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Connections between the mixture containing bis(2- ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP) and bisphenol A (BPA) and liver injury were explored through in silico investigation and 2 in vivo models. Comparative Toxicogenomics Database (CTD), ShinyGO, ToppCluster and Cytoscape were used for bioinformatic analysis. In vivo subacute study was performed on rats - five groups (n = 6): (1) Control: corn oil, (2) DEHP: 50 mg/kg b.w./day, (3) DBP: 50 mg/kg b.w./day, (4) BPA: 25 mg/kg b.w./day, (5) MIX: DEHP + DBP + BPA. Zebrafish embryos were exposed to the investigated substances in different doses, singularly and combined (binary and ternary mixtures). Liver injury was linked to 75 DEHP, DBP, and BPA genes, mostly connected to inflammation/oxidative stress. In rats, significant alterations in redox status/bioelements and pathohistology were most notable or exclusively present in MIX (probable additive effects). BPA decreased liver area (LA) index in dose-dependent manner. DEHP (< 2 µg/mL) and DBP (≤ 5 µg/mL) reduced LA values, while their higher doses increased LA index. The effect of DBP in binary mixtures led to a lethal outcome at the two highest concentrations, while the hepatotoxicity of DEHP/DBP/BPA mixture was dictated by BPA (confirmed by the benchmark dose analysis). [Display omitted] • Oxidative stress and inflammation – the most important mechanisms. • Changes in rat liver – most prominent/present only in the MIX group. • Redox status and bioelements changes – most prominent/present only in the MIX group. • Zebrafish: DBP in binary mixtures – lethal outcome at two highest concentrations. • Zebrafish: hepatotoxicity of DEHP/DBP/BPA mixture dictated by BPA. [ABSTRACT FROM AUTHOR]

Growing evidence suggests that developmental exposure to bisphenol A (BPA)—a synthetic endocrine disruptor—causes atypical reproductive phenotypes that may persist for generations. However, the precise mechanism(s) by which BPA causes these adverse consequences is unclear. Here, pregnant female mice were orally exposed to 50 μg, 5 mg, and 50 mg BPA/kg body weight (bw)/day from 7 to 14 days of gestation. Corn oil treatments were used as control. The first filial generation (F1) and F2 males were used to generate F3 by mating them with unexposed females. High BPA doses impaired F1 and/or F1–F2 (multigenerational effect) male reproduction (i.e., disrupted testicular germ cell organization and spermatogenesis, altered sperm biochemical properties, and decreased sperm count, motility, and fertility) but not that of F3 males (transgenerational effect). Moreover, the observed multigenerational transmission of the abnormal reproductive traits was associated with alterations in the sperm DNA methylation patterns of specific male generations, with substantial proteomic changes in F1–F3 at the highest BPA dose. Given that the proteins related to male fertility and epigenetic modification are highly conserved among vertebrates, our findings may shed light on how exposure to environmental factors during pregnancy affects fertility in future generations in both humans and the other animals. [Display omitted] • BPA affects germ cell organization, spermatogenesis, sperm function, and fertility. • BPA significantly impaired sperm function/male fertility in F1 and/or F1–F2 males. • BPA effects linked to DNA methylation and proteome changes in male germ cells. • Levels of BPA exposure need to be redefined that are currently thought to be nontoxic. [ABSTRACT FROM AUTHOR]