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Chromosomal instability as manifested by increases in aneuploidy and structural chromosome aberrations is believed to play a critical role in the intermediate to late stages in the development of cervical malignancies. The current study was designed to determine the role of tetraploidy in the formation of aneuploidy and ascertain the occurrence of these alterations during the earlier stages of cervical carcinogenesis. Cervical cell samples, with diagnoses ranging from Normal to high-grade lesions, (HSIL) were obtained from 143 women and were evaluated for chromosomal alterations using dual-probe fluorescence in situ hybridization. Cervical cells from a subset of the group were also evaluated for chromosomal instability in the form of micronuclei. The frequencies of cells exhibiting either tetrasomy or aneusomy for Chromosomes 3 and 17 increased significantly with disease progression and displayed distinctive patterns where aneusomy was rarely present in the absence of tetrasomy. The frequencies of micronuclei that formed through either chromosomal loss or breakage increased significantly in both the low-grade and high-grade diagnostic categories and were highly correlated with both the number of tetrasomic and aneusomic cervical cells. In addition, a unique chromosomal alteration involving a significant non-random loss of Chromosome 17 specific to near-tetraploid aneusomic cells (trisomy 17 and tetrasomy 3) was observed. We conclude that tetraploidy and chromosomal instability are related events occurring during the early stages of cervical carcinogenesis that predispose cervical cells to the formation of aneuploidy frequently involving the loss of Chromosome 17.

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Delineating the specific mechanisms by which metals alter redox homeostasis is key to understand the pathological processes that convey chronic neuronal dysfunction in neurodegenerative and neurodevelopmental disorders. Antioxid. Redox Signal. 28, 1669-1703.

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Inorganic arsenic (iAs) is an important natural pollutant. Millions of individuals worldwide drink water with high levels of iAs. Chronic exposure to iAs has been associated with lower IQ and learning disabilities as well as memory impairment. iAs is methylated in tissues such as the brain generating mono and dimethylated species. iAs methylation requires cellular glutathione (GSH), which is the main antioxidant in the central nervous system (CNS). In humans, As species cross the placenta and are found in cord blood. A CD1 mouse model was used to investigate effects of gestational iAs exposure which can lead to oxidative damage, disrupted cysteine/glutamate transport and its putative impact in learning and memory. On postnatal days (PNDs) 1, 15 and 90, the expression of membrane transporters related to GSH synthesis and glutamate transport and toxicity, such as xCT, EAAC1, GLAST and GLT1, as well as LAT1, were analyzed. Also, the expression of the glutamate receptor N-methyl-D-aspartate (NMDAR) subunits NR2A and B as well as the presence of As species in cortex and hippocampus were investigated. On PND 90, an object location task was performed to associate exposure with memory impairment. Gestational exposure to iAs affected the expression of cysteine/glutamate transporters in cortex and hippocampus and induced a negative modulation of NMDAR NR2B subunit in the hippocampus. Behavioral tasks showed significant spatial memory impairment in males while the effect was marginal in females.

Most cancers arise in epithelial tissues and these tissues are typically the targets of the carcinogens responsible for the tumors. Exfoliated epithelial cells have traditionally been used for cancer screening by cytopathologists and these cells also can be used for biomonitoring of genotoxic effects in humans. Cervical cancer results from the progression of preinvasive precursor lesions, called low-grade squamous intraepithelial lesions (LGSILs), to high-grade squamous intraepithelial lesions (HGSILs). The gradient from low to high-grade lesions is characterized by increasing nuclear atypia and the failure of cellular differentiation in progressively more superficial levels of the epithelium. These phenotypic changes are hypothesized to be accompanied by increased genetic instability that can be documented using the micronucleus (MN) assay in exfoliated cervical cells. A retrospective study was performed to investigate the frequency of micronucleated cells in cervical smears from women at high risk for developing cervical cancer. Papanicolaou (Pap) smears from 275 women previously studied at a cancer clinic were coded and analyzed for the frequency of micronucleated cells. LGSIL, HGSIL, and invasive carcinoma smears had significantly higher frequencies than normal and ASCUS (abnormal squamous cells of undetermined origin) smears. HGSIL or severely dysplastic smears had the highest frequency of micronucleated cells (although not significantly higher than LGSIL smears), an observation that that could be useful in confirming these types of lesions. The results indicate that the MN frequency in exfoliated cervical cells may be an additional criterion for establishing cervical cancer risk.

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