Inorganic arsenic (iAs) and fluoride (F⁻) are naturally occurring drinking water contaminants. However, co-exposure to these contaminants and its effects on human health are understudied. The goal of this study was examined exposures to iAs and F⁻ in Chihuahua, Mexico, where exposure to iAs in drinking water has been associated with adverse health effects. All 1119 eligible Chihuahua residents (>18 years) provided a sample of drinking water and spot urine samples. iAs and F⁻ concentrations in water samples ranged from 0.1 to 419.8 µg As/L and from 0.05 to 11.8 mg F⁻/L. Urinary arsenic (U-tAs) and urinary F⁻ (U-F⁻) levels ranged from 0.5 to 467.9 ng As/mL and from 0.1 to 14.4 µg F⁻/mL. A strong positive correlation was found between iAs and F⁻ concentrations in drinking water (r_s = 0.741). Similarly, U-tAs levels correlated positively with U-F⁻ concentrations (r_s = 0.633). These results show that Chihuahua residents exposed to high iAs concentrations in drinking water are also exposed to high levels of F⁻, raising questions about possible contribution of F⁻ exposure to the adverse effects that have so far been attributed only to iAs exposure. Thus, investigation of possible interactions between iAs and F⁻ exposures and its related health risks deserves immediate attention.

Background: Ovarian cancer is the leading cause of mortality among malignant gynecological tumors. Surgical resection and chemotherapy with intravenous platinum/taxanes drugs are the treatments of choice, with little effectiveness in later stages and severe toxicological effects. Therefore, this study aimed to evaluate the antineoplastic activity of gallic acid (GA) and myricetin (Myr) administrated peritumorally in Nu/Nu mice xenotransplanted with SKOV-3 cells. Methods: Biological activity of GA and MYR was evaluated in SKOV-3 and OVCAR-3 cells (ovarian adenocarcinomas) by confocal/transmission electron microscopy, PI-flow cytometry, H₂-DCF-DA stain, MTT, and Annexin V/PI assays. Molecular targets of compounds were determined with ACD/I-Labs and SEA. Antineoplastic activity was performed in SKOV-3 cells subcutaneously xenotransplanted into female Nu/Nu mice treated peritumorally with 50 mg/kg of each compound (2 alternate days/week) for 28 days. Controls used were paclitaxel (5 mg/kg) and 20 μL of vehicle (0.5% DMSO in 1X PBS). Tumor lesions, organs and sera were evaluated with NMR, USG, histopathological, and paraclinical studies. Results: In vitro studies showed a decrease of cell viability with GA and Myr in SKOV-3 (50 and 166 μg/mL) and OVCAR-3 (43 and 94 μg/mL) cells respectively, as well as morphological changes, cell cycle arrest, and apoptosis induction due to ROS generation (p ≤ 0.05, ANOVA). In silico studies suggest that GA and MYR could interact with carbonic anhydrase IX and PI3K, respectively. In vivo studies revealed inhibitory effects on tumor lesions development with GA and MYR up to 50% (p ≤ 0.05, ANOVA), with decreased vascularity, necrotic/fibrotic areas, neoplastic stroma retraction and apoptosis. However, toxicological effects were observed with GA treatment, such as leukocyte infiltrate and hepatic parenchyma loss, hypertransaminasemia (ALT: 150.7 ± 25.60 U/L), and hypoazotemia (urea: 33.4 ± 7.4 mg/dL), due to the development of chronic hepatitis (p ≤ 0.05, ANOVA). Conclusion: GA and Myr (50 mg/kg) administered by peritumoral route, inhibit ovarian tumor lesions development in rodents with some toxicological effects. Additional studies will be necessary to find the appropriate therapeutic dose for GA. Therefore, GA and Myr could be considered as a starting point for the development of novel anticancer agents.

Chronic exposure to inorganic arsenic (iAs) has been linked to an increased risk of diabetes, yet the specific disease phenotype and underlying mechanisms are poorly understood. In the present study we set out to identify iAs exposure-associated metabolites with altered abundance in nondiabetic and diabetic individuals in an effort to understand the relationship between exposure, metabolomic response, and disease status. A nested study design was used to profile metabolomic shifts in urine and plasma collected from 90 diabetic and 86 nondiabetic individuals matched for varying iAs concentrations in drinking water, body mass index, age, and sex. Diabetes diagnosis was based on measures of fasting plasma glucose and 2-h blood glucose. Multivariable models were used to identify metabolites with altered abundance associated with iAs exposure among diabetic and nondiabetic individuals. A total of 132 metabolites were identified to shift in urine or plasma in response to iAs exposure characterized by the sum of iAs metabolites in urine (U-tAs). Although many metabolites were altered in both diabetic and nondiabetic 35 subjects, diabetic individuals displayed a unique response to iAs exposure with 59 altered metabolites including those that play a role in tricarboxylic acid cycle and amino acid metabolism. Taken together, these data highlight the broad impact of iAs exposure on the human metabolome, and demonstrate some specificity of the metabolomic response between diabetic and nondiabetic individuals. These data may provide novel insights into the mechanisms and phenotype of diabetes associated with iAs exposure.

