PFAS association with kisspeptin and sex hormones in teenagers of the HBM4EU aligned studies

Andrea Rodríguez-Carrillo; Sylvie Remy; Gudrun Koppen; Natasha Wauters; Carmen Freire; Alicia Olivas-Martínez; Tessa Schillemans; Agneta Åkesson; Anteneh Desalegn; Nina Iszatt; Elly den Hond; Veerle Verheyen; Lucia Fábelová; Lubica Palkovicova Murinova; Susana Pedraza-Díaz; Argelia Castaño; José Vicente García-Lario; Bianca Cox; Eva Govarts; Kirsten Baken; Manuel Tena-Sempere; Nicolás Olea; Greet Schoeters; Mariana F Fernández

doi:10.1016/j.envpol.2023.122214

PFAS association with kisspeptin and sex hormones in teenagers of the HBM4EU aligned studies

Environ Pollut. 2023 Oct 15:335:122214. doi: 10.1016/j.envpol.2023.122214. Epub 2023 Jul 21.

Authors

Andrea Rodríguez-Carrillo¹, Sylvie Remy², Gudrun Koppen², Natasha Wauters², Carmen Freire³, Alicia Olivas-Martínez⁴, Tessa Schillemans⁵, Agneta Åkesson⁶, Anteneh Desalegn⁷, Nina Iszatt⁸, Elly den Hond⁹, Veerle Verheyen², Lucia Fábelová¹⁰, Lubica Palkovicova Murinova¹⁰, Susana Pedraza-Díaz¹¹, Argelia Castaño¹¹, José Vicente García-Lario¹², Bianca Cox², Eva Govarts², Kirsten Baken², Manuel Tena-Sempere¹³, Nicolás Olea¹⁴, Greet Schoeters¹⁵, Mariana F Fernández¹⁶

Affiliations

¹ VITO Health, Flemish Institute for Technological Research (VITO), 2400, Mol, Belgium; Toxicological Centre, University of Antwerp, Universiteitsplein, 1, 2610, Wilrijk, Belgium.
² VITO Health, Flemish Institute for Technological Research (VITO), 2400, Mol, Belgium.
³ Biomedical Research Center (CIBM), University of Granada, 18016 Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012, Granada, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Spain.
⁴ Biomedical Research Center (CIBM), University of Granada, 18016 Granada, Spain.
⁵ Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Sweden.
⁶ Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Spain.
⁷ Division of Food Safety, Norwegian Institute of Public Health, Norway.
⁸ Division of Climate and Environmental Health, Norwegian Institute of Public Health, Norway.
⁹ Provincial Institute for Hygiene, Antwerp, Belgium.
¹⁰ Department of Environmental Medicine, Faculty of Public Health, Slovak Medical University, Bratislava, Slovakia.
¹¹ National Centre for Environmental Health, Instituto de Salud Carlos III, Madrid, Spain.
¹² Hospital Universitario Clínico San Cecilio, Granada, Spain.
¹³ Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Menéndez Pidal s/n. 14004., Córdoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Campus de Rabanales, Ctra. Madrid-Cádiz, Km. 396. 14071. Córdoba, Spain; University Hospital Reina Sofía, Menéndez Pidal s/n. 14004, Córdoba, Spain; CIBER Pathophysiology of Obesity and Nutrition, Carlos III Health Institute, Menéndez Pidal s/n. 14004. Córdoba, Spain.
¹⁴ Biomedical Research Center (CIBM), University of Granada, 18016 Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012, Granada, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Spain; Department of Radiology and Physical Medicine, School of Medicine, University of Granada, 18016 Granada, Spain.
¹⁵ VITO Health, Flemish Institute for Technological Research (VITO), 2400, Mol, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
¹⁶ Biomedical Research Center (CIBM), University of Granada, 18016 Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012, Granada, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Spain; Department of Radiology and Physical Medicine, School of Medicine, University of Granada, 18016 Granada, Spain. Electronic address: marieta@ugr.es.

PMID: 37482334
DOI: 10.1016/j.envpol.2023.122214

Abstract

Exposure to Perfluoroalkyl acids (PFAS) can impair human reproductive function, e.g., by delaying or advancing puberty, although their mechanisms of action are not fully understood. We therefore set out to evaluate the relationship between serum PFAS levels, both individually and as a mixture, on the Hypothalamic-Pituitary-Gonadal (HPG) axis by analyzing serum levels of reproductive hormones and also kisspeptin in European teenagers participating in three of the HBM4EU Aligned Studies. For this purpose, PFAS compounds were measured in 733 teenagers from Belgium (FLEHS IV study), Slovakia (PCB cohort follow-up), and Spain (BEA study) by high performance liquid chromatography-tandem mass spectrometry (HPLC/MS) in laboratories under the HBM4EU quality assurance quality control (QA/QC) program. In the same serum samples, kisspeptin 54 (kiss-54) protein, follicle-stimulating hormone (FSH), total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG) levels were also measured using immunosorbent assays. Sex-stratified single pollutant linear regression models for separate studies, mixed single pollutant models accounting for random effects for pooled studies, and g-computation and Bayesian kernel machine regression (BKMR) models for the mixture of the three most available (PFNA, PFOA, and PFOS) were fit. PFAS associations with reproductive markers differed according to sex. Each natural log-unit increase of PFOA, PFNA, and PFOS were associated with higher TT [18.41 (6.18; 32.31), 15.60 (7.25; 24.61), 14.68 (6.18; 24.61), respectively] in girls, in the pooled analysis (all studies together). In males, G-computation showed that PFAS mixture was associated with lower FSH levels [-10.51 (-18.81;-1.36)]. The BKMR showed the same patterns observed in G-computation, including a significant increase on male Kiss-54 and SHBG levels. Overall, effect biomarkers may enhance the current epidemiological knowledge regarding the adverse effect of PFAS in human HPG axis, although further research is warranted.

Keywords: Effect biomarkers; HBM4EU; Kisspeptin; PFAS; Reproductive hormones.

MeSH terms

Adolescent
Alkanesulfonic Acids*
Bayes Theorem
Environmental Pollutants*
Female
Fluorocarbons*
Follicle Stimulating Hormone
Gonadal Steroid Hormones
Humans
Kisspeptins
Male
Testosterone

Substances

Kisspeptins
Gonadal Steroid Hormones
Testosterone
Environmental Pollutants
Follicle Stimulating Hormone
Alkanesulfonic Acids
Fluorocarbons