Retroelement-Age Clocks: Epigenetic Age Captured by Human Endogenous Retrovirus and LINE-1 DNA methylation states.

Human endogenous retroviruses (HERVs), the remnants of ancient viral infections embedded within the human genome, and long interspersed nuclear elements 1 (LINE-1), a class of autonomous retrotransposons, are silenced by host epigenetic mechanisms including DNA methylation. The resurrection of particular retroelements has been linked to biological aging. Whether the DNA methylation states of locus specific HERVs and LINEs can be used as a biomarker of chronological age in humans remains unclear. We show that highly predictive epigenetic clocks of chronological age can be constructed from retroelement DNA methylation states in the immune system, across human tissues, and pan-mammalian species. We found retroelement epigenetic clocks were reversed during transient epigenetic reprogramming, accelerated in people living with HIV-1, responsive to antiretroviral therapy, and accurate in estimating long-term culture ages of human brain organoids. Our findings support the hypothesis of epigenetic dysregulation of retroelements as a potential contributor to the biological hallmarks of aging.

A meta-analysis of immune-cell fractions at high resolution reveals novel associations with common phenotypes and health outcomes.

BACKGROUND: Changes in cell-type composition of tissues are associated with a wide range of diseases and environmental risk factors and may be causally implicated in disease development and progression. However, these shifts in cell-type fractions are often of a low magnitude, or involve similar cell subtypes, making their reliable identification challenging. DNA methylation profiling in a tissue like blood is a promising approach to discover shifts in cell-type abundance, yet studies have only been performed at a relatively low cellular resolution and in isolation, limiting their power to detect shifts in tissue composition. METHODS: Here we derive a DNA methylation reference matrix for 12 immune-cell types in human blood and extensively validate it with flow-cytometric count data and in whole-genome bisulfite sequencing data of sorted cells. Using this reference matrix, we perform a directional Stouffer and fixed effects meta-analysis comprising 23,053 blood samples from 22 different cohorts, to comprehensively map associations between the 12 immune-cell fractions and common phenotypes. In a separate cohort of 4386 blood samples, we assess associations between immune-cell fractions and health outcomes. RESULTS: Our meta-analysis reveals many associations of cell-type fractions with age, sex, smoking and obesity, many of which we validate with single-cell RNA sequencing. We discover that naïve and regulatory T-cell subsets are higher in women compared to men, while the reverse is true for monocyte, natural killer, basophil, and eosinophil fractions. Decreased natural killer counts associated with smoking, obesity, and stress levels, while an increased count correlates with exercise and sleep. Analysis of health outcomes revealed that increased naïve CD4 + T-cell and N-cell fractions associated with a reduced risk of all-cause mortality independently of all major epidemiological risk factors and baseline co-morbidity. A machine learning predictor built only with immune-cell fractions achieved a C-index value for all-cause mortality of 0.69 (95%CI 0.67-0.72), which increased to 0.83 (0.80-0.86) upon inclusion of epidemiological risk factors and baseline co-morbidity. CONCLUSIONS: This work contributes an extensively validated high-resolution DNAm reference matrix for blood, which is made freely available, and uses it to generate a comprehensive map of associations between immune-cell fractions and common phenotypes, including health outcomes.

Arsenic exposure of child populations in Northern Argentina.

Chronic exposure to inorganic arsenic (As) is associated with numerous adverse effects. Argentina is one of the countries affected by arsenicism; however, there are few studies that evaluate inorganic As exposure and its effects on child population. The aim of this study is to evaluate exposure to As through water and food in child populations living in the provinces of Santiago del Estero and Chaco (n = 101), and to determine the impact of this exposure analysing biomarkers of exposure (urine and hair As contents) and effect [8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG)]. The populations selected live in three areas with different levels of As in the drinking water (Santa Teresa de Carballo, 0.925 mg/L; Taco Pozo, 0.210 mg/L; Jumi Pozo, 0.016 mg/L). The As intakes through water and food are especially high in the areas with the greatest As exposure (Santa Teresa de Carballo, 1575 ±â€¯8 µg/day; Taco Pozo, 386 ±â€¯8 µg/day; Jumi Pozo, 39 ±â€¯1 µg/day). The total As contents in most of the samples of hair (0.11-13.11 mg/kg) and urine (31-4258 µg/g creatinine) are higher than the reference values (hair: 1 mg/kg; urine: 50 µg/g creatinine). The increase in the level of As exposure alters the profile of metabolites in urine, with a decrease of dimethylarsinic acid (10%) and an increase in the percentages of monomethylarsonic acid (4%) and inorganic As (6%). The results also show high values of 8-OHdG (3.7-37.8 µg/g creatinine), a oxidative DNA damage marker, in the two areas with greater As exposure.

