{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T22:43:05Z","timestamp":1791240185300,"version":"4.1.0"},"reference-count":23,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UK Medical Research Council and Wellcome","award":["MR\/Z505924\/1"],"award-info":[{"award-number":["MR\/Z505924\/1"]}]},{"DOI":"10.13039\/501100000883","name":"University of Bristol","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000883","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/0524sp257","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100022270","name":"School of Biosciences, University of Nottingham","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100022270","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/01ee9ar58","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Circulating insulin-like peptide 3 (INSL3) is a constitutively secreted product of mature Leydig cells and is considered a stable biomarker of Leydig cell functional capacity, a key determinant of androgenic status across the male lifespan. Since the adult Leydig cell population is established during late childhood and puberty, nutritional and metabolic exposures during these periods may contribute to later variation in young adult INSL3. To investigate whether childhood and adolescent nutritional\/metabolic markers, particularly vitamin D, fatty acids, amino acids, and dietary trace-element intake, are associated with circulating INSL3 concentrations in young adulthood. Methods: Data were analysed from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based UK birth cohort. Nutritional and metabolic markers measured during childhood and adolescence included vitamin D, fatty acid-related traits, glutamine, leucine, dietary zinc intake, and dietary selenium intake. Associations with circulating INSL3 at 17 and 24 years were first explored using bivariate correlation analysis. Variables showing signals of interest were then examined in multiple linear regression models using log-transformed data and relevant covariates, including BMI at 8 years and log-transformed exact age at the age-24 clinic visit. Results: Among the variables examined, vitamin D at 9 years showed a small positive association with INSL3 at 24 years (r = 0.098, n = 735, p = 0.008), remaining below the corrected threshold after both Benjamini\u2013Hochberg and Bonferroni correction (q = 0.032 and Bonferroni-adjusted p = 0.032). This relationship remained evident after adjustment for BMI at 8 years and after further adjustment for log-transformed exact age at the age-24 clinic visit. In these multivariable models, BMI at 8 years showed little evidence of association with INSL3 at 24 years, whereas log-transformed exact age at the age-24 clinic visit showed a negative association with INSL3. In contrast, no meaningful associations were observed for fatty-acid-related measures. Among amino acids and dietary trace-element measures, glutamine at 17 years showed a weak nominal positive association with INSL3 at 24 years, but this did not remain below the threshold after multiple-testing correction. Conclusions: Childhood vitamin D status, particularly at 9 years of age, may represent an early-life factor associated with variation in adult Leydig cell functional capacity. Fatty acid-related measures showed no clear associations, while glutamine yielded only a weak exploratory signal. These findings support the concept that the childhood metabolic environment may influence the developmental establishment of adult Leydig cell capacity.<\/jats:p>","DOI":"10.3390\/nu18152426","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:49:27Z","timestamp":1785131367000},"page":"2426","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Childhood Vitamin D Status and Circulating Insulin-like Peptide 3 as a Marker of Leydig Cell Functional Capacity in Young Adulthood: Findings from the Avon Longitudinal Study of Parents and Children"],"prefix":"10.3390","volume":"18","author":[{"given":"Bilal","family":"Tulumcu","sequence":"first","affiliation":[{"name":"School of Biosciences, University of Nottingham, Sutton Bonington LE12 5RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Ivell","sequence":"additional","affiliation":[{"name":"School of Biosciences, University of Nottingham, Sutton Bonington LE12 5RD, UK"},{"name":"School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington LE12 5RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4976-4314","authenticated-orcid":false,"given":"Ravinder","family":"Anand-Ivell","sequence":"additional","affiliation":[{"name":"School of Biosciences, University of Nottingham, Sutton Bonington LE12 5RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1095\/biolreprod.113.108969","article-title":"INSL3 as a biomarker of Leydig cell functionality","volume":"88","author":"Ivell","year":"2013","journal-title":"Biol. Reprod."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1111\/andr.13220","article-title":"Association of age, hormonal, and lifestyle factors with the Leydig cell biomarker INSL3 in aging men from the European Male Aging Study cohort","volume":"10","author":"Heng","year":"2022","journal-title":"Andrology"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Tulumcu, B., Ivell, R., Alhujaili, W., and Anand-Ivell, R. (2025). Defining the end of puberty in boys: INSL3 and the acute determinants of adult Leydig-cell functional capacity. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1574760"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ivell, R., Heng, K., Severn, K., Antonio, L., Bartfai, G., Casanueva, F.F., Huhtaniemi, I.T., Giwercman, A., Maggi, M., and O\u2019Connor, D.B. (2022). The Leydig cell biomarker INSL3 as a predictor of age-related morbidity: Findings from the EMAS cohort. