Life-cycle triphenyl phosphate exposure triggers gender-specific reproductive and transgenerational toxicities in zebrafish

Triphenyl phosphate (TPHP), a prevalent organophosphate ester flame retardant, is recognized as a ubiquitous environmental pollutant in aquatic ecosystems. Although its reproductive toxicity has been acknowledged, the sex-specific and intergenerational impacts remain inadequately understood. In this investigation, zebrafish underwent life-cycle exposure to TPHP at an environmentally relevant concentration (26 μg/L) to assess reproductive impairment in F0 generation and potential transgenerational effects on F1 progeny. Results demonstrated significant gonadal bioaccumulation of TPHP, with testicular concentrations approximately seven times higher than ovarian levels. TPHP exposure led to a female-biased sex ratio and reduced reproductive output, accompanied by severe gonadal impairments, including inhibited spermatogenesis in males and arrested oocyte maturation in females. These adverse effects were associated with sex-dependent disruptions in the hypothalamus-pituitary-gonad-liver (HPGL) axis, as evidenced by altered serum levels of key hormones and dysregulated gene expression within HPGL axis. Notably, parental TPHP exposure induced significant developmental toxicity in unexposed F1 offspring, characterized by increased mortality, elevated rates of malformations, reduced heart rate, and decreased body length, along with endocrine disruption. Both parental lineages contributed to these effects; however, some effects were occasionally more pronounced following paternal exposure. Molecular docking suggested that TPHP might exert its effects through complex mechanisms involving androgen receptor (AR), estrogen receptor (ER), and aromatase (CYP19) dependent pathways. This study illustrates that TPHP induces sex-specific reproductive and transgenerational toxicities, which unveil significant ecological risks for aquatic populations and emphasize the urgent need for environmental measures to safeguard the ecosystems.