Association of Global DNA Methylation and Global DNA Hydroxymethylation with Metals and Other Exposures in Human Blood DNA Samples

Background: The association between human blood DNA global methylation and global hydroxymethylation has not been evaluated in population-based studies. No studies have evaluated environmental determinants of global DNA hydroxymethylation, including exposure to metals.Objective: We evaluated the association between global DNA methylation and global DNA hydroxymethylation in 48 Strong Heart Study participants for which selected metals had been measured in urine at baseline and DNA was available from 1989–1991 (visit 1) and 1998–1999 (visit 3).Methods: We measured the percentage of 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in samples using capture and detection antibodies followed by colorimetric quantification. We explored the association of participant characteristics (i.e., age, adiposity, smoking, and metal exposure) with both global DNA methylation and global DNA hydroxymethylation.Results: The Spearman’s correlation coefficient for 5-mC and 5-hmC levels was 0.32 (p = 0.03) at visit 1 and 0.54 (p < 0.001) at visit 3. Trends for both epigenetic modifications were consistent across potential determinants. In cross-sectional analyses, the odds ratios of methylated and hydroxymethylated DNA were 1.56 (95% CI: 0.95, 2.57) and 1.76 (95% CI: 1.07, 2.88), respectively, for the comparison of participants above and below the median percentage of dimethylarsinate. The corresponding odds ratios were 1.64 (95% CI: 1.02, 2.65) and 1.16 (95% CI: 0.70, 1.94), respectively, for the comparison of participants above and below the median cadmium level. Arsenic exposure and metabolism were consistently associated with both epigenetic markers in cross-sectional and prospective analyses. The positive correlation of 5-mC and 5-hmC levels was confirmed in an independent study population.Conclusions: Our findings support that both epigenetic measures are related at the population level. The consistent trends in the associations between these two epigenetic modifications and the characteristics evaluated, especially arsenic exposure and metabolism, suggest the need for understanding which of the two measures is a better biomarker for environmental epigenetic effects in future large-scale epidemiologic studies.Citation: Tellez-Plaza M, Tang WY, Shang Y, Umans JG, Francesconi KA, Goessler W, Ledesma M, Leon M, Laclaustra M, Pollak J, Guallar E, Cole SA, Fallin MD, Navas-Acien A. 2014. Association of global DNA methylation and global DNA hydroxymethylation with metals and other exposures in human blood DNA samples. Environ Health Perspect 122:946–954; http://dx.doi.org/10.1289/ehp.1306674     

Caloric beverage drinking patterns are differentially associated with diet quality and adiposity among Spanish girls and boys

The present study assesses the impact of beverage consumption pattern on diet quality and anthropometric proxy measures for abdominal adiposity in Spanish adolescents. Data were obtained from a representative national sample of 1,149 Spanish adolescents aged 10–18 years. Height, weight, and waist circumferences were measured. Dietary assessment was performed with a 24-h recall. Beverage patterns were identified by cluster analysis. Adherence to the Mediterranean diet was measured by the KIDMED index. Three beverage clusters were identified for boys—“whole milk” (62.5 %), “low-fat milk” (17.5 %) and “soft drinks” (20.1 %)—and for girls—^“whole milk” (57.8 %), “low-fat milk” (20.8 %) and juice (21.4 %), accounting for 8.3, 9.6, 13.9, 8.6, 11.5 and 12.9 % of total energy intake, respectively. Each unit of increase in the KIDMED index was associated with a 14.0 % higher (p?=?0.004) and 11.0 % lower (p?=?0.048) probability of membership in the “low-fat milk” and “soft drinks” cluster in girls and boys, respectively, compared with the “whole milk” cluster. Boys in the “soft drinks” cluster had a higher risk of 1-unit increase in BMI z score (29.0 %, p?=?0.040), 1-cm increase in waist circumference regressed on height and age (3.0 %, p?=?0.027) and 0.1-unit increase in waist/height ratio (21.4 %, p?=?0.031) compared with the “whole milk” cluster. Conclusion: A caloric beverage pattern dominated by intake of “soft drinks” is related to general and abdominal adiposity and diet quality in Spanish male adolescents.     

Lung cancer mortality among males of Catalonia and Spain compared with other European countries between 1975–1977 and 1987–1989

This study compares the lung cancer mortality rates among males in the years 1975–1977 and 1987–1989 in Catalonia and Spain with other European countries selected for their geographical proximity. Adjusted calculations using the direct method have been made for male lung cancer mortality. Adjusted truncated rates for the age groups 0–44, 45–64 and more than 65 years were also calculated, as well as percent differences between the mortality rates of each period studied. Lung cancer mortality rates for males in Catalonia and Spain show relative increments of 46.58% and 52.41%, respectively. In contrast, lung cancer mortality in countries such as England-Wales and Switzerland have decreased. Moreover, the 0–44 year age group in Catalonia and Spain shows the absolute highest rates in the 1987–1989 period among all the countries analyzed. The marked contrast of the lung cancer mortality rate evolution in Catalonia and Spain compared with some other European countries and the considerable increase of the mortality in younger age groups indicate the need to intensify lung cancer control measures. © 1996 Wiley-Liss, Inc.     

