About

Professor Donald R Smith is a faculty member in the Department of Microbiology and Environmental Toxicology (METX) at UC Santa Cruz. His work is situated within a collaborative, interdisciplinary environment where faculty, researchers, and students investigate how chemicals and microbes, including toxicants and pathogens, impact human and environmental health. The department's research focuses on revealing the underlying factors of disease, the bioavailability of toxins, and organisms' responses to harmful agents. This research leads to the development of novel therapies, bioremediation strategies, and exposure markers. The METX department is unique worldwide in studying the interaction of toxins, microbes, and health, and it frequently collaborates with seven other departments. Professor Smith's research contributes to this mission by exploring the mechanisms through which microbes cause disease, influence toxicant bioavailability, and shape organismal responses to harmful agents. The department's interdisciplinary approach unites biology and environmental science to reveal disease mechanisms and create solutions that protect people and the planet. Through a hands-on training environment, METX prepares the next generation of leaders for careers in academia, industry, government, and beyond.

Research topics

• Chemistry
• Internal medicine
• Medicine
• Endocrinology
• Psychology
• Biochemistry
• Biology
• Neuroscience
• Physiology
• Statistics
• Mathematics
• Nursing
• Gerontology
• Environmental chemistry
• Family medicine
• Environmental health

Selected publications

• Oral guanfacine treatment ameliorates the ADHD-like symptoms caused by developmental manganese exposure

  Progress in Neuro-Psychopharmacology and Biological Psychiatry · 2025-10-01

  articleOpen accessSenior author

  receptor agonist, has proven to be an effective non-stimulant ADHD medication, although it is unknown whether this drug is effective in treating the ADHD-like symptoms produced by developmental Mn exposure. The present study was designed to test this hypothesis. Additionally, due to the pharmacological specificity of guanfacine, its use may provide mechanistic insight into the role of noradrenergic dysfunction as a contributor to the Mn-induced impairments. Male Long-Evans neonatal rats were orally dosed with vehicle or Mn (50 mg Mn/kg/d) from postnatal day 1-21, and orally treated with guanfacine (0, 0.1, or 0.3 mg/kg/d) during behavioral testing as adults. The results revealed that developmental Mn exposure produced lasting impairments in impulse control, attention, and sensorimotor function, and that oral guanfacine was efficacious in ameliorating the Mn-induced impairments in all three functional domains, although the treatment duration needed for efficacy varied by functional domain. In addition, in control (unexposed) animals, there was little or no effect of guanfacine on any functional domain. There was also little effect of the drug in the Mn-exposed animals under trial conditions where Mn deficits did not emerge. These findings 1) demonstrate the efficacy of oral guanfacine to ameliorate the lasting ADHD-like symptoms caused by developmental Mn exposure, and 2) provide additional support for the hypothesis that hypofunctioning of the noradrenergic system contributes to these lasting Mn deficits. Collectively, these findings suggest that individuals with environmentally-induced ADHD, such as that induced by developmental Mn exposure, may benefit from oral guanfacine treatment.

  PublisherDOI

• NR4A1 is a HIF-dependent repressor of SLC30A10 transcription that controls manganese homeostasis

  Journal of Biological Chemistry · 2025-09-11

  articleOpen access

  The primary mechanism that controls manganese (Mn) homeostasis in mammals is the activation of hypoxia-inducible factor (HIF) transcription factors by elevated Mn, which transcriptionally upregulates expression of the Mn efflux transporter SLC30A10 to reduce cellular/organismal Mn levels. Here, we identify an additional unexpected component of the Mn-induced and HIF-dependent homeostatic response that represses SLC30A10 expression. In cells, (1) Mn treatment upregulated expression of the transcription factor NR4A1 (also called Nur77); (2) NR4A1 knockdown increased SLC30A10 expression and reduced the sensitivity of wildtype, but not ΔSLC30A10, cells to Mn toxicity; and (3) overexpression of NR4A1 reduced SLC30A10 expression and increased sensitivity to Mn toxicity. Thus, NR4A1 is a Mn-responsive gene that contributes to the control of Mn homeostasis by repressing SLC30A10 expression. In addition, (1) in cells, the Mn-induced upregulation of NR4A1 was attenuated by knockdown of both HIF1α and HIF2α and (2) in mice, Mn exposure upregulated expression of NR4A1 in the liver of control or tissue-specific HIF1α but not tissue-specific HIF2α knockout mice. Thus, the induction of NR4A1 by elevated Mn is HIF2 dependent. Collectively, current and prior results imply that the activation of HIF1/HIF2 during elevated Mn exposure has two opposing effects on SLC30A10 expression, direct transcriptional upregulation and indirect repression via NR4A1, that together set SLC30A10 expression to the level necessary to restore cellular Mn to the physiological range. The repressive arm of the HIF-mediated transcriptional cascade that controls SLC30A10 expression may be designed to prevent Mn deficiency, which may otherwise occur from prolonged or excessive upregulation of SLC30A10.