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1016107"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/BF00215884","article-title":"A quantitative morphological study of human Leydig cells from birth to adulthood","volume":"246","author":"Nistal","year":"1986","journal-title":"Cell Tissue Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1093\/humupd\/dmv008","article-title":"Morphological and functional maturation of Leydig cells: From rodent models to primates","volume":"21","author":"Teerds","year":"2015","journal-title":"Hum. Reprod. Update"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"105589","DOI":"10.1016\/j.jsbmb.2020.105589","article-title":"Vitamin D and sex steroid production in men with normal or impaired Leydig cell function","volume":"199","author":"Holt","year":"2020","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1093\/humrep\/deq024","article-title":"Vitamin D receptor and vitamin D metabolizing enzymes are expressed in the human male reproductive tract","volume":"25","author":"Nielsen","year":"2010","journal-title":"Hum. Reprod."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"184","DOI":"10.4103\/1008-682X.190323","article-title":"Fatty acid intake in relation to reproductive hormones and testicular volume among young healthy men","volume":"19","author":"Chavarro","year":"2017","journal-title":"Asian J. Androl."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1038\/s42003-022-03972-y","article-title":"Omega-6 highly unsaturated fatty acids in Leydig cells facilitate male sex hormone production","volume":"5","author":"Ri","year":"2022","journal-title":"Commun. Biol."},{"key":"ref_11","first-page":"539","article-title":"The Role of the PI3K\/AKT\/mTOR Signalling Pathway in Male Reproduction","volume":"21","author":"Deng","year":"2021","journal-title":"Curr. Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Lin, Y., Li, J., Wang, K., Fang, Z., Che, L., Xu, S., Feng, B., Zhuo, Y., Li, J., and Wu, D. (2022). Effects of dietary L-leucine supplementation on testicular development and semen quality in boars. Front. Vet. Sci., 9.","DOI":"10.3389\/fvets.2022.904653"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"112765","DOI":"10.1016\/j.biopha.2022.112765","article-title":"Glutamine restores testicular glutathione-dependent antioxidant defense and upregulates NO\/cGMP signaling in sleep deprivation-induced reproductive dysfunction in rats","volume":"148","author":"Hamed","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"127124","DOI":"10.1016\/j.jtemb.2022.127124","article-title":"Correlation between serum zinc and testosterone: A systematic review","volume":"76","author":"Te","year":"2023","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1093\/ije\/dys064","article-title":"Cohort Profile: The \u2018Children of the 90s\u2019\u2014The index offspring of the Avon Longitudinal Study of Parents and Children","volume":"42","author":"Boyd","year":"2013","journal-title":"Int. J. Epidemiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1093\/ije\/dys066","article-title":"Cohort Profile: The Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort","volume":"42","author":"Fraser","year":"2013","journal-title":"Int. J. Epidemiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"51","DOI":"10.12688\/wellcomeopenres.15132.1","article-title":"The Avon Longitudinal Study of Parents and Children (ALSPAC): An update on the enrolled sample of index children in 2019","volume":"4","author":"Northstone","year":"2019","journal-title":"Wellcome Open Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"689","DOI":"10.12688\/wellcomeopenres.25018.1","article-title":"The Avon Longitudinal Study of Parents and Children (ALSPAC): An update on the enrolled sample of index children (the G1 cohort) in 2025","volume":"10","author":"Northstone","year":"2025","journal-title":"Wellcome Open Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.jbi.2008.08.010","article-title":"Research electronic data capture (REDCap)\u2014A metadata-driven methodology and workflow process for providing translational research informatics support","volume":"42","author":"Harris","year":"2009","journal-title":"J. Biomed. Inform."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1039\/b910205a","article-title":"High-throughput serum NMR metabonomics for cost-effective holistic studies on systemic metabolism","volume":"134","author":"Soininen","year":"2009","journal-title":"Analyst"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/sj.ejcn.1602741","article-title":"Dietary patterns in pregnancy and associations with socio-demographic and lifestyle factors","volume":"62","author":"Northstone","year":"2008","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1111\/andr.12851","article-title":"Effects of acute hCG stimulation on serum INSL3 and 25-OH vitamin D in Klinefelter syndrome","volume":"8","author":"Santi","year":"2020","journal-title":"Andrology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1210\/jc.2011-2516","article-title":"Risk factors for variation in 25-hydroxyvitamin D(3) and D(2) concentrations and vitamin D deficiency in children","volume":"97","author":"Tolppanen","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/15\/2426\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T04:19:27Z","timestamp":1785298767000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/15\/2426"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,24]]},"references-count":23,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["nu18152426"],"URL":"https:\/\/doi.org\/10.3390\/nu18152426","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,24]]}}}