Zhoumeng Lin

Pharmacokinetics of metallic nanoparticles

Metallic nanoparticles (NPs) have been widely applied in the field of nanomedicine. A comprehensive understanding of their pharmacokinetics is crucial for proper risk assessment and safe biomedical applications. This review focuses on gold and silver (Ag) NPs, and briefly discusses iron oxide, titanium dioxide (TiO2 ), and zinc oxide NPs. Pharmacokinetics of metallic NPs depends on the particle type, size, surface charge, surface coating, protein binding, exposure route, dose, and species. Generally, blood half-life is shorter in rodents than in larger laboratory animals (e.g., rabbits or monkeys) and differs between intravenous and oral exposures. Oral, dermal, or inhalational absorption is low (≤5%), but may increase with smaller sizes, negative charge, and appropriate coatings. Metallic NPs can be distributed throughout the body, primarily accumulating in the liver, spleen, and lymph node due to nonspecific uptake by reticuloendothelial cells, and could remain in the body for ≥6 months. Metallic NPs (≤100 nm) can cross the blood-brain barrier (BBB), favored by coating with BBB-permeable neuropeptides. Placental transfer depends on the stage of embryonic/placental maturation and surface composition, and may be enhanced by coating with biocompatible molecules (e.g., ferritin or polyethylene glycol). Renal and biliary excretion is generally low due to persistent accumulation in tissues, but renal elimination could be substantially increased with smaller sizes and specific coatings (e.g., glutathione). Physiologically based pharmacokinetic models for gold/dendrimer composite nanodevices, AgNPs, and TiO2 NPs have been developed in rats and the AgNP and TiO2 NP models have been extrapolated to humans to support risk assessment and nanomedicine applications.

Serum Vitamin D Levels and Polycystic Ovary syndrome: A Systematic Review and Meta-Analysis

Vitamin D deficiency (VDD) is common in women with and without polycystic ovary syndrome (PCOS) and may be associated with metabolic and endocrine disorders in PCOS. The aim of this meta-analysis is to assess the associations of serum vitamin D levels with metabolic and endocrine dysregulations in women with PCOS, and to determine effects of vitamin D supplementation on metabolic and hormonal functions in PCOS patients. The literature search was undertaken through five databases until 16 January 2015 for both observational and experimental studies concerning relationships between vitamin D and PCOS. A total of 366 citations were identified, of which 30 were selected (n = 3182). We found that lower serum vitamin D levels were related to metabolic and hormonal disorders in women with PCOS. Specifically, PCOS patients with VDD were more likely to have dysglycemia (e.g., increased levels of fasting glucose and homeostatic model assessment-insulin resistance index (HOMA-IR)) compared to those without VDD. This meta-analysis found no evidence that vitamin D supplementation reduced or mitigated metabolic and hormonal dysregulations in PCOS. VDD may be a comorbid manifestation of PCOS or a minor pathway in PCOS associated metabolic and hormonal dysregulation. Future prospective observational studies and randomized controlled trials with repeated VDD assessment and better characterization of PCOS disease severity at enrollment are needed to clarify whether VDD is a co-determinant of hormonal and metabolic dysregulations in PCOS, represents a consequence of hormonal and metabolic dysregulations in PCOS or both.

Short-term atrazine exposure causes behavioral deficits and disrupts monoaminergic systems in male C57BL/6 mice.

