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- Mapping susceptibility to air pollution and its association with birth defects: a tool for public health interventionPublication . Aniceto, Carlos; Braz, Paula; Machado, Ausenda; Dias, Carlos MatiasEpidemiological studies evaluating the relation of environmental air pollution (AP) and birth defect (BD) are relevant to public health. Some limitations on these studies may derive from multiple factors contributing to the spatial variation of AP. This study aimed to integrate multifactorial AP indicators into an index and explore its application in a case-control study conducted in Portugal between 2016 and 2021. Spatial multicriteria analysis was employed to identify areas susceptible to AP. Variables included: (i) Euclidean distance to industrial units; (ii) kernel estimation of industrial units density; (iii) land occupation; (iv) Euclidean distance to main roads; and (v) areas conductive to radiation fog formation. Variables were classified into high, moderate, and low susceptibility. An AP susceptibility map was generated using the weighted linear combination method, with the analytic hierarchy process assigning weights to the variables. Georeferenced BD cases and controls were overlaid with environmental exposure variables and the AP index. Three AP susceptibility areas were identified: consolidated urban, peri-urban area, and a residential–industrial area. In areas of high susceptibility, 47 cases (29%) and 65 controls (31%) were observed; and in areas of low susceptibility 25 cases (15%) and 21 controls (10%) were observed. The development of the AP susceptibility map has been demonstrated to be a valuable tool for identifying patterns, generating hypotheses regarding the potential environmental exposure of NB to AP agents during pregnancy. When integrated into more complex analyses, these findings may contribute to assess the potential risk factors that play a major role in BD.
- A genetic variant in the 3′-UTR of PIWIL4 confers risk for extreme phenotypes of male infertility by altering miR-215 and miR-136 binding affinityPublication . González-Muñoz, Sara; Cerván-Martín, Miriam; Guzmán-Jiménez, Andrea; Rodríguez-Martín, Ana Isabel; Garrido, Nicolás; Castilla, José A.; Gonzalvo, M. Carmen; Clavero, Ana; Molina, Marta; Vilches, Miguel Ángel; Espuch-Oliver, Andrea; Maldonado, Vicente; García-Peña, María Luisa; Galiano-Gutiérrez, Noelia; Santamaría, Esther; González, Cristina; Quintana-Ferraz, Fernando; Gómez, Susana; Amorós, David; Martínez-Granados, Luis; Ortega-González, Yanira; Burgos, Miguel; Pereira-Caetano, Iris; Pinto, Graça S.; Aguiar, Ana; Pereira, Isabel S.; López-Rodrigo, Olga; Bassas, Lluís; Seixas, Susana; Gonçalves, João; Lopes, Alexandra M.; Larriba, Sara; Bossini-Castillo, Lara; Carmona, F. David; Palomino-Morales, Rogelio J.Study question: What is the functional impact of the rs508485 genetic polymorphism, located in the 3'-untranslated region (UTR) region of the PIWIL4 gene, on non-obstructive azoospermia (NOA)? Summary answer: The rs508485 genetic variant contributes to the pathogenesis of extreme patterns of NOA by modulating PIWIL4 expression through microRNA (miRNA) interactions. What is known already: Male infertility represents a significant global health challenge with profound societal and economic consequences. One of the most severe forms of male infertility is NOA, which is characterized by severe spermatogenic failure (SPGF) of idiopathic origin in most cases. Cumulating knowledge increasingly suggests that this idiopathic form of NOA may represent a multifactorial condition involving complex interactions between genetic and environmental factors. The PIWI protein subfamily, particularly PIWIL4, plays a pivotal role in spermatogenesis by processing PIWI-interacting RNAs, which silence retrotransposons to protect genomic integrity. Genetic variations in this gene have been found to be associated with susceptibility to NOA. Study design, size, duration: A case-control study was conducted in a European cohort including 1516 infertile men with SPGF and 2451 fertile controls. Logistic regression and functional assays were employed to investigate the functional role of the rs508485 polymorphism in PIWIL4. Participants/materials, setting, methods: Participants were genotyped for the rs508485 polymorphism. Associations between the polymorphism and NOA phenotypes, including Sertoli cell-only (SCO) syndrome and testicular sperm extraction (TESE) outcomes, were assessed. In silico tools predicted miRNA binding effects, which were subsequently validated using luciferase reporter assays. Main results and the role of chance: The T allele of rs508485 was significantly associated with the SCO phenotype (P = 2.69E-03, OR = 1.34) and unfavourable TESE outcomes (P = 1.09E-03, OR = 1.54). In silico analyses predicted that the rs508485 variant might alter binding sites in the 3'-UTR region of PIWIL4 for different miRNAs, such as hsa-miR-215-3p and hsa-miR-136-3p. Functional validation using luciferase assays confirmed that these miRNAs differentially bind to the T and C alleles of this polymorphism, influencing PIWIL4 regulation. Large scale data: N/A. Limitations, reasons for caution: The study is limited to a single genetic polymorphism and functional assays were performed in vitro. Additional studies are required to validate these findings across diverse populations and explore additional genetic interactions. Wider implications of the findings: These findings highlight the critical role of miRNA regulation in extreme forms of male infertility by influencing the expression of essential spermatogenesis genes, such as PIWIL4. Our study sheds light on the genetic mechanisms underlying spermatogenesis and suggests potential therapeutic targets for NOA.