Obesity significantly alters the human sperm proteome, with potential implications for fertility

Abstract

Purpose In men, obesity may lead to poor semen parameters and reduced fertility. However, the causative links between obesity and male infertility are not totally clear, particularly on a molecular level. As such, we investigated how obesity modifies the human sperm proteome, to elucidate any important implications for fertility. Methods Sperm protein lysates from 5 men per treatment, classified as a healthy weight (body mass index (BMI) ≤ 25 kg/m 2) or obese (BMI ≥ 30 kg/m 2), were FASP digested, submitted to liquid chromatography tandem mass spectrometry, and compared by label-free quantification. Findings were confirmed for several proteins by qualitative immunofluorescence and a quantitative protein immunoassay. Results A total of 2034 proteins were confidently identified, with 24 proteins being significantly (p < 0.05) less abundant (fold change < 0.05) in the spermatozoa of obese men and 3 being more abundant (fold change > 1.5) compared with healthy weight controls. Proteins with altered abundance were involved in a variety of biological processes, including oxidative stress (GSS, NDUFS2, JAGN1, USP14, ADH5), inflammation (SUGT1, LTA4H), translation (EIF3F, EIF4A2, CSNK1G1), DNA damage repair (UBEA4), and sperm function (NAPA, RNPEP, BANF2). Conclusion These results suggest that oxidative stress and inflammation are closely tied to reproductive dysfunction in obese men. These processes likely impact protein translation and folding during spermatogenesis, leading to poor sperm function and subfertility. The observation of these changes in obese men with no overt andrological diagnosis further suggests that traditional clinical semen assessments fail to detect important biochemical changes in spermatozoa which may compromise fertility.

Mitochondrial Reactive Oxygen Species (ROS) Production Alters Sperm Quality

“…As a consequence of oxidative stress, the antioxidant capacity significantly decreases within the testicular environment because of high-energy intake, especially impairing the activity of the proliferators-activated receptor γ coactivator1α (PGC-1α) and sirtuin 3 (SIRT3) [ 135 ]. Obese or overweight men have, in fact, lower sperm count and motility, higher DNA damage, and an altered sperm proteome involved in biological processes such as inflammation, translation, DNA damage repair and sperm functions [ 136 , 137 ]. ROS production in the testis and sperm is also exacerbated by the chronic inflammation generated by obesity.…”

Effects of Metabolic Syndrome on Semen Quality and Circulating Sex Hormones: A Systematic Review and Meta-Analysis

“…Besides, individuals with obesity, dyslipidemia or hypertension were also reported with a decrease in semen quality and changes in sex hormones. These might contribute to concomitant oxidative stress and inflammation, and impaired seminal antioxidant capacity (34,35). In this meta-analysis, we found a decrease of sperm total count, sperm concentration, sperm normal morphology, sperm progressive motility, and sperm vitality and an increase of sperm DNA fragmentation and MMP, while no significant difference was found in semen volume and sperm total motility.…”

“…Besides, individuals with obesity, dyslipidemia or hypertension were also reported with a decrease in semen quality and changes in sex hormones. These might contribute to concomitant oxidative stress and inflammation, and impaired seminal antioxidant capacity ( 34 , 35 ).…”

Impact of metabolic syndrome on sex hormones and reproductive function: a meta-analysis of 2923 cases and 14062 controls

“…The DNA fragmentation in sperms was more common in obese males than normal-weight males [ 42 ]. Furthermore, overweight and obese individuals had an increasing level of oxidative stress and inflammation, which disturbed the spermatogenesis [ 43 ]. On the other hand, diabetes also demonstrated an association with the abnormalities in sex hormone levels and semen quality [ 44 ].…”