Axon reflexes or ephaptic responses simulating blink reflex R1 after XII-VII nerve anastomosis

It has been claimed that functional recovery of the blink reflex occurs after hypoglossal-facial nerve anastomosis. This has been explained through central nervous system plasticity and reorganization of neuronal connections. In 5 patients with reinnervated facial muscles after hypoglossal-facial nerve anastomosis, we observed “R1-like” responses that fulfilled criteria for facial nerve axon reflexes or ephapses. First, displacement of the stimulating electrode from the supraorbital to the zygomatic area shortened the latency of the evoked response. Second, these responses were stable (jitter mean consecutive difference < 25 μs) and they had complex potential shapes unmodified by high-frequency stimulation. Finally, collision techniques demonstrated antidromic conduction of impulses in the facial nerve from supraorbital to zygomatic points. Therefore, these “R1-like” responses are not the early component of a functionally recovered blink reflex but motor axon reflexes or ephaptic responses similar to the short latency responses observed following facial nerve regeneration or from sutured nerves in human forearms. © 1996 John Wiley & Sons, Inc.     

Gene expression profiles of breast cancer metastasis according to organ site

In advanced breast cancer, biomarker identification and patient selection using a metastatic tumor biopsy is becoming more necessary. However, the biology of metastasis according to the organ site is largely unknown. Here, we evaluated the expression of 771 genes in 184 metastatic samples across 11 organs, including liver, lung, brain, and bone, and made the following observations. First, all PAM50 molecular intrinsic subtypes were represented across organs and within immunohistochemistry‐based groups. Second, HER2‐low disease was identified across all organ sites, including bone, and HER2 expression significantly correlated with ERBB2 expression. Third, the majority of expression variation was explained by intrinsic subtype and not organ of metastasis. Fourth, subtypes and individual subtype‐related genes/signatures were significantly associated with overall survival. Fifth, we identified 74 genes whose expression was organ‐specific and subtype‐independent. Finally, immune profiles were found more expressed in lung compared to brain or liver metastasis. Our results suggest that relevant tumor biology can be captured in metastatic tissues across a variety of organ sites; however, unique biological features according to organ site were also identified and future studies should explore their implications in diagnostic and therapeutic interventions.     

Intensive Medical Nutrition Therapy Alone or with Added Metformin to Prevent Gestational Diabetes Mellitus among High-Risk Mexican Women: A Randomized Clinical Trial

The aim of this study was to examine the efficacy of intensive medical nutrition therapy (MNT) plus metformin in preventing gestational diabetes mellitus (GDM) among high-risk Mexican women. An open-label randomized clinical trial was conducted. Inclusion criteria were pregnant women with three or more GDM risk factors: Latino ethnic group, maternal age >35 years, body mass index >25 kg/m², insulin resistance, and a history of previous GDM, prediabetes, a macrosomic neonate, polycystic ovarian syndrome, or a first-degree relative with type 2 diabetes. Women before 15 weeks of gestation were assigned to group 1 (n = 45): intensive MNT-plus metformin (850 mg twice/day) or group 2 (n = 45): intensive MNT without metformin. Intensive MNT included individual dietary counseling, with ≤50% of total energy from high carbohydrates. The primary outcome was the GDM incidence according to the International Association of Diabetes Pregnancy Study Groups criteria. There were no significant differences in baseline characteristics and adverse perinatal outcomes between the groups. The GDM incidence was n = 11 (24.4%) in the MNT plus metformin group versus n = 7 (15.5%) in the MNT without metformin group: p = 0.42 (RR: 1.57 [95% CI: 0.67–3.68]). There is no benefit in adding metformin to intensive MNT to prevent GDM among high-risk Mexican women. Clinical trials registration: {"type":"clinical-trial","attrs":{"text":"NCT01675310","term_id":"NCT01675310"}}NCT01675310.     

Targeted Analysis of Tears Revealed Specific Altered Metal Homeostasis in Age-Related Macular Degeneration

PurposeSpecific altered metal homeostasis has been investigated in the tear film of age-related macular degeneration (AMD) patients considering that metal dyshomeostasis contributes to the production of free radicals, inflammation, and apoptosis and results in conformational changes of proteins.MethodsA multitargeted approach based on spectrophotometry and mass spectrometry techniques has been implemented to the multiplexed quantitation of lactoferrin (LF), S100 calcium binding protein A6 (S100A6), metallothionein 1A (MT1A), complement factor H (CFH), clusterin (CLU), amyloid precursor protein (APP), Mg, P, Na, Fe, Cu, Zn, and Ca, in the tear film from 60 subjects, 31 patients diagnosed with the dry form of AMD, and 29 healthy individualsResultsSignificant up-regulations of MT1A (1.9-fold) and S100A6 (1.4-fold) and down-regulations of LF (0.7-fold), Fe (0.6-fold), Mg (0.7-fold), and Cu (0.7-fold) were observed in AMD patients, when compared to control subjects. Of all the studied variables, only APP showed negative correlation with age in the AMD group. Also, positive correlations were observed for the variables Mg and Na, Cu and Mg, and P and Mg in both the AMD and control groups, whereas positive correlations were exclusively determined in the AMD group for Cu and LF, Na and Ca, and Mg and Ca. The panel constituted of MT1A, Na, and Mg predicts AMD disease in 73% of cases.ConclusionsThe different levels of target metals and (metallo-)proteins in the tear film suggest altered metal homeostasis in AMD patients. These observed pathophysiological changes may be related with the anomalous protein aggregation in the macula.