Environmental factors have been associated with psychiatric disorders and recent epidemiological studies suggest an association between prenatal lead (Pb2+) exposure and schizophrenia (SZ). Pb2+ is a potent antagonist of the N-methyl-D-aspartate receptor (NMDAR) and converging evidence indicates that NMDAR hypofunction has a key role in the pathophysiology of SZ. The glutamatergic hypothesis of SZ posits that NMDAR hypofunction results in the loss of parvalbumin (PV)-positive GABAergic interneurons (PVGI) in the brain. Loss of PVGI inhibitory control to pyramidal cells alters the excitatory drive to midbrain dopamine neurons increasing subcortical dopaminergic activity. We hypothesized that if Pb2+ exposure in early life is an environmental risk factor for SZ, it should recapitulate the loss of PVGI and reproduce subcortical dopaminergic hyperactivity. We report that on postnatal day 50 (PN50), adolescence rats chronically exposed to Pb2+ from gestation through adolescence exhibit loss of PVGI in SZ-relevant brain regions. PV and glutamic acid decarboxylase 67 kDa (GAD67) protein were significantly decreased in Pb2+ exposed rats with no apparent change in calretinin or calbindin protein levels suggesting a selective effect on the PV phenotype of GABAergic interneurons. We also show that Pb2+ animals exhibit a heightened locomotor response to cocaine and express significantly higher levels of dopamine metabolites and D2-dopamine receptors relative to controls indicative of subcortical dopaminergic hyperactivity. Our results show that developmental Pb2+ exposure reproduces specific neuropathology and functional dopamine system changes present in SZ. We propose that exposure to environmental toxins that produce NMDAR hypofunction during critical periods of brain development may contribute significantly to the etiology of mental disorders.

Background: Unusually large CAG repeat expansions (>60) in exon one of Huntingtin (HTT) are invariably associated with a juvenile-onset form of Huntington's disease (HD), characterized by a more extensive and rapidly progressing neuropathology than the more prevalent adult-onset form. However, existing mouse models of HD that express the full-length Htt gene with CAG repeat lengths associated with juvenile HD (ranging between ∼75 to ∼150 repeats in published models) exhibit selective neurodegenerative phenotypes more consistent with adult-onset HD. Objective: To determine if a very large CAG repeat (>200) in full-length Htt elicits neurodegenerative phenotypes consistent with juvenile HD. Methods: Using a bacterial artificial chromosome (BAC) system, we generated mice expressing full-length mouse Htt with ∼225 CAG repeats under control of the mouse Htt promoter. Mice were characterized using behavioral, neuropathological, biochemical and brain imaging methods.

Following the World Trade Center tragedy of September 11, 2001 rescue workers as well as New York City residents were exposed to thousands of tons of complex particulate matter that was inhaled and ingested over an extended period of time. Some of the immediate effects of these pollutants included “World Trade Center Cough,” a condition that resulted in increased coughing, respiratory pathway irritation, and decreases in lung function. Though there are several known carcinogens found within the heterogeneous mixture of particles that make up World Trade Center dust, there is has been no clearly defined link between World Trade Center dust inhalation and specific cancer development. This study investigated the physical and chemical properties of World Trade Center dust using in vitro methods. A sample of this dust from the tragic events was given for this research by Dr. Paul Lioy of Rutgers University in New Jersey, who was the leader of the 20+ scientists who analyzed and published information on the chemical contents of this particulate matter. Human lung fibroblast cells (MRC-5 and WI-38) were exposed to various concentrations of World Trade Center dust and controls to simulate the World Trade Center dust exposure in in vivo lung systems. Proliferation and apoptosis rates were measured in cells exposed to various concentrations of World Trade Center dust. Assays such as the Apo-Live Glo Multiplex Assay (Promega) utilizing the techniques of luminescence and fluorescence were read by 96 well plate reader. The goal was to elucidate any physical or chemical interactions between cells and particles that may decrease cell viability and induce injury or mutation in DNA. These studies indicate that there is a very specific timing and concentration of particulate matter exposure which leads to noticeable apoptotic events in cultured cells. Apoptosis occurs after 24 hours of incubation for cells exposed to 25 ppm, but likely occurs earlier in cells exposed to 50 ppm and greater. An Ames assay was also performed to further demonstrate possible mutagenic effects that various concentrations of World Trade Center dust may have on living systems. Mutations were incurred by Salmonella typhimurium cells and successfully point to the increased possibility that World Trade Center dust would be a definite mutagenic material. These studies conclude that analysis of proliferation and the timing of apoptosis in cells exposed to World Trade Center dust, in conjunction with Ames assay, allow for a better understanding of the future risks to be faced by personnel exposed to particulate matter pollution following the World Trade Center attack of 9-11. Citation Format: Barbara Soares, Kayla Cortese, Ann Marie DiLorenzo. Analysis of potential mutagenic effects of World Trade Center dust on in vitro systems. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 820. doi:10.1158/1538-7445.AM2015-820

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