Silent Legacy I: Paternal Phthalate Exposure Shifts Androgen–Estrogen Receptor Balance and Induces Transgenerational Reproductive Disruption, Signs of Autism, Feminization and Homosexuality in Mice

The increasing prevalence of reproductive and neurodevelopmental disorders has raised concern over endocrine-disrupting chemicals (EDCs). Phthalates, including di-butyl phthalate (DBP) and di-(2-ethylhexyl) phthalate (DEHP), are widely used industrial chemicals that disrupt hormonal regulation and impair male fertility. This study examined the effects of paternal prepubertal exposure to DBP and DEHP on endocrine function, receptor expression, and sexual behavior in Swiss albino mice. Sixty-three F₀ males (21 days old) were divided into control and treated groups receiving DBP & DEHP at 100, 200 & 400 mg/kg body weight for 15 days, followed by recovery. Hormonal assays for testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were performed, and estrogen receptor alpha (ERα) and androgen receptor (AR) expression were evaluated immunohistochemically. Low dose exposed males were bred to generate F₁ and subsequently F₂ offspring. Paternal phthalate exposure reduced testosterone, increased LH and FSH, upregulated ERα, and attenuated AR expression, with alterations persisting into adulthood. Behavioral assessments revealed impaired sexual performance, delayed mating, reduced motivation, feminization, homosexuality, autism like traits, and circadian rhythm disruption in F₀ males, effects persisting in F₁ offspring. These findings demonstrate that paternal phthalate exposure induces lasting endocrine, receptor, and behavioral disturbances with multigenerational consequences, underscoring the need for safety evaluation.