Chronic Fatigue, Physical Impairments and Quality of Life in Women with Endometriosis: A Case-Control Study

The authors are indebted with all participants, without whom this work would not have been possible. We are grateful to Ana Yara Postigo-Fuentes for her assistance with the English language. This paper is part of the PhD thesis developed by A. Lara-Ramos in the Official Doctoral Programme in Clinical Medicine and Public Health of the University of Granada.Aim: To explore endometriosis-related fatigue (ERF), health-related fitness, sleep quality, and health-related quality of life (HRQoL) in women with endometriosis in comparison with matched controls. Methods: Twenty-five affected women and twenty-five age and height-matched women without endometriosis were included. ERF was assessed through the Piper Fatigue Scale; health-related fitness was assessed through the Schöber, flamingo, and 6-min walking tests and dynamometry; and body composition was assessed through impedanciometry. Self-perceived physical fitness, sleep quality, and HRQoL were assessed through the International Fitness Scale, the Pittsburgh Sleep Quality Index, and the 12-item Short Form Health Survey, respectively. Results: Affected women exhibited higher levels of ERF than controls, increased fat mass, and physical deconditioning (reduced back strength, lumbar flexibility, body balance, and functional capacity, p-values < 0.050). Moreover, cases also had poorer perceived physical fitness, sleep quality, and HRQoL (p-value < 0.050). Finally, we observed deteriorated health-related fitness, sleep quality, and HRQoL in those women with endometriosis with higher levels of ERF. Conclusions: This study constitutes the first evidence that women with endometriosis describe a generalized physical deconditioning, even more pronounced in affected women with higher levels of ERF. Further studies assessing the efficacy of rehabilitation interventions to face these physical impairments in women with endometriosis are warranted.Health Institute Carlos III (ISCIII)-FEDER PI17/01743PAIDI group CTS-206University of Granada, Plan Propio de Investigacion 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES)Junta de AndaluciaConsejeria de Conocimiento, Investigacion y UniversidadesEuropean Union (EU) SOMM17/6107/UG

BDNF as a potential mediator between childhood BPA exposure and behavioral function in adolescent boys from the INMA-Granada cohort

