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.

Observation of Emerging Photoinitiator Additives in Household Environment and Sewage Sludge in China

“…2-Cl-TX, which was not found in the collected commercial products and indoor dust samples, could be positively identified in 10% of the sludge samples, with concentrations ranging from < MQL to 16.9 ng/ g. The occurrence of 2-Cl-TX in sludge samples might imply multiple inputs and/or transformation of TX contaminants in WWTPs. Due to the reported antiandrogenic and antiestrogenic activities for 2-ITX, DETX and 2-Cl-TX in vitro studies, 39 the occurrence of these TX chemicals in the environment should be of concern.…”

Disruption of endocrine function in H295R cell in vitro and in zebrafish in vivo by naphthenic acids

“…H295R cells have been used for rapid screening of potential disruption of steroidogenic pathways as well as determining mechanisms of action of toxicants [39][40][41][42]. And determination of steroid hormones released into the medium has been suggested to be the most integrative, functional endpoint and has been established previously in H295R cells [25,26,43]. In the current study, significantly inhibited production of T and induced production of E2 and P4 were observed in H295R cells after exposure to OS-NAs and C-NAs.…”

Adrenocortical endocrine disruption

“…The use of gas chromatography tandem mass spectrometry analysis of H295R media has been developed, and used to evaluate steroid profiles, and compared with metabolomics methodology using ultra performance liquid chromatography-time-of-flight-mass-spectrometry (UPLC-ToF-MS) to identify specific "fingerprints" of endocrine disrupting chemicals (see [52,53]). It has also been proposed to use this cell line, along with other assays, in an integrated testing strategy for oestrogenicity to broaden sensitivity in identification of endocrine disruption through this mechanism [54].…”

“…It has also been proposed to use this cell line, along with other assays, in an integrated testing strategy for oestrogenicity to broaden sensitivity in identification of endocrine disruption through this mechanism [54]. Although the endpoints reported in these studies [52][53][54] pertain largely to sex steroids, they can also be applied to develop fingerprints using cortisol, aldosterone and other steroids specific to adrenocortical function. Such a development to the OECD Test Guideline on H295R in endocrine disruption evaluation [55], which currently only considers production of 17b-oestradiol and testosterone as endpoints, and validation of cortisol and aldosterone as endpoints, would be a major step in recognizing the unique role of the adrenal cortex and the extent to which glucocorticoid and/or mineralocorticoid producing adrenocortical cells may be a target for endocrine disruption.…”