Can mono-2-ethylhexyl phthalate exposure disrupt testosterone production and androgen signaling?

Exposure to mono-2-ethylhexyl phthalate (MEHP), the primary active metabolite of the plasticizer DEHP, significantly impairs male endocrine function by directly targeting Leydig cells.

Mechanistic explanations

• Redox-sensitive modulation: MEHP exposure induces dose-dependent reactive oxygen species (ROS) generation in Leydig cells. Although low concentrations can transiently elevate basal steroidogenesis, higher or chronic concentrations trigger severe oxidative stress and disrupt mitochondrial membrane potential.
• Impaired cholesterol transport: MEHP represses the hormone-induced transcription and maturation of steroidogenic acute regulatory (StAR) protein, blocking the critical, rate-limiting transport of cholesterol into the mitochondria.
• Enzymatic suppression: Under luteinizing hormone (LH) or hCG stimulation, MEHP-induced oxidative stress suppresses the activities of core steroidogenic enzymes, including CYP11A1, CYP17A1 (specifically its 17,20-lyase activity), 3β-HSD, and 17β-HSD.
• Developmental gene modulation: MEHP exposure alters insulin-like factor 3 (INSL3) expression, downregulating it in developmental and fetal contexts, which disrupts early testicular signaling.

Impact on androgen signaling

• Lowered testosterone production: The combined failure of substrate mobilization (StAR) and enzymatic conversion leads to a robust decline in hormone-stimulated testosterone output.
• Weakened downstream signaling: This steroidogenic decline diminishes downstream active androgens, specifically 5α-dihydrotestosterone (5α-DHT) and androstenedione. It also suppresses 5α-reductase in developing Leydig cells, ultimately compromising androgen-dependent signaling pathways.

Bottom line

• MEHP exposure directly disrupts male steroidogenesis by inhibiting StAR-mediated mitochondrial cholesterol transport and suppressing key steroidogenic enzymes through oxidative stress, resulting in significantly lowered testosterone production and weakened downstream androgen signaling.