This research would not have been achieved without the selfless col-laboration of the INMA-Granada boys and families who took part in the study. Vicente Mustieles, Alicia Olivas-Martinez and Shereen Cynthia D'Cruz were under contract within the HBM4EU project. Additionally, we acknowledge the Biomedical Research Networking Center-CIBER de Epidemiologia y Salud Publica (CIBERESP) , and the Instituto de Salud Carlos III (ISCIII) (FIS-PI16/01820, FIS-PI16/01858, FIS-PI17/01526, and FIS-PI20/01568) . The authors also thank the ISCIII and "Fondo Europeo de Desarrollo Regional" (ISCIII/FEDER) for the Miguel Servet Type I Program granted to C. Freire (grant no. MS16/00085) , the Sara Borrell postdoctoral research contract granted to F. Vela-Soria (grant no. CD17/00212) , and the Spanish Ministry of Education for the predoctoral fellowships (FPU) granted to A. Rodriguez-Carrillo (FPU 16/03011) and to I. Reina-Perez (FPU 17/01848) . Dr. JP Arrebola is under contract within the Ramon y Cajal Program (RYC-2016-20155, from Ministerio de Economia, Industria y Competitividad, Spain) . The authors also ac-knowledge the contribution of the Pediatric Unit of San Cecilio University Hospital of Granada (recruitment and clinical evaluation) , Marina Molina (field work and biospecimen processing) , Raquel Quesada and Beatriz Suarez (chemical exposure data) and Mario Murcia (data curation) , as well as the Human Genotyping Laboratory at the Spanish National Cancer Research Centre, CeGen-PRB3, which is sup-ported by grant no. PT17/0019, of the PE I + D + i 2013-2016, funded by Instituto de Salud Carlos III (ISCIII) and ERDF. This article will be part of the doctoral thesis developed by Andrea Rodriguez-Carrillo in the context of the "Clinical Medicine and Public Health Program" of the University of Granada (Spain) .This study was supported in part by the European Union's Horizon 2020 research and innovation program HBM4EU [Grant Agreement No. 733032], Biomedical Research Networking Center-CIBER de Epidemiología y Salud Pública (CIBERESP), and the Instituto de Salud Carlos III (ISCIII) [Grant no. CP16/00085 and FIS-PI17/01526]. The funders had no role in the study design, data collection or analysis, decision to publish, or preparation of the manuscript. Funding for open access charge: Universidad de Granada / CBUA.Background: Bisphenol A (BPA) exposure has been linked to altered behavior in children. Within the European Human Biomonitoring Initiative (HBM4EU), an adverse outcome pathway (AOP) network was constructed supporting the mechanistic link between BPA exposure and brain-derived neurotrophic factor (BDNF). Objective: To test this toxicologically-based hypothesis in the prospective INMA-Granada birth cohort (Spain). Methods: BPA concentrations were quantified by LC-MS/MS in spot urine samples from boys aged 9-11 years, normalized by creatinine and log-2 transformed. At adolescence (15-17 years), blood and urine specimens were collected, and serum and urinary BDNF protein levels were measured using immunoassays. DNA methylation levels at 6 CpGs in Exon IV of the BDNF gene were also assessed in peripheral blood using bisulfite-pyrosequencing. Adolescent's behavior was parent-rated using the Child Behavior Checklist (CBCL/6-18) in 148 boys. Adjusted linear regression and mediation models were fit. Results: Childhood urinary BPA concentrations were longitudinally and positively associated with thought problems (beta = 0.76; 95% CI: 0.02, 1.49) and somatic complaints (beta = 0.80; 95% CI: -0.16, 1.75) at adolescence. BPA concentrations were positively associated with BDNF DNA methylation at CpG6 (beta = 0.21; 95% CI: 0.06, 0.36) and mean CpG methylation (beta = 0.10; 95% CI: 0.01, 0.18), but not with total serum or urinary BDNF protein levels. When independent variables were categorized in tertiles, positive dose-response associations were observed between BPA-thought problems (p-trend = 0.08), BPA-CpG6 (p-trend <_ 0.01), and CpG6-thought problems (p-trend <_ 0.01). A significant mediated effect by CpG6 DNA methylation was observed (beta = 0.23; 95% CI: 0.01, 0.57), accounting for up to 34% of the BPA-thought problems association. Conclusions: In line with toxicological studies, BPA exposure was longitudinally associated with increased BDNF DNA methylation, supporting the biological plausibility of BPA-behavior relationships previously described in the epidemiological literature. Given its novelty and preliminary nature, this effect biomarker approach should be replicated in larger birth cohorts.Instituto de Salud Carlos III"Fondo Europeo de Desarrollo Regional" (ISCIII/FEDER) MS16/00085Sara Borrell postdoctoral research contract grant CD17/00212Spanish Government FPU 16/03011- FPU 17/01848Ramon y Cajal Program (Ministerio de Economia, Industria y Competitividad, Spain) RYC-2016-20155Human Genotyping Laboratory at the Spanish National Cancer Research Centre, CeGen-PRB3 PT17/0019Instituto de Salud Carlos III European CommissionEuropean Commissio

‘Physio-EndEA’ Study: A Randomized, Parallel-Group Controlled Trial to Evaluate the Effect of a Supervised and Adapted Therapeutic Exercise Program to Improve Quality of Life in Symptomatic Women Diagnosed with Endometriosis

This research was funded by the Health Institute Carlos III (FEDER funds), grant number PI17/01743, and donations from particular endometriosis women that believed in this project from the beginning. It was also partly supported by funds from the PAIDI group CTS-206 (Oncologia Basica y Clinica). This study takes place thanks to the additional funding from the University of Granada, Plan Propio de Investigacion 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES).Aim: The ‘Physio-EndEA’ study aims to explore the potential benefits of a therapeutic exercise program (focused on lumbopelvic stabilization and tolerance to exertion) on the health-related quality of life (HRQoL) of symptomatic endometriosis women. Design: The present study will use a parallel-group randomized controlled trial design. Methods: A total of 22 symptomatic endometriosis women will be randomized 1:1 to the Physio-EndEA or usual care groups. The ‘Physio-EndEA’ program will consist of a one-week lumbopelvic stabilization learning phase followed by an eight-week phase of stretching, aerobic and resistance exercises focused on the lumbopelvic area that will be sequentially instructed and supervised by a trained physiotherapist (with volume and intensity progression) and adapted daily to the potential of each participant. The primary outcome measure is HRQoL. The secondary outcome measures included clinician-reported outcomes (pressure pain thresholds, muscle thickness and strength, flexibility, body balance and cardiorespiratory fitness) and patient-reported outcomes (pain intensity, physical fitness, chronic fatigue, sexual function, gastrointestinal function and sleep quality). Discussion: Findings of this study will help to identify cost-effective non-pharmacological options (such as this exercise-based intervention) that may contribute to the improvement of HRQoL in symptomatic endometriosis women.Health Institute Carlos III (FEDER funds) PI17/01743PAIDI groupUniversity of Granad

