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Homosalate (HS) and octisalate (OS), which are used in sunscreen for the purpose of blocking ultraviolet rays, are frequently detected in water environment. Although effects on estrogens and androgens have been reported, studies on thyroid and growth hormone endocrine disruption are limited. In the present study, larval mortality was compared in wild-type and two knockout fish (thyroid hormone receptor alpha a knockout (thrαa-/-) and dre-miR-499 knockout (dre-miR-499-/-)) after 96 h of exposure to HS and OS (0, 0.003, 0.03, 0.3, 3, 30 and 300 µg/L). To investigate the mechanisms of thyroid and growth hormone endocrine disruption, we measured the levels of triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH), growth hormone (GH), and insulin-like growth factor-1 (IGF-1), and the regulation of representative genes related to the hypothalamus-pituitary-thyroid (HPT) and GH/IGF axis in wild-type zebrafish exposed to target chemicals. The significantly lower larval survival rate of thrαa-/- and dre-miR-499-/- fish exposed to 300 μg/L of HS and OS suggest that thyroid hormone receptors and dre-miR-499 play a crucial role in the toxic effects of HS and OS. The finding of a significant increase in T3 and T4 in zebrafish larvae exposed to HS and OS supports a significant decrease in the crh gene. The reduction of GH and IGF-1 in fish exposed to HS and OS is well supported by the regulation of genes involved in the GH/IGF axis. Our observations suggest that exposure to HS and OS affects not only thyroid hormone receptors and their associated miRNAs, but also the feedback routes of HPT and GH/IGF axes, ultimately leading to growth reduction. [Display omitted] • Thrαa-/- and miR-499-/- can sensitively identify thyroid endocrine disruptors. • Body length reduced with increasing homosalate (HS) and octisalate (OS) exposure. • HS increased T3 and T4 contents, and decreased TSH, GH, and IGF-1 concentrations. • HS upregulated genes related to thyroid hormone synthesis (trαa, tpo, and nis). • OS increased T4 contents, while T3 and TSH were not statistically significant. [ABSTRACT FROM AUTHOR]

Abstract Homosalate is an organic ultraviolet filter used in most sunscreens but has been reported to be toxic to marine organisms. The estrogenic activity of homosalate has also been reported, but its endocrine-disrupting effect remains unclear. Although homosalate has been detected in human placental tissues, its effect on the survival of human trophoblast cells needs to be investigated. Therefore, in this study, we evaluated if HTR8/SVneo, a human trophoblast cell line, treated with homosalate showed decreasing proliferative activity in a dose-dependent manner. Homosalate promoted the death of HTR8/SVneo cells with elevated lipid peroxidation and intracellular Ca2+ concentration. It also induced endoplasmic reticulum stress and mitochondrial morphological disturbances associated with the differentiation of human trophoblast cells. However, when the intracellular Ca2+ or reactive oxygen species were removed using BAPTA-AM or N-acetyl-L-cysteine (NAC), the cell proliferation suppressed by homosalate was restored. Homosalate also significantly inhibited the invasion of HTR8/SVneo cells. Furthermore, it modulated phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) signaling pathways, which were involved in the cross-talk between both signaling pathways in HTR8/SVneo cells. Thus, homosalate adversely affects the survival, proliferation, and invasiveness of human trophoblast cells and therefore pregnant women should practice caution while using personal care products containing homosalate. Graphical abstract A schematic diagram illustrating current working hypothesis regarding the effects of homosalate on human trophoblast cells. Homosalate induces ROS production in human trophoblast cells, followed by excessive lipid peroxidation. Furthermore, elevated ROS increases cytosolic Ca2+ concentration accompanied by loss of mitochondrial membrane potential (MMP). The disruption of mitochondrial membrane causes apoptotic cell death of human trophoblast cells. Moreover, homosalate activates phosphorylation of PI3K/AKT pathways and MAPK pathways with cross-talk between the two pathways. Finally, the alteration of signaling pathways causes transcriptional regulation in nucleus, leading to downregulation of proliferation and invasion of human trophoblast cells. Image Highlights • Homosalate inhibits survival and proliferation and invasion of human trophoblasts. • Homosalate blocks AKT and MAPK signaling pathways in trophoblast cells. • Homosalate-induced oxidative stress results in disruption of mitochondrial membrane. [ABSTRACT FROM AUTHOR]