Browsing by Author "Melin, Vanessa Estella"

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    Effects of Quaternary Ammonium Disinfectants on Mouse Reproductive Function
    Melin, Vanessa Estella (Virginia Tech, 2015-07-25)
    Quaternary ammonium compounds (QACs) are antimicrobial disinfectants commonly used in commercial and household settings. While these compounds have been used for decades, reproductive toxicity has not been thoroughly evaluated. Extensive use of QACs results in ubiquitous human exposure to potentially toxic compounds. Reproductive toxicity of two common QACs, alkyl dimethyl benzyl ammonium chloride (ADBAC) and didecyl dimethyl ammonium chloride (DDAC), was investigated to determine gender-specific toxicity with an emphasis on male reproductive function. Breeding pairs of mice exposed for six months to ADBAC+DDAC exhibited decreases in fertility and fecundity, with fewer pregnancies and decreased numbers of pups over a six month period. Females proceeded through significantly fewer estrus cycles, and both ovulation and implantation rates were reduced. Males exhibited declines in both sperm concentration and motility. Male reproductive toxicity was further assessed in a series of in-vitro and in-vivo experiments. ADBAC+DDAC were cytotoxic to testicular Sertoli cells in culture at concentrations greater than or equal to 0.0005%. Changes in blood-testis-barrier integrity (BTB) were observed at 0.01% ADBAC+DDAC using a two-compartment culture system that measures transepithelial electrical resistance (TER). Sertoli cell cytotoxicity correlated with decreased TER at ADBAC+DDAC concentrations above 0.001%. In-vitro fertilization capacity of epididymal sperm was reduced in males given a 10-day rest period following ADBAC+DDAC exposure. Multigenerational changes in sperm parameters and in mRNA expression of enzymes involved with epigenetic modifications were evaluated across three generations. Sperm concentration and motility were reduced in F0 males exposed directly to ADBAC+DDAC. In F1 males, sperm concentration was increased and motility decreased, while there was no change in the F2 progeny. Genes involved in epigenetic modifications were altered in the exposed F0, with upregulation of two histone acetyltransferases (Hat1 and Kat2b) and downregulation of one lysine-specific demethylase (Kdm6b). F1 and F2 generations were not different from controls except for downregulation of the methyltransferase Dnmt1 in F1 progeny. The reproductive toxicity of ADBAC+DDAC identified in these studies, particularly to the male, compels further investigation into the potential effects that these compounds may have on human reproduction.
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    Neural tube defects in rodents caused by a tap water contaminant
    Melin, Vanessa Estella (Virginia Tech, 2011-09-28)
    In May of 2006, the Hrubec group suddenly began to observe neural tube defects (NTDs) in embryos of untreated control mice. Unintentional exposure to a teratogenic agent in tap water was identified as the cause. We aimed to identify the contaminant, but first we demonstrated that the NTDs were pathological being present on both gestational day 9 and 10. We also found that a second species, rats, developed NTDs when exposed to tap waters. Disinfection by-products (DBPs) arise when natural organic matter in municipal water sources reacts with disinfectants used in the water treatment process. Purge and trap gas chromatography-mass spectrometry (PT GC-MS) and animal exposure studies were used to determine if the teratogenic contaminant was a DBP. Since the distribution pattern of DBPs did not match the distribution pattern of NTDs, we concluded that a DBP was not likely to be responsible for the observed malformations. Pharmaceuticals and personal care products have emerged as ubiquitous contaminants of ground and surface waters, and have been detected in drinking water. In order to analyze for these compounds, we submitted different water samples to a commercial water analysis lab (AXYS Analytical Services, Sidney, BC, Canada). Several pharmaceuticals were identified in a number of samples, including a known teratogenic drug used to treat mood disorders and seizures: carbamazepine. Further analysis for carbamazepine was conducted in-house. Carbamazepine was found in several ground, surface, and tap waters, at various concentrations. To establish whether or not carbamazepine was responsible for NTDs in our mice, we conducted 2 dosing studies. Carbamazepine was provided to mice at concentrations detected in tap water, as well as approximately 2 x and 1000 x that concentration. Both studies found no significant differences in NTD rates among the dose groups. As no dose effect was observed, we concluded that CBZ was not directly responsible for the malformations. The identity of the teratogenic contaminant is not known at this time, but is unlikely to be a DBP or low concentrations of the pharmaceutical carbamazepine.