Impacto psicosocial y calidad de vida en mujeres con endometriosis: situación actual en España

La endometriosis es una enfermedad ginecológica de carácter benigno que se caracteriza por la proliferación de tejido de naturaleza endometrial fuera de la cavidad uterina, pudiéndose diferenciar distintos estadios clínicos de la enfermedad. Se trata de una enfermedad altamente prevalente con estimaciones que sugieren que ~10% de las mujeres en edad reproductiva podrían padecer esta enfermedad, lo que supone alrededor de 176 millones de mujeres afectadas a nivel mundial. Hasta la fecha, poco se conoce de la etiología y patogénesis de la enfermedad y, por tanto, sobre las opciones de tratamiento. En cualquier caso, la presencia de un microambiente oxidativo e inflamatorio crónico es frecuentemente observado en las zonas afectadas. Además, se ha observado una profusa vascularización e inervación de estas lesiones, lo que parece ser el factor crucial relacionado con la severidad del dolor en estas pacientes. Así, las mujeres con endometriosis generalmente refieren dismenorrea (menstruación dolorosa), dispareunia (dolor durante las relaciones sexuales), disquecia (defecación dolorsa) y disuria (micción) y, en general, dolor en la región pélvica. De hecho, el dolor, considerado en sus múltiples versiones, es reconocido como el síntoma más común e incapacitante en estas pacientes, aunque la carga sintomática de esta enfermedad es altamente variable, lo que repercute en un enorme coste económico para los servicios de salud, con costes (directos+indirectos) que superan los 27.000$/paciente/año en EEUU. Sin embargo, ningún estudio ha abordado el impacto psicosocial y en calidad de vida que causa esta enfermedad en población española. Por ello, esta tesis doctoral trata de analizar el estado psicosocial, el desempeño ocupacional y la calidad de vida de mujeres residentes en el territorio nacional diagnosticadas con endometriosis, así como analizar el papel que juega el dolor y otros síntomas menos conocidos como la fatiga relacionada con la endometriosis en la calidad de vida y el desempeño ocupacional de estas mujeres. Para ello, se llevó a cabo un estudio transversal que incluyó a un total de 230 mujeres de todas las regiones del país con un diagnóstico clínico de endometriosis. Mediante instrumentos validados y estandarizados, se obtuvo información de la intensidad del dolor pélvico actual y el promedio de dolor pélvico en la última semana, así como el nivel de dismenorrea, dispareunia, disquecia y disuria que experimentan estas mujeres. También se obtuvo información de los niveles de fatiga relacionada con la endometriosis que presentaban las participantes, los niveles de ansiedad, depresión, ira/hostilidad y de catastrofización del dolor. Por otro lado, se obtuvo información de la presencia de problemas gastrointestinales, de la función sexual, de la calidad del sueño, del grado de apoyo social y de la calidad de vida autopercibida. Finalmente, se analizó el desempeño ocupacional analizando la presencia de dificultades en la realización de las actividades básicas e instrumentales de la vida diaria. Los resultados obtenidos mostraron una alta prevalencia de alteraciones psicosociales, tales como altas tasas de ansiedad y depresión entre las participantes, así como una elevada presencia de pensamientos catastrofistas y de sentimientos de ira/hostilidad. También se identificó disfunción sexual, mala calidad del sueño y presencia de molestias gastrointestinales en una amplia proporción de las participantes. Dichas alteraciones estaban estrechamente relacionadas con la presencia de dolor pélvico en las mujeres. En relación a la importancia de la fatiga relacionada con la endometriosis en la vida diaria de estas pacientes, se observó que 1 de cada 2 participantes experimentó fatiga severa, la cual estaba estrechamente asociada con la presencia de un amplio abanico de alteraciones psicosociales, entre las que destacan los niveles de ansiedad y depresión, los sentimientos de ira/hostilidad o la disfunción sexual y la mala calidad del sueño. Además, se observó que la fatiga relacionada con la endometriosis, además de los pensamientos catastrofistas relacionados con el dolor, juega un papel mediador entre la presencia de dolor y una peor calidad de vida en estas mujeres. Finalmente, los resultados de esta tesis doctoral confirman la presencia de dificultades en la realización de las actividades de la vida diaria en mujeres con endometriosis. En concreto, se observó que casi la mitad de las participantes percibía dificultad para realizar alguna actividad de la vida diaria, siendo aquellas actividades más complejas y de mayor requerimiento energético como las labores del hogar o la realización de la compra, las que más comúnmente estaban afectadas. Además, se ha identificado que la intensidad del dolor y la fatiga experimentados, así como la presencia de pensamientos catastrofistas relacionados con el dolor en estas mujeres está relacionado con la aparición de dificultades en alguna de estas actividades de la vida diaria. En concreto, se ha observado que la sensación de fatiga y la presencia de pensamientos catastrofistas son mediadores de la relación entre la presencia de dolor pélvico y mayor dificultad en la realización de las actividades de la vida diaria.Tesis Univ. Granada

