflammation and pathology in a sex- and region-dependent manner in this rodent model.

  PublisherDOI

• Chronic NLRP3 inflammasome activation drives neutrophil brain entry and interactions with microglia

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-23

  article

  NOD-like receptor family pyrin domain-containing 3 (NLRP3) is a cytosolic regulator of an inflammasome-mediated innate immune response. In the central nervous system (CNS), NLRP3 inflammasome activation has been implicated in multiple neurodegenerative diseases, yet the mechanisms by which it contributes to disease remain unclear. Here, we investigated the CNS effects of chronic NLRP3 activation using a humanized NLRP3 gain-of-function mouse model (hNLRP3_D305N). Bulk brain analyses confirmed constitutive inflammasome activation, widespread cytokine induction, and the increased presence of blood-associated proteins suggestive of dysfunction at CNS border sites and the blood-brain barrier (BBB). Furthermore, cerebrospinal fluid (CSF) neurofilament light chain levels were elevated, indicating neuronal damage. Single-cell RNA-sequencing of CD45+ immune cells in the brain demonstrated that microglia adopt distinct reactive states and that peripheral immune cells infiltrate the CNS, with neutrophils emerging as the predominant infiltrating immune cell type. This finding was confirmed by untargeted bulk brain and CSF proteomics that also suggest neutrophil reactivity. Immunohistochemistry further revealed regional neutrophil entry into the brain parenchyma, concurrent with reactive microglia and engulfment of neutrophils, suggesting functional microglia-neutrophil interactions. Collectively, these findings establish a direct pathogenic role for the NLRP3 inflammasome in the CNS independent of other neurodegeneration-related disease pathologies.

  PublisherDOI

• Microglial transcriptional profiles of a transgenic rat model closely model Alzheimer's disease

  Journal of Alzheimer s Disease · 2026-01-05

  articleOpen accessSenior author

  Single-cell RNA-sequencing has identified that Alzheimer's disease (AD) pathology in humans is associated with activation of disease-associated microglia (DAM). Microglial signatures of human AD have not been consistently identified in AD mouse models. Since the inflammatory response of rats is more like humans, we profiled microglial transcriptomes in aging TgF344-AD rats, which overexpress two human AD risk genes. Classic DAM gene activation ( ApoE , Trem2 , Gpnmb ), and upregulation (MHC class-II) and downregulation ( Ifngr1 and Fkbp5) of human AD microglial genes were identified in aging TgF344-AD rats. Thus, the TgF344-AD rat better recapitulates the microglial gene signature observed in human AD.

  PublisherDOI

• Lithium supplements to prevent Alzheimer’s disease: A poisoned chalice?

  Open Access Government · 2026-01-16

  articleOpen accessSenior author

  Lithium supplements to prevent Alzheimer’s disease: A poisoned chalice? Matthew J. Armstrong, Anthony E. Valenzuela, and Pamela J. Lein explore the use of lithium supplements to prevent Alzheimer’s disease and whether this approach is a poisoned chalice. Globally, an estimated 55 million people live with Alzheimer’s disease, a number expected to exceed 152 million by 2050. Alzheimer’s is a progressive and fatal neurodegenerative disease and the most common form of dementia. There are no cures for Alzheimer’s, and currently available treatments only modestly slow disease progression. Identifying effective therapeutics has been difficult because while genetic factors contribute to Alzheimer’s, cases with single causative mutations are rare (1-5%).

  PublisherDOI

Recent grants

• NIH Grant R21ES011771

  NIH · $320k · 2005

• NIH Grant R01ES017425

  NIH · $2.0M · 2015

• NIH Grant R15NS036401

  NIH · $97k · 2000

• Advanced Training in Environmental Health Sciences

  NIH · $9.9M · 1978–2028

• NIH Grant R21NS045037

  NIH · $315k · 2006

Frequent coauthors

• Donald A. Bruun

  University of California, Davis

  193 shared

• Jill L. Silverman

  University of California, Davis

  144 shared

• Elizabeth L. Berg

  University of California, Davis

  135 shared

• Jason P. Lerch

  133 shared

• Jacob Ellegood

  Hospital for Sick Children

  133 shared

• Josef K. Rivera

  University of California, Davis

  130 shared

• Markus Wöhr

  KU Leuven

  130 shared

• Tianna M Ching

  University of California, Davis

  129 shared

Education

• Postdoctoral fellow, Molecular Immunology

  Roswell Park Cancer Institute

  1992

• Ph.D., Pharmacology and Toxicology

  University at Buffalo - The State University of New York

  1990

• M.S., Environmental Health Sciences

  East Tennessee State University

  1983

• B.S. in Biology

  Cornell University

  1981