Excessive exposure to the widely used herbicide atrazine (ATR) affects several organ systems, including the brain, where neurochemical alterations reflective of dopamine (DA) circuitry perturbation have been reported. The present study aimed to investigate effects of short-term oral exposure to a dose-range (0, 5, 25, 125, or 250 mg/kg) of ATR on behavioral, neurochemical, and molecular indices of toxicity in adult male C57BL/6 mice. The experimental paradigm included open field, pole and grip tests (day 4), novel object recognition (NOR) and forced swim test (FST; day 9), followed by tissue collection 4h post dosing on day 10. After 4 days of exposure, ATR decreased locomotor activity (≥125 mg/kg). On day 9, ATR-exposed mice exhibited dose-dependent decreased performance in the NOR test (≥25 mg/kg) and spent more time swimming and less time immobile during the FST (≥125 mg/kg). Neurochemically, short-term ATR exposure increased striatal DA and DA turnover (its metabolite homovanillic acid [HVA] and the HVA/DA ratio; ≥125 mg/kg). In addition, ATR exposure increased the levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the striatum (≥125 mg/kg) and it also increased DA turnover (≥125 mg/kg), 5-HIAA (125 mg/kg), and norepinephrine (≥125 mg/kg) levels in the prefrontal cortex. In the hippocampus, the only effect of ATR was to increase the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG; 250 mg/kg). At the molecular level, the expression of key striatal (protein) or nigral (mRNA) markers associated with nigrostriatal DA function, such as tyrosine hydroxylase, DA transporter, vesicular monoamine transporter 2, and DA receptors, was not affected by ATR. These results indicate that short-term ATR exposure targets multiple monoamine pathways at the neurochemical level, including in the striatum, and induces behavioral abnormalities suggestive of impaired motor and cognitive functions and increased anxiety. Impaired performance in the NOR behavioral test was the most sensitive endpoint affected by ATR; this should be taken into consideration for future low-dose ATR studies and for the assessment of risk associated with overexposure to this herbicide.

Neurochemical and electrophysiological deficits in the ventral hippocampus and selective behavioral alterations caused by high-fat diet in female C57BL/6 mice.

Mounting experimental evidence, predominantly from male rodents, demonstrates that high-fat diet (HFD) consumption and ensuing obesity are detrimental to the brain. To shed additional light on the neurological consequences of HFD consumption in female rodents and to determine the relatively early impact of HFD in the likely continuum of neurological dysfunction in the context of chronic HFD intake, this study investigated effects of HFD feeding for up to 12weeks on selected behavioral, neurochemical, and electrophysiological parameters in adult female C57BL/6 mice; particular focus was placed on the ventral hippocampus (vHIP). Selected locomotor, emotional and cognitive functions were evaluated using behavioral tests after 5weeks on HFD or control (low-fat diet) diets. One week later, mice were sacrificed and brain regional neurochemical (monoamine) analysis was performed. Behaviorally naïve mice were maintained on their respective diets for an additional 5-6weeks at which time synaptic plasticity was determined in ex vivo slices from the vHIP. HFD-fed female mice exhibited increased: (i) locomotor activity in the open field testing, (ii) mean turn time on the pole test, (iii) swimming time in the forced swim test, and (iv) number of marbles buried in the marble burying test. In contrast, the novel object recognition memory was unaffected. Mice on HFD also had decreased norepinephrine and dopamine turnover, respectively, in the prefrontal cortex and the vHIP. HFD consumption for a total of 11-12weeks altered vHIP synaptic plasticity, evidenced by significant reductions in the paired-pulse ratio and long-term potentiation (LTP) magnitude. In summary, in female mice, HFD intake for several weeks induced multiple behavioral alterations of mainly anxiety-like nature and impaired monoamine pathways in a brain region-specific manner, suggesting that in the female, certain behavioral domains (anxiety) and associated brain regions, i.e., the vHIP, are preferentially targeted by HFD.

A computational framework for interspecies pharmacokinetics, exposure and toxicity assessment of gold nanoparticles.

AIM To develop a comprehensive computational framework to simulate tissue distribution of gold nanoparticles (AuNP) across several species. MATERIALS & METHODS This framework was built on physiologically based pharmacokinetic modeling, calibrated and evaluated with multiple independent datasets. RESULTS Rats and pigs seem to be more appropriate models than mice in animal-to-human extrapolation of AuNP pharmacokinetics and that the dose and age should be considered. Incorporation of in vitro and/or in vivo cellular uptake and toxicity data into the model improved toxicity assessment of AuNP. CONCLUSION These results partially explain the current low translation rate of nanotechnology-based drug delivery systems from mice to humans. This simulation approach may be applied to other nanomaterials and provides guidance to design future translational studies.