Background: A growing number of studies link chronic exposure to inorganic arsenic (iAs) with the risk of diabetes. Many of these studies assessed iAs exposure by measuring arsenic (As) species in urine. However, this approach has been criticized because of uncertainties associated with renal function and urine dilution in diabetic individuals. Objectives: Our goal was to examine associations between the prevalence of diabetes and concentrations of As species in exfoliated urothelial cells (EUC) as an alternative to the measures of As in urine. Methods: We measured concentrations of trivalent and pentavalent iAs methyl-As (MAs) and dimethyl-As (DMAs) species in EUC from 374 residents of Chihuahua, Mexico, who were exposed to iAs in drinking water. We used fasting plasma glucose, glucose tolerance tests, and self-reported diabetes diagnoses or medication to identify diabetic participants. Associations between As species in EUC and diabetes were estimated using logistic and linear regression, adjusting for age, sex, and body mass index. Results: Interquartile-range increases in trivalent, but not pentavalent, As species in EUC were positively and significantly associated with diabetes, with ORs of 1.57 (95% CI: 1.19, 2.07) for iAsIII, 1.63 (1.24, 2.15) for MAsIII, and 1.31 (0.96, 1.84) for DMAsIII. DMAs/MAs and DMAs/iAs ratios were negatively associated with diabetes (OR = 0.62; 95% CI: 0.47, 0.83 and OR = 0.72; 95% CI: 0.55, 0.96, respectively). Conclusions: Our data suggest that uncertainties associated with measures of As species in urine may be avoided by using As species in EUC as markers of iAs exposure and metabolism. Our results provide additional support to previous findings suggesting that trivalent As species may be responsible for associations between diabetes and chronic iAs exposure. Citation: Currier JM, Ishida MC, González-Horta C, Sánchez-Ramírez B, Ballinas-Casarrubias L, Gutiérrez-Torres DS, Hernández Cerón R, Viniegra Morales D, Baeza Terrazas FA, Del Razo LM, García-Vargas GG, Saunders RJ, Drobná Z, Fry RC, Matoušek T, Buse JB, Mendez MA, Loomis D, Stýblo M. 2014. Associations between arsenic species in exfoliated urothelial cells and prevalence of diabetes among residents of Chihuahua, Mexico. Environ Health Perspect 122:1088–1094; http://dx.doi.org/10.1289/ehp.1307756

Background. Obesity and pregnancy increase levels of maternal oxidative stress (OS). However, little is known about the maternal, placental, and neonatal OS status. Objective. To analyze the relation between prepregnancy obesity and the expression of OS markers and antioxidant capacity in the fetomaternal unit and their association with dietary intake. Methods. This cross-sectional study included 33 women with singleton, noncomplicated pregnancies. Two groups were formed: women with prepregnancy body mass index (pBMI) within normal range (18.5-24.9 kg/m², n = 18) and women with pBMI ≥ 30 kg/m², suggestive of obesity (n = 15). Dietary and clinical information was obtained by questionnaire and from clinical records. Total antioxidant capacity (TAC) and malondialdehyde (MDA) concentration were measured on maternal and cord serum by colorimetric techniques, and placental expression of glutathione peroxidase 4 (GPx4) was measured by immunohistochemistry. Results. Placental GPx4 expression was lower in the group with pBMI suggestive of obesity than in the normal weight group (ß = -0.08, p = 0.03, adjusted for gestational age and magnesium intake). Concentrations of TAC and MDA in maternal and cord blood were not statistically different between groups (p>0.05). Cord MDA concentration was related to maternal MDA concentration (ß = 0.40, p < 0.01), vitamin A intake (tertile 2: ß = -0.04, p = 0.40, tertile 3: ß = 0.13, p = 0.03, vs tertile 1), and placental GPx4 expression (ß = -0.09, p = 0.02). Conclusion. Prepregnancy obesity is associated with a decrease in GPx4 expression in the placenta, which is related to OS in the newborn. The influence of micronutrient intake on OS biomarkers highlights the importance of nutritional assessment during pregnancy and adequate prenatal care.