Kisspeptin as Potential Biomarker of Environmental Chemical Mixtures Effect on Reproductive Hormone Profile: A Pilot Study in Adolescent Males

Abstract

Background: Kisspeptin has been proposed as effect biomarker to understand the mechanisms by which some environmental chemicals alter the human reproductive system.Objective: To ascertain whether kisspeptin serum protein and DNA methylation levels are associated with exposure to several contaminants (assessed individually and as a mixture) and the reproductive hormone profile in adolescent males.

Methods: Several phenols, metals, and pesticides were measured in urine samples of 133 adolescent males aged 15-17 years from the INMA-Granada cohort. In blood samples collected on the same day, DNA methylation of the KISS1 gene at four CpGs of exon IV, and serum levels of kiss54 protein, total testosterone (T), estradiol (E2), sex hormone binding-globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), luteinizing hormone (LH), and follicle stimulating hormone (FSH) were measured. Multiple linear regression and mixture (quantile g-computation) models were fit.

Results: Urinary MDA and DCCA concentrations were associated with higher kiss54 levels [% change (95%CI) for each log-unit increase in concentration=2.90 (0.32;5.56), and 1.93 (0.45,3.43), respectively]; IMPy with lower DNA methylation percentage at CpG1 and total CpGs [% change (95%CI)=-1.15 (-1.96;-0.33): -0.89 (-1.73;-0.01), respectively]; and BP3 and DCCA with lower total CpGs methylation [-0.53 (-1.04;-0.01) and -0.69 (-1.37;-0.01), respectively]. The pesticide mixture and the whole chemical mixture were associated with higher kiss54 [% change (95%CI)=9.09 (3.29;15.21) and 11.61 (3.96;19.82), respectively] and lower methylation levels at several CpGs. Additionally, serum kiss54 in the third tertile was associated with higher LH levels [% change (95%CI)=28.69 (3.75-59.63)], and third-tertile CpG1, CpG2, and total CpG methylation percentages were associated with lower FSH and E2.

Conclusion: The findings of the present study and the negative correlation between serum kiss54 levels and KISS1 DNA methylation percentages suggested that kisspeptin may be a promising effect biomarker

Note:

Funding Information: The authors greatly acknowledge the support received by Tena-Sempere M. Also, the European Union’s Horizon 2020 research and innovation program HBM4EU for the financial support under Grant Agreement #733032. The study was further supported by the ISCIII with grants no. CP16/00085 and PI 17/01526, and the Human Genotyping Laboratory at the Spanish National Cancer Research Centre, CeGen-PRB3, which was supported by grant no. PT17/0019, of the PE I+D+i 2013-2016, funded by the Instituto de Salud Carlos III (ISCIII) and ERDF.

Declaration of Interests: The authors included in the present work declare no actual or potential conflicts of interest.

Ethics Approval Statement: The informed consent was signed by the parents’ participants and the study protocol was approved by the Biomedical Research Ethics Committee of Granada (protocol number 0509-N17, date of approval March 28 2017).

Keywords: Kisspeptin, HBM4EU, chemical mixtures, Endocrine disrupting chemicals, Effect Biomarker, epigenetic markers