Urinary phthalate/DINCH metabolites associations with kisspeptin and reproductive hormones in teenagers: A cross-sectional study from the HBM4EU aligned studies

Andrea Rodríguez-Carrillo; Sylvie Remy; Gudrun Koppen; Natasha Wauters; Vicente Mustieles; Anteneh Desalegn; Nina Iszatt; Elly den Hond; Veerle J Verheyen; Lucia Fábelová; Lubica Palkovicova Murinova; Susana Pedraza-Díaz; Marta Esteban; Rafael M Poyatos; Eva Govarts; Alexander L N van Nuijs; Adrian Covaci; Greet Schoeters; Nicolás Olea; Mariana F Fernández

doi:10.1016/j.scitotenv.2024.172426

Urinary phthalate/DINCH metabolites associations with kisspeptin and reproductive hormones in teenagers: A cross-sectional study from the HBM4EU aligned studies

Sci Total Environ. 2024 Apr 15:929:172426. doi: 10.1016/j.scitotenv.2024.172426. Online ahead of print.

Authors

Andrea Rodríguez-Carrillo¹, Sylvie Remy², Gudrun Koppen², Natasha Wauters², Vicente Mustieles³, Anteneh Desalegn⁴, Nina Iszatt⁴, Elly den Hond⁵, Veerle J Verheyen², Lucia Fábelová⁶, Lubica Palkovicova Murinova⁶, Susana Pedraza-Díaz⁷, Marta Esteban⁷, Rafael M Poyatos⁸, Eva Govarts², Alexander L N van Nuijs⁹, Adrian Covaci⁹, Greet Schoeters¹⁰, Nicolás Olea¹¹, Mariana F Fernández¹²

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 & School of Medicine, 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 Division of Climate and Environmental Health, Norwegian Institute of Public Health, Norway.
⁵ Provincial Institute for Hygiene, Antwerp, Belgium.
⁶ Department of Environmental Medicine, Faculty of Public Health, Slovak Medical University, Bratislava, Slovakia.
⁷ National Centre for Environmental Health, Instituto de Salud Carlos III, Madrid, Spain.
⁸ Unidad de Gestión Clínica de Laboratorios, Hospital Universitario Clínico San Cecilio, Granada, Spain.
⁹ Toxicological Centre, University of Antwerp, Universiteitsplein, 1, 2610 Wilrijk, Belgium.
¹⁰ Department of Radiology and Physical Medicine, School of Medicine, University of Granada, 18016 Granada, Spain.
¹¹ Biomedical Research Center & School of Medicine, University of Granada, 18016 Granada, Spain; Department of Radiology and Physical Medicine, School of Medicine, 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.
¹² Biomedical Research Center & School of Medicine, University of Granada, 18016 Granada, Spain; Department of Radiology and Physical Medicine, School of Medicine, 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. Electronic address: marieta@ugr.es.

PMID: 38631641
DOI: 10.1016/j.scitotenv.2024.172426

Abstract

Background: Exposure to phthalate/DINCH metabolites can induce human reproductive toxicity, however, their endocrine-disrupting mechanisms are not fully elucidated.

Objective: To investigate the association between concentrations of phthalate/DINCH metabolites, serum kisspeptin, and reproductive hormones among European teenagers from three of the HBM4EU Aligned Studies.

Methods: In 733 Belgian (FLEHS IV study), Slovak (PCB cohort follow-up), and Spanish (BEA study) teenagers, ten phthalate and two DINCH metabolites were measured in urine by high-performance liquid chromatography-tandem mass spectrometry. Serum kisspeptin (kiss54) protein, follicle-stimulating hormone (FSH), total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG) levels were measured by immunosorbent assays. Free Androgen Index (FAI) was calculated as a proxy of free testosterone. Adjusted sex-stratified linear regression models for individual studies, mixed effect models (LME) accounting for random effects for pooled studies, and g-computation and Bayesian kernel machine regression (BKMR) models for the phthalate/DINCH mixture were performed.

Results: The LME suggested that each IQR increase in ln-transformed levels of several phthalates was associated with lower kisspeptin [MnBP: %change (95%CI): -2.8 (-4.2;-0.4); MEHP: -1.4 (-3.4,0.2)] and higher FSH [∑DINP: 11.8 (-0.6;25.1)] levels in females from pooled studies. G-computation showed that the phthalates/DINCH mixture was associated with lower kisspeptin [-4.28 (-8.07;-0.34)] and higher FSH [22.13 (0.5;48.4)] also in females; BKMR showed similar although non-significant pattern. In males, higher phthalates metabolites [MEHP: -12.22 (-21.09;-1.18); oxo-MEHP: -12.73 (-22.34;-1.93)] were associated with lower TT and FAI, although higher DINCH [OH-MINCH: 16.31 (6.23;27.35), cx-MINCH: 16.80 (7.03;27.46), ∑DINCH: 17.37 (7.26;29.74)] were associated with higher TT levels. No mixture associations were found in males.

Conclusion: We observed sex-specific associations between urinary concentrations of phthalate/DINCH metabolites and the panel of selected effect biomarkers (kisspeptin and reproductive hormones). This suggests that exposure to phthalates would be associated with changes in kisspeptin levels, which would affect the HPG axis and thus influence reproductive health. However, further research is needed, particularly for phthalate replacements such as DINCH.

Keywords: DINCH; Effect biomarkers; HBM4EU; Kisspeptin; Phthalates; Reproductive hormones.