title: Endocrine-disrupting effects of thioxanthone photoinitiators.
abstract: Photoinitiators used in food packaging ink, such as 2-isopropylthioxanthone (2-ITX), have been shown to migrate into food and beverages. Recently, several studies indicated that 2-ITX might be an endocrine-disrupting chemical. In this work, the effects of 2-ITX, 4-isopropylthioxanthone (4-ITX), 2,4-diethylthio xanthone (2,4-diethyl-TX), 2-chlorothioxanthone (2-chloro-TX), and 1-chloro-4-propoxythioxanthone (1-chloro-4-propoxy-TX) on steroidogenesis and androgen and estrogen receptor-mediated transcription activation have been studied using human H295R adrenocarcinoma cells and yeast hormone bioassays, respectively. None of the compounds showed androgenic or estrogenic activities, but clear antiandrogenic and antiestrogenic activities were observed for 2-ITX, 4-ITX, and 2,4-diethyl-TX, whereas 2-chloro-TX showed only antiandrogenic activity. In an adapted version of the H295R steroidogenesis assay, using gas chromatography-tandem mass spectrometry analysis of H295R media, all five compounds increased levels of 17ß-estradiol and estrone. H295R cells incubated with 2-ITX also showed significantly reduced androgen and increased pregnenolone and progesterone levels. Expression of particular steroidogenic genes, including the one encoding for aromatase (CYP19A1), was significantly upregulated after incubation of H295R cells with 2-ITX, 4-ITX, and 2,4-diethyl-TX. In line with the increased CYP19A1 mRNA expression, 2-ITX increased catalytic activity of aromatase in H295R cells as measured by cognate aromatase assays. The results indicate that thioxanthone derivatives can act as potential endocrine disruptors both at the level of nuclear receptor signaling and steroid hormone production.
authors.affiliation: RIKILT-Institute of Food Safety, Wageningen UR, Wageningen, The Netherlands.
authors.forename: Marit
authors.initials: M
authors.lastname: Reitsma
authors.forename: Toine F H
authors.initials: TF
authors.lastname: Bovee
authors.forename: Ad A C M
authors.initials: AA
authors.lastname: Peijnenburg
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Hendriksen
authors.forename: Ron L A P
authors.initials: RL
authors.lastname: Hoogenboom
authors.forename: Jeroen C W
authors.initials: JC
authors.lastname: Rijk
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D052244:Endocrine Disruptors / Q000633:toxicity*; D008401:Gas Chromatography-Mass Spectrometry; D012739:Gonadal Steroid Hormones / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D017319:Photosensitizing Agents / Q000633:toxicity*; D060888:Real-Time Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D053719:Tandem Mass Spectrometry; D013892:Thioxanthenes / Q000633:toxicity; D044004:Xanthones / Q000633:toxicity*
chemical_list: D017931:DNA Primers; D052244:Endocrine Disruptors; D012739:Gonadal Steroid Hormones; D017319:Photosensitizing Agents; D013892:Thioxanthenes; D044004:Xanthones; C484911:thioxanthone