Diseño, cálculo de prestaciones y cualidades de vuelo de un avión de combate basado en el Saab Gripen

[ES] El presente trabajo se basa en el diseño, cálculo de prestaciones y cualidades de vuelo de un avión de combate a partir de ciertas características operacionales del Saab Gripen. El diseño de la aeronave ha sido realizado a partir de las directrices de diseño de Dassault Aviation. Tras definir el modelo geométrico se han calculado las diferentes prestaciones de la aeronave tanto a baja como a alta velocidad definiendo los diagramas de dominio de vuelo y maniobrabilidad. Tanto las características geométricas como la evaluación de prestaciones permiten validar el diseño debido a la similitud con los valores del avión real. En lo que respecta a las cualidades de vuelo, con el fin de respetar los criterios de vuelos del avión de referencia se ha diseñado un sistema de control tanto para vuelo longitudinal como para transversal a partir de MATLAB y Simulink. El diseño del controlador ha sido validado a partir de simulaciones en diferentes condiciones de vuelo.[EN] This work is based on the design, evaluation of performances and flight qualities of a fighter from several Saab Gripen operational requirements. The design has been done following the guidelines of Dassault Aviation Design Office. The geometry definition has allowed the evaluation of performances at low and high speed, defining the flight domain and maneuverability diagram. Comparing with the values of the Saab Gripen, is possible to validate both geometric definition and performances evaluation. Finally, in order to respect the Saab Gripen flight qualities, a flight control system has been developed for longitudinal and lateral stability with MATLAB and Simulink. The design of this controller has been validated with simulation in different flight conditions.López Navarro, JA.; Barreres Del Mundo, LL. (2019). Projet Avion. Avion de référence : Saab JAS-39 Gripen. Universitat Politècnica de València. http://hdl.handle.net/10251/143543TFG

Caracterización tecnológica de las unidades de producción de tomate bajo invernadero en Puebla

This work describes the technological characteristics of the tomato production units (UPJ) (Lycopersicon esculentumMill.) under greenhouse and the socioeconomic characteristics of the producers, in four municipalities of the state of Puebla. The data were obtained from a sample of producers, with a reliability of 95% and precision 10% of the value of the average of the greenhouse surface. 103 producer surveys wereapplied in the second half of 2017. A technological index (IT) was constructed from variables of technological management and equipment. 25% of UPJuse low technological levels, 66% medium levels and 9% high levels. The explanation of the technological level used by the UPJ was estimated with a Probit interval regression model. The level of education, the experience in greenhouse production and the size of the greenhouse have a significant influence (p≤ 0.5). Therefore, it is concluded that the technological level in the production units, as well as the school level, the cultivated area and the experience in greenhouse production by the producers, are factors closely related to the productivity of the crop. Based on these results, strategies can be developed and implemented to provide advice and training in the proper use of the technologies and equipment necessary to achieve high homogeneous yields in the areaEste trabajo describe las características tecnológicas de las unidades de producción de jitomate (UPJ) (Lycopersicon esculentum Mill.) bajo invernadero y las características socioeconómicas de los productores, en cuatro municipios del estado de Puebla. Los datos se obtuvieron de una muestra de productores, con una confiabilidad de 95% y precisión 10% del valor de la media de superficie del invernadero. Se aplicaron 103 encuestas a productores en el segundo semestre de 2017. Se construyó un índice tecnológico (IT) a partir de variables de manejo tecnológico y de equipamiento. El 25% de las UPJ utiliza niveles tecnológicos bajos, 66% niveles medios y 9% niveles altos. La explicación del nivel tecnológico utilizado por las UPJ se estimó con un modelo regresión Probit por intervalos. El nivel de escolaridad, la experiencia en la producción bajo invernadero y el tamaño del invernadero tienen influencia significativa (p≤ 0.5). Por lo tanto, se concluye que el nivel tecnológico en las unidades de producción, así como el nivel escolar, la superficie cultivada y la experiencia en la producción bajo invernadero por parte de los productores, son factores estrechamente relacionado con la productividad del cultivo. A partir de estos resultados, se podrán desarrollar e implementar estrategias que permitan brindar asesoría y capacitación en el uso adecuado de las tecnologías y equipos necesarios para lograr altos rendimientos homogéneos en la zona