Ingestas diarias de selenio a partir de su cuantificación en alimentos cocinados en una región endémica afectada por arsenicismo en Argentina / Daily selenium intakes from quantification in foods cooked in an arsenic-endemic region of Argentina

RESUMEN Cuantificar los niveles de selenio en alimentos cocinados y consumidos en una zona endémica de arsénico y calcular las ingestas diarias para estudiar si contribuyen a disminuir la acción tóxica del arsénico. Se muestrearon n= 38 alimentos consumidos en comedores escolares y en una casa de familia de Taco Pozo. La cuantifícación se realizó con Flow Injection Hydride Generation Atomic Absorption Spectrometry (FI-HG-AAS). Para el cálculo de ingesta se consideró los pesos de las porciones de alimentos consumidos y el peso corporal de referencia para los individuos (adultos y menores) según la edad. Las concentraciones promedios de selenio en los desayunos/meriendas oscilan entre 32,2 a 69,1 ng/g peso húmedo (ph), los almuerzos/cenas entre 14,0 a 67,6 ng/g ph. La ingesta diaria total se encuentra entre 13,0 a 67,4 μg/día. Los desayunos presentaron mayores concentraciones que los almuerzos/cenas. Las ingestas diarias resultaron inferiores a la dosis diaria recomendada a excepción de uno de los puntos muestreados. Se estima que estas dietas no mitigarían los efectos tóxicos del arsénico, aumentando la posibilidad de apariciones de patologías asociadas a éste.

ABSTRACT Quantify selenium levels in cooked and consumed foods in an arsenic endemic area and calculate the daily intakes to study if they contribute to diminish the toxic action of arsenic. We sampled n= 38 foods consumed in school canteens and in a family home in Taco Pozo. Quantification was performed with Flow Injection Hydride Generation Atomic Absorption Spectrometry (FI-HG-AAS). The weights of the portions of food consumed and the reference body weight for individuals (adults and minors) according to age were considered for the calculation of intake. We quantified selenium levels in foods cooked and consumed in an arsenic-endemic area and calculated daily intake to study if consumption contributed to a decrease in the toxic activity of arsenic. Thirty-eight foods consumed in school cafeterias and in a family home in Taco Pozo were sampled. Quantification was performed using Flow Injection Hydride Generation Atomic Absorption Spectrometry (FI-HG-AAS). For consumption calculation, we considered portion weight of each food and the body weight of the individuals studied. The average selenium concentration in breakfast / snacks ranged from 32.2 to 69.1 ng/g wet weight (ww) and between 14.0 and 67.6 ng/g ww for lunches/dinners. The total daily intake was between 13.0 and 67.4 μg/day1. The daily intakes were lower than the recommended daily dose except for one of the points sampled. These diets do not help to mitigate the toxic effects of arsenic, thus increasing the possibility of occurrences of associated pathologies.

Afectación de las funciones cognitivas y motoras en niños residentes de zonas rurales de Jujuy y su relación con plaguicidas inhibidores de la colinesterasa: Un estudio piloto / Impairment of cognitive and motor functions in children from rural areas of Jujuy, and its relationship with cholinesterase inhibitor pesticides: A pilot study

El objetivo de este trabajo fue estudiar el efecto de la exposición a plaguicidas en las funciones cognitivas y motoras de 42 niños de una zona rural con mayor probabilidad de exposición a plaguicidas organofosforados y carbámicos (Yuto, Jujuy). Los resultados de las pruebas realizadas para estudiar el efecto fueron comparados con los resultados obtenidos con 29 niños con menor exposición a plaguicidas (León, Jujuy). A todos los participantes se les realizó historia clínica, evaluación médica, revisión de antecedentes, pruebas neuroconductuales, de motricidad gruesa y equilibrio, y medición de biomarcadores (colinesterasa plasmática y eritrocitaria). Se realizó una historia clínica neurológica estándar con las siguientes pruebas: Subtest de Dígitos y Símbolos, Subtest de Recuerdo de Dígitos, Subtest de Laberinto del WISC-III de Wechsler. En la prueba de Laberintos realizada en el presente estudio se observan diferencias entre las localidades y se comprobó una relación lineal inversa entre los años de residencia y la puntuación de la prueba. Se observó reducción en las actividades de acetilcolinesterasas en los niños pertenecientes a Yuto. No se observó una correlación signifca-tiva entre los niveles de actividad de las enzimas y el rendimiento en la prueba, para ninguna de las dos localidades. Los resultados señalaron la probabilidad de que la exposición crónica a bajas dosis de plaguicidas pudiera estar dañando algunas funciones cognitivas y que esto dependería de la duración de la exposición. Por falta de correlación entre las actividades de las enzimas y los resultados adversos en las pruebas neuroconductuales de motricidad y de equilibrio, no fue evidente una asociación entre ambos.

