Arsenic in brown rice: do the benefits outweigh the risks?

Brown rice has been advocated for as a healthier alternative to white rice. However, the concentration of arsenic and other pesticide contaminants is greater in brown rice than in white. The potential health risks and benefits of consuming more brown rice than white rice remain unclear; thus, mainstream nutritional messaging should not advocate for brown rice over white rice. This mini-review aims to summarize the most salient concepts related to dietary arsenic exposure with emphasis on more recent findings and provide consumers with evidence of both risks and benefits of consuming more brown rice than white rice. Despite risk-benefit assessments being a challenging new frontier in nutrition, researchers should pursue an assessment to validate findings and solidify evidence. In the interim, consumers should be cognizant that the dose of arsenic exposure determines its toxicity, and brown rice contains a greater concentration of arsenic than white rice.

Geospatial Assessment of Pesticide Concentration in Ambient Air and Colorectal Cancer Incidence in Arkansas, 2013-2017.

Exposure to various agricultural pesticides has been linked to colorectal cancer (CRC), mostly among farmworkers and applicators. Given the potential pesticide drift in ambient air, residents near farmland may be exposed to carcinogenic pesticides even if they are not actively engaged in pesticide application. Pesticide air pollution at the county level was estimated using the 2014 National Air Toxics Assessment. CRC incidence data were acquired from the Arkansas Central Cancer Registry for 2013-2017. We ran ordinary least squares (OLS) regression models, finding significant spatial autocorrelation of residuals for most models. Using geographically weighted regression (GWR) we found age-adjusted CRC incidence rates vary in an increasing west-to-east gradient, with the highest rates in the Arkansas Delta region. A similar gradient was observed in the distribution of the population living below the poverty line and the population percentage of Black people. Significant associations between Trifluralin (crude model only), Carbon Tetrachloride, and Ethylene Dibromide with CRC incidence rates in OLS models only explained 5-7% of the variation and exhibited spatial autocorrelation of residuals. GWR models explained 24-32% (adjusted r2 9-16%) of CRC incidence rate variation, suggesting additional factors may contribute to the association between pesticides and CRC.

Association Between Household Income and Self-Perceived Health Status and Poor Mental and Physical Health Among Cancer Survivors.

Background: Health-related quality of life (HRQoL) is multidimensional and is composed of, at a minimum, self-perceived health status, physical functioning, and psychological well-being. HRQoL measures reflect the extent of disability and dysfunction associated with a chronic disease such as cancer. The objective of this study is to examine factors associated with HRQoL among cancer survivors. Methods: Data from the 2009 Behavioral Risk Factor Surveillance System survey was used to examine factors associated with HRQoL among participants who reported having ever been diagnosed with cancer. Four questions associated with HRQoL included self-perceived health status, number of bad physical health days, and number of bad mental health days per month. Least square regression and logistic regression models, adjusted for confounding variables, were used for an ordinal and dichotomous [5 (bad) vs. 1-4 (excellent, very good, good, fair)] scale of HRQoL, respectively. Results: Fifty nine thousand one hundred seventy three participants reported having ever been diagnosed with cancer. Adjusted mean self-perceived health status (5-point scale) among survivors of thyroid, colon, lung, cervical, breast, prostate, and ovarian cancer was 3.83 (0.05), 4.02 (0.04), 4.36 (0.06), 3.77 (0.03), 3.88 (0.03), 3.78 (0.04), and 3.96 (0.05), respectively. After adjusting for confounders, a positive dose-response effect was observed between income range and all three HRQoL measures across all seven cancer sites. Income was consistently and inversely associated with a higher chance for reporting poorer HRQoL [OR: 0.64, 95% CI: 0.57-0.71], [OR: 0.63, 95% CI: 0.48-0.82], [OR: 0.67, 95% CI: 0.56-0.80], [OR: 0.69, 95% CI: 0.56-0.86], [OR: 0.55, 95% CI: 0.49-0.62], [OR:0.55, 95% CI: 0.44-0.69], [OR: 0.75, 95% CI: 0.62-0.91] among those with thyroid, colon, lung, cervical, breast, prostate, and ovarian cancer, respectively. Discussion: This study found that income range was associated with HRQoL among cancer survivors. It is plausible that financial resources may lessen the overall burden of cancer survivors, which could improve health-related quality of life among cancer survivors.

Low­Level Environmental Heavy Metals are Associated with Obesity Among Postmenopausal Women in a Southern State.

