Replacement bisphenols, phthalates, and micro-/nanoplastic exposures in human reproductive endocrinology

Restrictions on bisphenol A (BPA), continued exposure to phthalates, and the emergence of micro- and nanoplastics (MNPs) have altered the plastic-associated exposure landscape relevant to human reproduction. Existing reviews commonly address these exposures separately or summarize broad reproductive outcomes. This review instead develops a comparative mechanistic framework centered on two connected mechanisms: disruption of gonadotropin-responsive steroidogenesis and oxidative stress, inflammation, and barrier dysfunction. Human biomonitoring, reproductive-tissue, fertility-clinic, and epidemiological evidence are prioritized, while experimental studies are used to resolve mechanisms that cannot be tested directly in humans. Replacement bisphenols can reproduce BPA-like estrogenic, anti-androgenic, and steroidogenic effects, but their actions are analogue-, tissue-, dose-, and time-dependent. Selected phthalates and metabolites have been shown in experimental and ex vivo studies to impair androgen synthesis through altered gonadotropin signaling, cholesterol transport, mitochondrial function, and steroidogenic enzymes. MNPs are heterogeneous particulate exposures whose biological effects depend on polymer composition, size, shape, surface properties, weathering, corona formation, additives, and co-contaminants. Experimental studies using specific MNP models suggest mainly indirect effects on steroidogenesis through particle uptake, altered gonadotropin-responsive signaling, organelle stress, inflammation, and barrier injury. Despite different initiating mechanisms, evidence across the three exposure classes implicates steroidogenesis, redox regulation, inflammatory signaling, and reproductive tissue barriers, although the strength and directness of evidence differ. Human evidence is strongest for phthalates, emerging and analogue-specific for replacement bisphenols, and still methodologically limited for MNP-related clinical outcomes. The framework separates direct catalytic inhibition from altered expression, tissue detection from toxicity, and mechanistic plausibility from demonstrated human effect, supporting targeted research, cautious clinical communication, safer chemical substitution, and MNP exposure mitigation.