Caspase-11 plays an essential role in methamphetamine-induced dopaminergic neuron apoptosis.

Methamphetamine (METH) is an extremely addictive stimulant drug that is widely used with high potential of abuse. Previous studies have shown that METH exposure damages the nervous system, especially dopaminergic neurons. However, the exact molecular mechanisms of METH-induced neurotoxicity remain unclear. We hypothesized that caspase-11 is involved in METH-induced neuronal apoptosis. We tested our hypothesis by examining the change of caspase-11 protein expression in dopaminergic neurons (PC12 and SH-SY5Y) and in the midbrain of rats exposed to METH with Western blotting. We also determined the effects of blocking caspase-11 expression with wedelolactone (a specific inhibitor of caspase-11) or siRNA on METH-induced apoptosis in PC12 cells and SH-SY5Y cells using Annexin V and TUNEL staining. Furthermore, we observed the protein expression changes of the apoptotic markers, cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase 1 (PARP), after silencing the caspase-11 expression in rat midbrain by injecting LV-shcasp11 lentivirus using a stereotaxic positioning system. Results showed that METH exposure increased caspase-11 expression both in vitro and in vivo, with the effects in vitro being dose- and time-dependent. Inhibition of caspase-11 expression with either wedelolactone or siRNAs reduced the number of METH-induced apoptotic cells. In addition, blocking caspase-11 expression inhibited METH-induced activation of caspase-3 and PARP in vitro and in vivo, suggesting that caspase-11/caspase-3 signal pathway is involved in METH-induced neurotoxicity. These results indicate that caspase-11 plays an essential role in METH-induced neuronal apoptosis and may be a potential gene target for therapeutics in METH-caused neurotoxicity.

Estimation of placental and lactational transfer and tissue distribution of atrazine and its main metabolites in rodent dams, fetuses, and neonates with physiologically based pharmacokinetic modeling.

Atrazine (ATR) is a widely used chlorotriazine herbicide, a ubiquitous environmental contaminant, and a potential developmental toxicant. To quantitatively evaluate placental/lactational transfer and fetal/neonatal tissue dosimetry of ATR and its major metabolites, physiologically based pharmacokinetic models were developed for rat dams, fetuses and neonates. These models were calibrated using pharmacokinetic data from rat dams repeatedly exposed (oral gavage; 5mg/kg) to ATR followed by model evaluation against other available rat data. Model simulations corresponded well to the majority of available experimental data and suggest that: (1) the fetus is exposed to both ATR and its major metabolite didealkylatrazine (DACT) at levels similar to maternal plasma levels, (2) the neonate is exposed mostly to DACT at levels two-thirds lower than maternal plasma or fetal levels, while lactational exposure to ATR is minimal, and (3) gestational carryover of DACT greatly affects its neonatal dosimetry up until mid-lactation. To test the models cross-species extrapolation capability, a pharmacokinetic study was conducted with pregnant C57BL/6 mice exposed (oral gavage; 5mg/kg) to ATR from gestational day 12 to 18. By using mouse-specific parameters, the model predictions fitted well with the measured data, including placental ATR/DACT levels. However, fetal concentrations of DACT were overestimated by the model (10-fold). This overestimation suggests that only around 10% of the DACT that reaches the fetus is tissue-bound. These rodent models could be used in fetal/neonatal tissue dosimetry predictions to help design/interpret early life toxicity/pharmacokinetic studies with ATR and as a foundation for scaling to humans.

