Bisphenol AP is anti-estrogenic and may cause adverse effects at low doses relevant to human exposure

Highlights: • BPAP shows weak estrogenicity but strong antiestrogenicity in vitro. • BPAP shows antiuterotrophic effect in mice at doses of 80 μg kg⁻¹ bw/day and higher. • BPAP disrupts glycemic homeostasis in mice at doses relevant to human exposure. • BPAP induces opposite patterns of gene regulation than that of E₂ in mouse uteri. A recent increase in the use of bisphenol A (BPA) alternatives to manufacture plastics has led to safety concerns. Here, we evaluated the estrogenic and anti-estrogenic activities of bisphenol AP (BPAP), a poorly studied BPA alternative, using in vitro, in vivo and in silico tools. BPAP exhibited weak estrogenicity but strong anti-estrogenicity (IC₅₀ = 2.35 μM) in a GeneBLAzer™ β-lactamase reporter gene assay. BPAP, when administered alone or in combination with E₂ (50 μg kg⁻¹ bw d⁻¹) for 3 d, significantly decreased the uterine weights of post-weaning CD-1 mice at doses of 10 mg kg⁻¹ bw d⁻¹ and higher. When administered alone to prepubertal CD-1 mice for 10 d, BPAP significantly decreased the uterine weights at doses of 80 μg kg⁻¹ bw d⁻¹ and higher. Toxicogenomic analysis showed that BPAP regulated an opposite patterns of gene expression than that of E₂ in mouse uteri. In a glucose tolerance test using male mice, BPAP was found to disrupt the blood glucose homeostasis at low doses relevant to human exposure (1 and 100 μg kg⁻¹ bw d⁻¹). Our results suggest that BPAP should be of great concern which might affect the sexual development in immature feminine and disrupt the blood glucose homeostasis at very low doses.