  PublisherOA PDFDOI

• Comparing 0.9% sterile saline to phosphate buffered saline as a transport media for Tritrichomonas foetus RT-qPCR testing

  American Association of Bovine Practitioners Conference Proceedings · 2025-03-26

  articleOpen access

  The limit of detection for T. foetus RT-qPCR is 1 organism/ex­traction in phosphate buffered saline (PBS) without prior cul­ture. The objective of this study was to determine if 0.9% ster­ile saline (SAL), a readily available media, was not inferior to PBS as a transport media for T. foetus RT-qPCR testing at that concentration.

  PublisherOA PDFDOI

• PHD2 enzyme is an intracellular manganese sensor that initiates the homeostatic response against elevated manganese

  Proceedings of the National Academy of Sciences · 2024-06-21 · 11 citations

  articleOpen access

  Intracellular sensors detect changes in levels of essential metals to initiate homeostatic responses. But, a mammalian manganese (Mn) sensor is unknown, representing a major gap in understanding of Mn homeostasis. Using human-relevant models, we recently reported that: 1) the primary homeostatic response to elevated Mn is upregulation of hypoxia-inducible factors (HIFs), which increases expression of the Mn efflux transporter SLC30A10; and 2) elevated Mn blocks the prolyl hydroxylation of HIFs by prolyl hydroxylase domain (PHD) enzymes, which otherwise targets HIFs for degradation. Thus, the mammalian mechanism for sensing elevated Mn likely relates to PHD inhibition. Moreover, 1) Mn substitutes for a catalytic iron (Fe) in PHD structures; and 2) exchangeable cellular levels of Fe and Mn are comparable. Therefore, we hypothesized that elevated Mn directly inhibits PHD by replacing its catalytic Fe. In vitro assays using catalytically active PHD2, the primary PHD isoform, revealed that Mn inhibited, and Fe supplementation rescued, PHD2 activity. However, a mutation in PHD2 (D315E) that selectively reduced Mn binding without substantially impacting Fe binding or enzymatic activity resulted in complete insensitivity of PHD2 to Mn in vitro. Additionally, hepatic cells expressing full-length PHD2 D315E were less sensitive to Mn-induced HIF activation and SLC30A10 upregulation than PHD2 wild-type . These results: 1) define a fundamental Mn sensing mechanism for controlling Mn homeostasis—elevated Mn inhibits PHD2, which functions as a Mn sensor, by outcompeting its catalytic Fe, and PHD2 inhibition activates HIF signaling to up-regulate SLC30A10; and 2) identify a unique mode of metal sensing that may have wide applicability.

  PublisherOA PDFDOI

• Cognitive and functional brain changes among Italian adolescents and young adults with COVID-19 infection: a longitudinal case control study

  ISEE Conference Abstracts · 2024-07-31

  articleOpen access
  PublisherDOI

• Methylphenidate alleviates cognitive dysfunction caused by early manganese exposure: Role of catecholaminergic receptors

  Progress in Neuro-Psychopharmacology and Biological Psychiatry · 2024-01-22 · 7 citations

  articleSenior authorCorresponding
  PublisherDOI

• Sex-specific associations between co-exposure to multiple metals and externalizing symptoms in adolescence and young adulthood

  Environmental Research · 2024-02-15 · 3 citations

  articleOpen access
  PublisherOA PDFDOI

• Brain-Environmental interactions: a time sensitive matter

  ISEE Conference Abstracts · 2024-07-31

  articleOpen access
  PublisherDOI

• A multi-environmental source approach to explore associations between metals exposure and olfactory identification among school-age children residing in northern Italy

  Journal of Exposure Science & Environmental Epidemiology · 2024-05-27 · 3 citations

  articleOpen access
  PublisherOA PDFDOI

• Sex-specific associations between co-exposure to multiple metals and externalizing symptoms in adolescence and young adulthood

  ISEE Conference Abstracts · 2024-07-31

  articleOpen access
  PublisherDOI

Recent grants

• NIH Grant R01ES010788

  NIH · $1.3M · 2008

• Mechanisms and therapies for the neurobehavioral deficits from early Mn exposure

  NIH · $2.8M · 2018–2025

• NIH Grant R01ES007535

  NIH · $457k · 2000

• Metal mixtures, exposure windows, and neurodevelopmental trajectories from adolescence to adulthood

  NIH · $9.1M · 2010–2027

• Manganese Exposure Windows and Neurologic Function in Adolescence

  NIH · $270k · 2010–2016

Frequent coauthors

• Roberto G. Lucchini

  Florida International University

  156 shared

• Manish Arora

  Icahn School of Medicine at Mount Sinai

  81 shared

• Christine Austin

  Icahn School of Medicine at Mount Sinai

  65 shared

• Brenda Eskenazi

  Center for Environmental Health

  59 shared

• Robert O. Wright

  57 shared

• Asa Bradman

  University of California, Merced

  51 shared

• Maria Kowalkowski

  50 shared

• Debbie Camp

  St. Louis County Missouri

  50 shared