Development and Application of a Multiroute Physiologically Based Pharmacokinetic Model for Oxytetracycline in Dogs and Humans

Oxytetracycline (OTC) is a commonly used tetracycline antibiotic in veterinary and human medicine. To establish a quantitative model for predicting OTC plasma and tissue exposure, a permeability-limited multiroute physiologically based pharmacokinetic model was developed in dogs. The model was calibrated with plasma pharmacokinetic data in beagle dogs following single intravenous (5 mg/kg), oral (100 mg/kg), and intramuscular (20 mg/kg) administrations. The model predicted other available dog data well, including drug concentrations in the liver, kidney, and muscle after repeated exposure, and data in the mixed-breed dog. The model was extrapolated to humans and the human model adequately simulated measured plasma OTC concentrations after intravenous (7.14 mg/kg) and oral exposures (6.67 mg/kg). The dog model was applied to predict 24-h OTC area-under-the-curve after three therapeutic treatments. Results were 27.75, 51.76, and 64.17 μg/mL*h in the plasma, and 120.93, 225.64, and 279.67 μg/mL*h in the kidney for oral (100 mg/kg), intravenous (10 mg/kg), and intramuscular (20 mg/kg) administrations, respectively. This model can be used to predict plasma and tissue concentrations to aid in designing optimal therapeutic regimens with OTC in veterinary, and potentially, human medicine; and as a foundation for scaling to other tetracycline antibiotics and to other animal species.

A physiologically based pharmacokinetic model for atrazine and its main metabolites in the adult male C57BL/6 mouse

Atrazine (ATR) is a chlorotriazine herbicide that is widely used and relatively persistent in the environment. In laboratory rodents, excessive exposure to ATR is detrimental to the reproductive, immune, and nervous systems. To better understand the toxicokinetics of ATR and to fill the need for a mouse model, a physiologically based pharmacokinetic (PBPK) model for ATR and its main chlorotriazine metabolites (Cl-TRIs) desethyl atrazine (DE), desisopropyl atrazine (DIP), and didealkyl atrazine (DACT) was developed for the adult male C57BL/6 mouse. Taking advantage of all relevant and recently made available mouse-specific data, a flow-limited PBPK model was constructed. The ATR and DACT sub-models included blood, brain, liver, kidney, richly and slowly perfused tissue compartments, as well as plasma protein binding and red blood cell binding, whereas the DE and DIP sub-models were constructed as simple five-compartment models. The model adequately simulated plasma levels of ATR and Cl-TRIs and urinary dosimetry of Cl-TRIs at four single oral dose levels (250, 125, 25, and 5mg/kg). Additionally, the model adequately described the dose dependency of brain and liver ATR and DACT concentrations. Cumulative urinary DACT amounts were accurately predicted across a wide dose range, suggesting the models potential use for extrapolation to human exposures by performing reverse dosimetry. The model was validated using previously reported data for plasma ATR and DACT in mice and rats. Overall, besides being the first mouse PBPK model for ATR and its Cl-TRIs, this model, by analogy, provides insights into tissue dosimetry for rats. The model could be used in tissue dosimetry prediction and as an aid in the exposure assessment to this widely used herbicide.

Mathematical modeling and simulation in animal health - Part II: principles, methods, applications, and value of physiologically based pharmacokinetic modeling in veterinary medicine and food safety assessment.

This review provides a tutorial for individuals interested in quantitative veterinary pharmacology and toxicology and offers a basis for establishing guidelines for physiologically based pharmacokinetic (PBPK) model development and application in veterinary medicine. This is important as the application of PBPK modeling in veterinary medicine has evolved over the past two decades. PBPK models can be used to predict drug tissue residues and withdrawal times in food-producing animals, to estimate chemical concentrations at the site of action and target organ toxicity to aid risk assessment of environmental contaminants and/or drugs in both domestic animals and wildlife, as well as to help design therapeutic regimens for veterinary drugs. This review provides a comprehensive summary of PBPK modeling principles, model development methodology, and the current applications in veterinary medicine, with a focus on predictions of drug tissue residues and withdrawal times in food-producing animals. The advantages and disadvantages of PBPK modeling compared to other pharmacokinetic modeling approaches (i.e., classical compartmental/noncompartmental modeling, nonlinear mixed-effects modeling, and interspecies allometric scaling) are further presented. The review finally discusses contemporary challenges and our perspectives on model documentation, evaluation criteria, quality improvement, and offers solutions to increase model acceptance and applications in veterinary pharmacology and toxicology.