Contribution of Chronic Fatigue to Psychosocial Status and Quality of Life in Spanish Women Diagnosed with Endometriosis

Aim: To analyze the levels of chronic fatigue in Spanish women with endometriosis and its relationship with their psychosocial status and quality of life (QoL). Methods: A total of 230 Spanish women with a clinical diagnosis of endometriosis were recruited. Chronic fatigue (Piper Fatigue Scale) and pelvic pain (Numeric Rating Scale) were evaluated. An on-line battery of validated scales was used to assess psychosocial status [Hospital Anxiety and Depression Scale, Scale for Mood Assessment, Pain Catastrophizing Scale, Pittsburgh Sleep Quality Index, Gastrointestinal Quality of Life Index, Female Sexual Function Index and Medical Outcomes Study-Social Support Survey] and QoL [Endometriosis-Health Profile questionnaire-30]. Associations between fatigue and both psychosocial and QoL outcomes were explored through multivariate regression models. Results: One-third and one-half of women showed moderate and severe fatigue, respectively. Fatigue was associated with higher anxiety and depression, poorer sleep quality, poorer sexual functioning, worse gastrointestinal health, higher catastrophizing thoughts, higher anger/hostility scores and lower QoL (p-values < 0.050). Moreover, fatigue and catastrophizing thoughts showed a mediating effect on the association between pelvic pain and QoL. Conclusion: This work reveals the important role of fatigue in the association between pain, psychosocial status, and QoL of Spanish women with endometriosis.This research was funded by Health Institute Carlos III (ISCIII)-FEDER (grant number PI17/01743) and donations from particular women with endometriosis that believed in this project from the first time. It was also partly supported by the PAIDI group CTS-206 (Oncología Básica y Clínica) funds. This study takes place thanks to the additional funding from the University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES), and by the Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades and European Regional Development Fund (ERDF), ref. SOMM17/6107/UGR.Ye

Widespread Pain Hypersensitivity and Lumbopelvic Impairments in Women Diagnosed with Endometriosis

Objective: To explore hypersensitivity to pain and musculoskeletal impairments in the lumbopelvic area in women with and without endometriosis. Methods: This cross-sectional study included 66 women (41 women with endometriosis and 25 healthy women). Pain and related catastrophizing thoughts were assessed through a numeric rating scale, pressure pain thresholds (PPTs), the slump test, and the Pain Catastrophizing Scale. Lumbopelvic muscles were evaluated through ultrasound imaging, flexor/extensor resistance tests, and the lumbopelvic stability test. Results: Women with endometriosis showed increased self-reported intensity of current pelvic pain (CuPP), reduced local PPTs (42.8-64.7% in the affected area, P-value <.001) and higher prevalence of lumbar nerve root impingement/irritation pain and catastrophizing thoughts (P-value ≤.002). Moreover, affected women showed decreased thickness of transversus abdominis, reduced resistance of flexor and extensor trunk muscles and lower lumbopelvic stability (P-values <.030). Endometriosis stage and severity of CuPP were related to worse results in these parameters. Conclusions: The presence of pain sensitization signs and lumbopelvic impairments, more pronounced in patients with stage IV endometriosis and moderate/severe CuPP, warrants the development of rehabilitation interventions targeting pain and lumbopelvic impairments in women with endometriosis.Sin financiación3.750 JCR (2020) Q2, 43/169 Medicine, General & Internal0.893 SJR (2020) Q1, 26/122 Anesthesiology and Pain MedicineNo data IDR 2019UE

