Can DEHP-related phthalates disrupt Leydig cell steroidogenesis and lower testosterone in men?

Exposure to di(2-ethylhexyl) phthalate (DEHP) is increasingly recognized as a significant contributor to male endocrine disruption, particularly affecting aging and subfertile populations.

Clinical evidence of endocrine disruption

• Large-scale epidemiological studies, including NHANES analyses and clinical cohorts, demonstrate that elevated urinary levels of DEHP metabolites—specifically MEHP, MEHHP, and MEOHP—are consistently associated with lower total testosterone, free testosterone, and free androgen index.
• These adverse associations are most pronounced in middle-aged and older men (ages 40–60+) and subfertile cohorts.
• Exposed individuals often exhibit altered reproductive signaling, characterized by elevated sex hormone-binding globulin (SHBG) and a blunted hypothalamic-pituitary-gonadal feedback loop, where luteinizing hormone (LH) levels fail to rise adaptively despite declining testosterone.

Molecular mechanisms in Leydig cells

• The primary active metabolite, MEHP, directly induces the generation of reactive oxygen species (ROS) in Leydig cells, leading to severe oxidative stress.
• This oxidative environment impairs LH-stimulated adenylate cyclase activity, reducing cyclic AMP (cAMP) production and downstream protein kinase A (PKA) signaling.
• Suppressed cAMP/PKA signaling inhibits the transcriptional activity of steroidogenic factor-1 (SF-1), resulting in the downregulation of Steroidogenic Acute Regulatory (StAR) protein—the critical rate-limiting transporter required to shuttle cholesterol into the mitochondria.
• Concurrently, MEHP activates PPARalpha to downregulate translocator protein (TSPO) and directly suppresses downstream steroidogenic enzymes, including CYP11A1, CYP17A1, 3β-HSD, and 17β-HSD, halting the biosynthetic pathway of testosterone.

Bottom line

• DEHP-related phthalates disrupt male reproductive health by inducing Leydig cell oxidative stress, which suppresses crucial StAR-mediated mitochondrial cholesterol transport and key steroidogenic enzymes, ultimately manifesting clinically as lower testosterone and altered hormone signaling in adult men.