Both arsenic and cadmium are reported to be toxic to humans. The use of saliva as a biomarker of low-level exposures to these elements has not been adequately explored, and the putative relationship between exposure and obesity is unclear. This cross-sectional study aims to investigate the relationship between salivary arsenic and cadmium concentrations and their association with obesity. Arsenic and cadmium concentrations were analyzed in human saliva samples by Inductively Coupled Plasma-Mass Spectrometry on 270 randomly selected women who participated in the Arkansas Rural Community Health Study. Multivariable logistic regression was performed to evaluate the association between heavy metal concentrations and obesity. Stratified logistic regression was performed based on menopausal status. Generalized linear models were used to evaluate weight gain velocity. Significant positive associations were observed in postmenopausal women for both arsenic (OR = 4.43, 95% CI 1.91-10.28) and cadmium (OR = 2.72, 95% CI 1.23-5.99) concentrations, as well as significant trends among tertiles (p < 0.01 and p = 0.01, respectively). No relationship with obesity was evident among premenopausal women for either metal. A dose-response relationship was observed between increasing weight gain velocity and increasing metal concentrations. At concentrations well below governmental and industrial standards for acute toxicity, significant associations between obesity and concentration of these heavy metals are evident. The rate at which individuals gain weight is affected by metal concentrations and may play a role in the rapid increase in weight in postmenopausal women. These results might explain, in part, the missing variability in the increasing obesity pandemic in certain population exposed to these environmental toxicants.

Epigenetic Control of Cdkn2a.Arf Protects Tumor-Infiltrating Lymphocytes from Metabolic Exhaustion.

T-cell exhaustion in cancer is linked to poor clinical outcomes, where evidence suggests T-cell metabolic changes precede functional exhaustion. Direct competition between tumor-infiltrating lymphocytes (TIL) and cancer cells for metabolic resources often renders T cells dysfunctional. Environmental stress produces epigenome remodeling events within TIL resulting from loss of the histone methyltransferase EZH2. Here, we report an epigenetic mechanism contributing to the development of metabolic exhaustion in TIL. A multiomics approach revealed a Cdkn2a.Arf-mediated, p53-independent mechanism by which EZH2 inhibition leads to mitochondrial dysfunction and the resultant exhaustion. Reprogramming T cells to express a gain-of-function EZH2 mutant resulted in an enhanced ability of T cells to inhibit tumor growth in vitro and in vivo. Our data suggest that manipulation of T-cell EZH2 within the context of cellular therapies may yield lymphocytes that are able to withstand harsh tumor metabolic environments and collateral pharmacologic insults. SIGNIFICANCE: These findings demonstrate that manipulation of T-cell EZH2 in cellular therapies may yield cellular products able to withstand solid tumor metabolic-deficient environments. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/21/4707/F1.large.jpg.

Effect of Sulforaphane and 5-Aza-2'-Deoxycytidine on Melanoma Cell Growth.

Background: UV exposure-induced oxidative stress is implicated as a driving mechanism for melanoma. Increased oxidative stress results in DNA damage and epigenetic dysregulation. Accordingly, we explored whether a low dose of the antioxidant sulforaphane (SFN) in combination with the epigenetic drug 5-aza-2'-deoxycytidine (DAC) could slow melanoma cell growth. SFN is a natural bioactivated product of the cruciferous family, while DAC is a DNA methyltransferase inhibitor. Methods: Melanoma cell growth characteristics, gene transcription profiles, and histone epigenetic modifications were measured after single and combination treatments with SFN and DAC. Results: We detected melanoma cell growth inhibition and specific changes in gene expression profiles upon combinational treatments with SFN and DAC, while no significant alterations in histone epigenetic modifications were observed. Dysregulated gene transcription of a key immunoregulator cytokine-C-C motif ligand 5 (CCL-5)-was validated. Conclusions: These results indicate a potential combinatorial effect of a dietary antioxidant and an FDA-approved epigenetic drug in controlling melanoma cell growth.

Human uterine smooth muscle and leiomyoma cells differ in their rapid 17beta-estradiol signaling: implications for proliferation.

Uterine leiomyomas, benign uterine smooth muscle tumors that affect 30% of reproductive-aged women, are a significant health concern. The initiation event for these tumors is unclear, but 17beta-estradiol (E2) is an established promoter of leiomyoma growth. E2 not only alters transcription of E2-regulated genes but also can rapidly activate signaling pathways. The aim of our study is to investigate the role of rapid E2-activated cytoplasmic signaling events in the promotion of leiomyomas. Western blot analysis revealed that E2 rapidly increases levels of phosphorylated protein kinase C alpha (PKC alpha) in both immortalized uterine smooth muscle (UtSM) and leiomyoma (UtLM) cell lines, but increases levels of phosphorylated ERK1/2 only in UtLM cells. Our studies demonstrate a paradoxical effect of molecular and pharmacological inhibition of PKC alpha on ERK1/2 activation and cellular proliferation in UtLM and UtSM cells. PKC alpha inhibition decreases levels of phosphorylated ERK1/2 and proliferation in UtLM cells but raises these levels in UtSM cells. cAMP-PKA signaling is rapidly activated only in UtSM cells with E2 and inhibits ERK1/2 activation and proliferation. We therefore propose a model whereby E2's rapid activation of PKC alpha and cAMP-PKA signaling plays a central role in the maintenance of a low proliferative index in normal uterine smooth muscle via its inhibition of the MAPK cascade and these pathways are altered in leiomyomas to promote MAPK activation and proliferation. These studies demonstrate that rapid E2-signaling pathways contribute to the promotion of leiomyomas.