The aim of this research was to study the effects of these toxics on the cognitive and motor functions of a group of 42 children of a rural town with high percentage of exposure to organophosphate and carbamic pesticide (Yuto) and compare the results with a group of 29 children with low percentage of exposure to pesticides. In both cases a research of the patients history was done, a medical revision and a full checkup including neurobehavioral tests, motor and balance tests and biomarkers levels (plasma pseudocholinesterase and erythrocyte cholinesterase). The behavioral assessment was performed by a standard neurological clinic history, a digital and symbol subtest, a digital memory, a maze test, intelligence test WISC-III of Wechsler and gross motor and balance tests. In the group from Yuto, Pearson correlations were done between the years of residency and the neurobehavioral tests and the linear correlation between the years of residency and the acetylcholinesterase activities. In the maze test results there were differences between the two towns and it was proved an inverse lineal relation between the years of residency and the tests scores. It was also observed a reduction in the acetylcholinesterase activities both erythrocyte and plasma in the children from Yuto. Nevertheless there were not signifcant correlations between the levels of enzyme activities and the performance in the tests for neither of the towns. The results achieved did not point out that chronic exposure to low-dose pesticides can produce cognitive malfunctions, such as psychomotor problems. The lack of correlations between the activities of the acetylcholinesterase enzyme and the negative results of the neurobehavioral motor and balance tests couldn´t be associated.

Afectación de las funciones cognitivas y motoras en niños residentes de zonas rurales de Jujuy y su relación con plaguicidas inhibidores de la colinesterasa: Un estudio piloto / Impairment of cognitive and motor functions in children from rural areas of Jujuy, and its relationship with cholinesterase inhibitor pesticides: A pilot study

El objetivo de este trabajo fue estudiar el efecto de la exposición a plaguicidas en las funciones cognitivas y motoras de 42 niños de una zona rural con mayor probabilidad de exposición a plaguicidas organofosforados y carbámicos (Yuto, Jujuy). Los resultados de las pruebas realizadas para estudiar el efecto fueron comparados con los resultados obtenidos con 29 niños con menor exposición a plaguicidas (León, Jujuy). A todos los participantes se les realizó historia clínica, evaluación médica, revisión de antecedentes, pruebas neuroconductuales, de motricidad gruesa y equilibrio, y medición de biomarcadores (colinesterasa plasmática y eritrocitaria). Se realizó una historia clínica neurológica estándar con las siguientes pruebas: Subtest de Dígitos y Símbolos, Subtest de Recuerdo de Dígitos, Subtest de Laberinto del WISC-III de Wechsler. En la prueba de Laberintos realizada en el presente estudio se observan diferencias entre las localidades y se comprobó una relación lineal inversa entre los años de residencia y la puntuación de la prueba. Se observó reducción en las actividades de acetilcolinesterasas en los niños pertenecientes a Yuto. No se observó una correlación signifca-tiva entre los niveles de actividad de las enzimas y el rendimiento en la prueba, para ninguna de las dos localidades. Los resultados señalaron la probabilidad de que la exposición crónica a bajas dosis de plaguicidas pudiera estar dañando algunas funciones cognitivas y que esto dependería de la duración de la exposición. Por falta de correlación entre las actividades de las enzimas y los resultados adversos en las pruebas neuroconductuales de motricidad y de equilibrio, no fue evidente una asociación entre ambos.(AU)

