Abstract
Triclocarban is a phenyl ether that has recently been classified as a contaminant of emerging concern. Evidence shows that triclocarban is present in human tissues, but little is known about the impact of triclocarban on the nervous system, particularly at early developmental stages. This study demonstrated that triclocarban that was used at environmentally relevant concentrations induced apoptosis in mouse embryonic neurons, inhibited sumoylation, and changed the epigenetic status, as evidenced by impaired activities of HDAC, sirtuins, and DNMT, global DNA hypomethylation, and alterations of methylation levels of bax, bcl2, Ahr, and Car genes. The use of selective antagonists and specific siRNAs, which was followed by the co-localization of aryl hydrocarbon receptor (AHR) and constitutive androstane receptor (CAR) in mouse neurons, points to the involvement of AHR and CAR in triclocarban-induced neurotoxicity. A 24-h treatment with triclocarban enhanced protein levels of the receptors which was paralleled by Car hypomethylation and Ahr hypermethylation. Car hypomethylation is in line with global DNA hypomethylation and explains the increased mRNA and protein levels of CAR in response to triclocarban. Ahr hypermethylation could reflect reduced Ahr mRNA expression and corresponds to lowered protein levels after 3- and 6-h exposures to triclocarban that is likely related to proteasomal degradation of activated AHR. We hypothesize that the triclocarban-induced apoptosis in mouse neurons and the disruption of epigenetic status involve both AHR- and CAR-mediated effects, which may substantiate a fetal basis of the adult onset of neurological diseases; however, the expression of the receptors is regulated in different ways.
Highlights
Triclocarban (3,4,4′-trichlorocarbanilide) is a phenyl ether that is often added to personal and health care products, including cloths, plastics, and even products dedicated for newborns, as well as pharmaceuticals
Following a concern related to common exposures to triclocarban that was recently verbalized as the so-called The Florence Statement on Triclosan and Triclocarban documents [43], we demonstrated that triclocarban at environmentally relevant concentrations induced apoptosis in mouse embryonic neurons as indicated by a substantial loss of mitochondrial membrane potential, a decrease in BCL2/BAX ratio, and apoptotic fragmentation of cell nuclei
Our study demonstrated for the first time that the triclocarban-induced apoptosis of embryonic neuronal cells is a caspase-3- and BCL2/BAX-dependent process that involves the activation of aryl hydrocarbon receptor (AHR)- and constitutive androstane receptor (CAR)-mediated signaling
Summary
Triclocarban (3,4,4′-trichlorocarbanilide) is a phenyl ether that is often added to personal and health care products, including cloths, plastics, and even products dedicated for newborns, as well as pharmaceuticals. In a recent ranking of potentially dangerous organic pollutants, antimicrobial compound, such as triclocarban, was positioned in the middle of the ranking, but with a higher ranking than bisphenol A (BPA), which has been recognized as a developmental risk factor. Triclocarban accumulates in human tissues, including the maternal and umbilical cord sera where it reaches the values of 2.75 and 0.82 μg/l, respectively [3]. This antimicrobial agent has been detected in urine and cord blood of mother/child pairs from Brooklyn, New York, as well as in two distinct brain regions of the human brain, i.e., the hypothalamus and white-matter tissue [4, 5]. Nanomolar concentrations of triclocarban stimulated a cytotoxic effect of hydrogen peroxide in rat thymocytes, induced cancerogenesis, and altered the expression of thyroid hormone-regulated genes as well as the genes involved in lipid metabolism [7,8,9,10]
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