Effect of a Multimodal Supervised Therapeutic Exercise Program on Quality of Life, Pain, and Lumbopelvic Impairments in Women With Endometriosis Unresponsive to Conventional Therapy: A Randomized Controlled Trial

Abstract Objective: To evaluate the effectiveness of “Physio-EndEA”, a multimodal nine-week supervised exercise intervention, on quality of life, pain, and lumbopelvic impairments in women with endometriosis unresponsive to conventional therapy. Design: Parallel-group randomized controlled trial. Outcomes were measured at baseline, post-intervention, and at 1 year. Setting: Two Public University Hospitals. Participants: This trial included 31 women with endometriosis (N=31) randomly allocated to “Physio-EndEA” group (n=16) or control group (n=15). Four participants dropped out of the study for causes unrelated to the intervention. Interventions: The “Physio-EndEA” program consisted of a 1-week lumbopelvic stabilization learning phase followed by an 8-week phase of stretching, aerobic, and resistance exercises focused on the lumbopelvic area. It was sequentially instructed and supervised by a trained physiother- apist (with volume and intensity progression) and adapted daily to the potential of each participant. Control group received the usual treatment stipulated by their gynecologist. Main Outcome Measures: The primary outcome was quality of life. Secondary outcomes were pain intensity, pressure pain thresholds, pain- related catastrophic thoughts, abdominal and back strength, lumbopelvic stability, and muscle architecture. Results: Adherence rate was 90.6% and mean (§standard deviation) satisfaction was 9.44§0.73 out of 10. No remarkable health problems were reported during the trial. In comparison with controls, the quality of life was improved post-intervention and at 1 year in the Physio-EndEA group with large effect sizes (d>0.80). This group also evidenced: a reduced intensity of dyspareunia, catastrophic thoughts; an increase in pelvic, lum- bar, and distal pressure pain thresholds; increases in abdominal and back strength and lumbopelvic stability; and increased thickness of transversus abdominis (right side) and width of lumbar multifidus (left side).Health Institute Carlos III (FEDER funds, PI17/01743)University of Granada, Plan Propio de Investigación 20164.300 Q1 JCR 20221.062 Q1 SJR 2022No data IDR 2021UE

BDNF as a potential mediator between childhood BPA exposure and behavioral function in adolescent boys from the INMA-Granada cohort.

Bisphenol A (BPA) exposure has been linked to altered behavior in children. Within the European Human Biomonitoring Initiative (HBM4EU), an adverse outcome pathway (AOP) network was constructed supporting the mechanistic link between BPA exposure and brain-derived neurotrophic factor (BDNF). To test this toxicologically-based hypothesis in the prospective INMA-Granada birth cohort (Spain). BPA concentrations were quantified by LC-MS/MS in spot urine samples from boys aged 9-11 years, normalized by creatinine and log-2 transformed. At adolescence (15-17 years), blood and urine specimens were collected, and serum and urinary BDNF protein levels were measured using immunoassays. DNA methylation levels at 6 CpGs in Exon IV of the BDNF gene were also assessed in peripheral blood using bisulfite-pyrosequencing. Adolescent's behavior was parent-rated using the Child Behavior Checklist (CBCL/6-18) in 148 boys. Adjusted linear regression and mediation models were fit. Childhood urinary BPA concentrations were longitudinally and positively associated with thought problems (β = 0.76; 95% CI: 0.02, 1.49) and somatic complaints (β = 0.80; 95% CI: -0.16, 1.75) at adolescence. BPA concentrations were positively associated with BDNF DNA methylation at CpG6 (β = 0.21; 95% CI: 0.06, 0.36) and mean CpG methylation (β = 0.10; 95% CI: 0.01, 0.18), but not with total serum or urinary BDNF protein levels. When independent variables were categorized in tertiles, positive dose-response associations were observed between BPA-thought problems (p-trend = 0.08), BPA-CpG6 (p-trend ≤ 0.01), and CpG6-thought problems (p-trend ≤ 0.01). A significant mediated effect by CpG6 DNA methylation was observed (β = 0.23; 95% CI: 0.01, 0.57), accounting for up to 34% of the BPA-thought problems association. In line with toxicological studies, BPA exposure was longitudinally associated with increased BDNF DNA methylation, supporting the biological plausibility of BPA-behavior relationships previously described in the epidemiological literature. Given its novelty and preliminary nature, this effect biomarker approach should be replicated in larger birth cohorts