Developmental diethylstilbestrol exposure alters genetic pathways of uterine cytodifferentiation.

The formation of a simple columnar epithelium in the uterus is essential for implantation. Perturbation of this developmental process by exogenous estrogen, such as diethylstilbestrol (DES), results in uterine metaplasia that contributes to infertility. The cellular and molecular mechanism underlying this transformation event is not well understood. Here we use a combination of global gene expression analysis and a knockout mouse model to delineate genetic pathways affected by DES. Global gene expression profiling experiment revealed that neonatal DES treatment alters uterine cell fate, particularly in the luminal epithelium by inducing abnormal differentiation, characterized by the induction of stratified epithelial markers including members of the small proline-rich protein family and epidermal keratins. We show that Msx2, a homeodomain transcription factor, functions downstream of DES and is required for the proper expression of several genes in the uterine epithelium including Wnt7a, PLAP, and K2.16. Finally, Msx2-/- uteri were found to exhibit abnormal water trafficking upon DES exposure, demonstrating the importance of Msx2 in tissue responsiveness to estrogen exposure. Together, these results indicate that developmental exposure to DES can perturb normal uterine development by affecting genetic pathways governing uterine differentiation.

DNA hypomethylation and imbalanced expression of DNA methyltransferases (DNMT1, 3A, and 3B) in human uterine leiomyoma.

OBJECTIVE: Despite the high prevalence of uterine leiomyoma in women, little is known about the pathophysiology of this tumor. This study intends to define the epigenetic modulation of this tumor. METHODS: Twenty-three pairs of leiomyomas and their adjacent myometria were collected. Status of DNA global methylation was determined by using DNA methyl acceptance assay and immunohistochemistry staining with 5-methylcytidine antibody. MRNA level of DNA methyltransferases (DNMT1, 3A, and 3B) was assessed by quantitative real time PCR. RESULTS: DNA global hypomethylation was detected in the leiomyoma tissues as compared with the adjacent myometria. DNMT1 expression was increased in 47.5% and was equal in 47.5% in leiomyomas compared to the adjacent myometria. On the other hand, over 74% of cases showed decreased expression of DNMT3A and 3B in leiomyomas compared to the adjacent myometria. CONCLUSION: Global hypomethylation and imbalanced expression of DNMTs in uterine leiomyoma suggested a potential mechanism of epigenetic modulation in the development of this tumor.

DDT and its metabolites alter gene expression in human uterine cell lines through estrogen receptor-independent mechanisms.

Endocrine-disrupting organochlorines, such as the pesticide dichlorodiphenyltrichloroethane (DDT), bind to and activate estrogen receptors (ERs), thereby eliciting estrogen-like effects. Although ERs function predominantly through activation of transcription via estrogen-responsive elements, both ERs, alpha and ss, can interact with various transcription factors such as activator protein-1 (AP-1). Additionally, estrogens may regulate early signaling events, suggesting that the biological effects of environmental estrogens may not be mediated through classic ER (alpha and ss) activity alone. We hypothesized that known environmental estrogens, such as DDT and its metabolites, activate AP-1-mediated gene transactivation through both ER-dependent and ER-independent means. Using two Ishikawa human endometrial adenocarcinoma cell line variants that we confirmed to be estrogen responsive [Ishikawa(+)] and estrogen unresponsive [Ishikawa(-)], we generated stably transfected AP-1 luciferase cell lines to identify the role of an estrogen-responsive mechanism in AP-1-mediated gene expression by various stimuli. Our results demonstrate that DDT and dichlorodiphenyldichloroethane (DDD) were the most potent activators of AP-1 activity; 2,2-bis(p-chlorophenyl) acetic acid failed to activate. Although stimulated in both Ishikawa(+) and Ishikawa(-) cells by DDT and its congeners, AP-1 activation was more pronounced in the estrogen-unresponsive Ishikawa(-) cells. In addition, DDT, DDD, and dichlorodiphenyldichloroethylene (DDE) could also stimulate AP-1 activity in the estrogen-unresponsive human embryonic kidney 293 cells using a different promoter context. Thus, our data demonstrate that DDT and its metabolites activate the AP-1 transcription factor independent of ER (alpha or ss) status.