Paternal Cocaine Exposure and Its Testicular Legacy: Epigenetic, Physiological, and Intergenerational Consequences

Cocaine use remains a major public health concern, with rising global prevalence and a well-established profile of neurotoxicity and addictive potential. While the central nervous system has been the primary focus of cocaine research, emerging evidence indicates that cocaine also disrupts male reproductive physiology. In the testis, cocaine alters the endocrine microenvironment, induces cell-specific damage, and disrupts spermatogenesis. Cocaine also interferes with epigenetic programming in germ cells and mature sperm, potentially leading to heritable epimutations. Epidemiology data reveal that approximately two-thirds of regular cocaine users are males of reproductive age, and preclinical models have documented numerous behavioral and molecular alterations in their offspring, often linked to paternal cocaine exposure-such as increased drug resistance or vulnerability, altered anxiety-like behavior, impaired learning/memory, disrupted social behaviors, and shifts in neural circuitry and gene expression in reward-related brain regions. This review aims to integrate findings from studies that have independently examined testicular dysfunction, germline epigenetic reprogramming, and offspring outcomes, offering a unified perspective on their potential interconnections and highlighting future directions for research in the field of epigenetic inheritance.