The aim of this research was to study the effects of these toxics on the cognitive and motor functions of a group of 42 children of a rural town with high percentage of exposure to organophosphate and carbamic pesticide (Yuto) and compare the results with a group of 29 children with low percentage of exposure to pesticides. In both cases a research of the patients history was done, a medical revision and a full checkup including neurobehavioral tests, motor and balance tests and biomarkers levels (plasma pseudocholinesterase and erythrocyte cholinesterase). The behavioral assessment was performed by a standard neurological clinic history, a digital and symbol subtest, a digital memory, a maze test, intelligence test WISC-III of Wechsler and gross motor and balance tests. In the group from Yuto, Pearson correlations were done between the years of residency and the neurobehavioral tests and the linear correlation between the years of residency and the acetylcholinesterase activities. In the maze test results there were differences between the two towns and it was proved an inverse lineal relation between the years of residency and the tests scores. It was also observed a reduction in the acetylcholinesterase activities both erythrocyte and plasma in the children from Yuto. Nevertheless there were not signifcant correlations between the levels of enzyme activities and the performance in the tests for neither of the towns. The results achieved did not point out that chronic exposure to low-dose pesticides can produce cognitive malfunctions, such as psychomotor problems. The lack of correlations between the activities of the acetylcholinesterase enzyme and the negative results of the neurobehavioral motor and balance tests couldn´t be associated.(AU)

Determinación de fluoruro en aguas de Rinconadillas (Provincia de Jujuy) / Determination of the presence of fluorides in groundwaters to Rinconadillas (Jujuy)

El objetivo de la investigación fue determinar la presencia de fluoruros de aguas procedentes de vertientes y pozos cavados en la localidad de Rinconadillas de la Puna Jujeña. Dicha región fue seleccionada debido a que se quería corroborar la presencia de fluoruros, encontrados en la década del ‘80 por el organismo Agua Potable de la provincia de Jujuy, como así también ver si existía variación en la concentración de este contaminante natural en el transcurso del tiempo. La evaluación se realizó sobre 11 muestras de agua de vertientes y de pozos, que representan la totalidad de las fuentes en toda la localidad de Rinconadillas y alrededores. Otras 9 muestras fueron tomadas de Purmamarca, Tumbaya, Volcán, San Salvador de Jujuy y Palpalá, localidades que se alejan de Rinconadillas. Estas muestras consideradas testigos fueron seleccionadas sabiendo que, en estudios realizados anteriormente, no contenían fluoruros. De la totalidad de las muestras recolectadas en Rinconadillas, el 82 % superó el límite máximo recomendado por el Código Alimentario Argentino mientras que menos del 10% se encontraron por debajo de lo reglamentado. Las concentraciones de esta zona fueron superiores a las registradas en las muestras tomadas como referencias, determinándose diferencias significativas entre ambos grupos (p = 0,001). De las muestras testigos sólo una superó el límite superior recomendado por el Código Alimentario Argentino. Algunas de las concentraciones determinadas en el presente estudio fueron mayores a los registros de 15 años atrás y podrían indicar una variación creciente en el tiempo. Se ha observado que la población se ha dispersado en las cercanías a Rinconadillas con nuevas fuentes de aguas de bebida, que sólo reciben una eventual cloración. Se ha observado también en la población del lugar una marcada fluorosis dentalque debería ser evaluada clínica y epidemiológicamente.

The aim of this study was to determine the presence of fluorides in groundwaters from springs and wells belonging to Rinconadillas, a small town located in “La Puna” in the Province of Jujuy. This region was selected because fluoride has been detected during the '80 by Jujuy Water Agency and a comparative study of fluoride levels would provide information about the variation of concentrations of this “natural” contaminant along the time. In “La Puna” the study was conducted on eleven samples of groundwaters from springs and wells from Rinconadilllas and its surroundings. Nine further samples were obtained in Purmamarca, Tumbaya, Volcán, San Salvador de Jujuy and Palpalá, all ofthem far from Rinconadillas. Those samples were selected as prior studies determined that water from such towns does not contain fluoride. Eighty two percent of all the samples collected in Rinconadillas exceeded fluoride limits stated by Argentine Legislation (AL), while less than ten percent of the samples are below the stated values. Fluoride levels from this area were higher than the levels for the reference samples. For the blank samples, only one exceeds the maximum allowed level. Fluoride levels found in this study were higher than those coming from samples that have been analyzed 15 years ago indicating that fluoride levels in waters are increasing. It has also been observed that the population has moved to Rinconadillas surroundings having a drinking water form newsource that is only eventually chlorinated. A remarkable dental fluorosis is observed in the population, which should be clinically and epidemiologically assessed.