The Association of Certain Seminal Phthalate Metabolites on Spermatozoa Apoptosis: An Exploratory Mediation Analysis via Sperm Protamine

Feng Xiong; Bin Zhou; Nan-Xin Wu; Lang-Jing Deng; Jin-Ying Xie; Xiao-Jie Li; Ying-Jun Chen; Yi-Xin Wang; Qiang Zeng; Pan Yang

doi:10.1016/j.envpol.2022.118969

The Association of Certain Seminal Phthalate Metabolites on Spermatozoa Apoptosis: An Exploratory Mediation Analysis via Sperm Protamine

Environ Pollut. 2022 May 1:300:118969. doi: 10.1016/j.envpol.2022.118969. Epub 2022 Feb 11.

Authors

Feng Xiong¹, Bin Zhou², Nan-Xin Wu¹, Lang-Jing Deng¹, Jin-Ying Xie¹, Xiao-Jie Li¹, Ying-Jun Chen³, Yi-Xin Wang⁴, Qiang Zeng⁵, Pan Yang⁶

Affiliations

¹ Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, PR China.
² Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
³ Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
⁴ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵ Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Hubei, PR China.
⁶ Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, PR China; Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou, 510632, Guangdong, PR China. Electronic address: yangpan@jnu.edu.cn.

PMID: 35157934
DOI: 10.1016/j.envpol.2022.118969

Abstract

Earlier studies have suggested that exposure to phthalates (PAEs) may induce spermatozoa apoptosis. Sperm protamine as a molecular biomarker during spermatozoa apoptotic processes may mediate the association between PAE exposure and spermatozoa apoptosis. This study aimed to explore whether sperm protamine mediates the association of PAE exposure with spermatozoa apoptosis. We determined sperm protamine levels, 8 PAE metabolite concentrations in seminal plasma, and 3 spermatozoa apoptosis parameters among 111 men from an infertility clinic. The associations of PAEs as individual chemicals and mixtures with sperm protamine were determined. The mediating roles of protamine in the associations between PAEs and spermatozoa apoptosis parameters were examined by mediation analysis. After adjusting for confounders, we observed positive correlations between seminal plasma concentrations of mono(2-ethylhexyl) phthalate (MEHP) and sperm protamine-1 and protamine ratio. Estimates comparing highest vs. lowest quartiles of MEHP concentration were 4.65% (95% CI: 1.47%, 7.82%) for protamine-1 and 25.86% (95% CI: 3.05%, 53.73%) for protamine ratio. The quantile g-computation models showed that the adjusted protamine-1 per quartile increase in PAE mixture was 9.42% (95% CI: 1.00, 20.92) with MEHP being the major contributor. Although the joint association between PAE mixture and protamine ratio was negligible, MEHP was still identified as the main contributor. Furthermore, we found that protamine-2 and protamine ratio levels in the highest quartiles exhibited a decrease of 43.45% (95% CI: 60.54%, -19.75%) and an increase of 122.55% (95% CI: 60.00%, 209.57%) in Annexin V⁺/PI^- spermatozoa relative to the lowest quartiles, respectively. Mediation analysis revealed that protamine ratio significantly mediated 55.6% of the association between MEHP and Annexin V⁺/PI^- spermatozoa elevation (5.13%; 95% CI: 0.04%, 10.52%). Our findings provided evidence that human exposure to PAEs was associated with increased protamine levels which may mediate the process of spermatozoa apoptosis.

Keywords: Phthalate; Protamine; Seminal plasma; Sperm; Spermatozoa apoptosis.

MeSH terms

Apoptosis
Humans
Male
Mediation Analysis*
Phthalic Acids* / analysis
Protamines / metabolism
Spermatozoa / metabolism

Substances

Phthalic Acids
Protamines
phthalic acid