Organophosphorus Flame-Retardant 2-Isopropylphenyl Diphenyl Phosphate Antagonizes Estrogen, Retinoic Acid, and Retinoic X Receptors and Leads to Adverse Reproductive Outcomes in Japanese Medaka (Oryzias latipes)

Abstract

2-Isopropylphenyl diphenyl phosphate (2IPPDPP) is the main component of the widely used flame-retardant mixture Firemaster 550 (FM550) and is increasingly detected in the environment; however, few studies focused on its toxicity. Here, we identified its antagonistic activities against medaka estrogen receptor (mER), retinoic acid receptor (mRAR), and retinoid X receptor (mRXR) with 50% inhibitory concentrations of 29.0, 14.6, and 39.4 μM, respectively. After sexually mature female medaka were exposed to 2IPPDPP at 136.2, 838.1, and 1433.7 ng/L for 35 days, its concentrations in the ovary (327.7−2746.1 ng/g lipid weight (lw)) and muscle (109.3−2797.1 ng/g lw) were higher than those in the liver (89.7−1164.8 ng/g lw) and brain (64.4−1152.6 ng/g lw), showing high exposure for eggs. The antiestrogenic activity may contribute to the downregulation of vtg gene expressions in the liver, therefore leading to ovarian retardation, which may reduce egg production by 32.4% at 838.1 ng/L and 37.3% at 1433.7 ng/L. 2IPPDPP exposure impacted embryonic development at 1 h postfertilization, causing abnormal mitosis, uneven cell division, and ultimately early embryonic mortality (42.7% at 838.1 ng/L and 51.7% at 1433.7 ng/L) by inhibiting pdk1 expression. Such toxicity may also occur in higher vertebrates, raising concerns about its risks.