Prenatal Exposure to Triclocarban Impairs ESR1 Signaling and Disrupts Epigenetic Status in Sex-Specific Ways as Well as Dysregulates the Expression of Neurogenesis- and Neurotransmitter-Related Genes in the Postnatal Mouse Brain

Abstract

Triclocarban is a highly effective and broadly used antimicrobial agent. Humans are continually exposed to triclocarban, but the safety of prenatal exposure to triclocarban in the context of neurodevelopment remains unknown. In this study, we demonstrated for the first time that mice that had been prenatally exposed to environmentally relevant doses of triclocarban had impaired estrogen receptor 1 (ESR1) signaling in the brain. These mice displayed decreased mRNA and protein expression levels of ESR1 as well as hypermethylation of the Esr1 gene in the cerebral cortex. Prenatal exposure to triclocarban also diminished the mRNA expression of Esr2, Gper1, Ahr, Arnt, Cyp19a1, Cyp1a1, and Atg7, and the protein levels of CAR, ARNT, and MAP1LC3AB in female brains and decreased the protein levels of BCL2, ARNT, and MAP1LC3AB in male brains. In addition, exposure to triclocarban caused sex-specific alterations in the methylation levels of global DNA and estrogen receptor genes. Microarray and enrichment analyses showed that, in males, triclocarban dysregulated mainly neurogenesis-related genes, whereas, in females, the compound dysregulated mainly neurotransmitter-related genes. In conclusion, our data identified triclocarban as a neurodevelopmental risk factor that particularly targets ESR1, affects apoptosis and autophagy, and in sex-specific ways disrupts the epigenetic status of brain tissue and dysregulates the postnatal expression of neurogenesis- and neurotransmitter-related genes.

Drug discovery and potential gene and pathway associated with polycystic ovary syndrome through text mining and biomedical databases

“…Interestingly, CYP19A1 mutations are usually accompanied by ESR1 mutations in relapsed breast cancer patients [15] . In addition, triclocarban, a risk factor for ESR1, can affect apoptosis and autophagy [18] . Dual inhibition of IGF1R and MAPK/ERK enhances susceptibility to autophagy inhibition in pancreatic cancer [19] .…”

Posttreatment with PaPE-1 Protects from Aβ-Induced Neurodegeneration Through Inhibiting the Expression of Alzheimer’s Disease-Related Genes and Apoptosis Process That Involves Enhanced DNA Methylation of Specific Genes

“…Specific methylation of Bax and Bcl2 genes was measured as described previously [ 32 , 33 ]. Genomic DNA was obtained with GenElute™ Mammalian Genomic DNA Miniprep Kits, and the quantity of obtained DNA was assessed spectrophotometrically at wavelengths of 260 nm and 260/280 nm with a NanoDrop ND-1000 UV‒Vis Spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA).…”

Emerging Evidence on Membrane Estrogen Receptors as Novel Therapeutic Targets for Central Nervous System Pathologies

“…Nuclear- and membrane-initiated estrogen signaling cooperate to orchestrate the pleiotropic effects of estrogens. It is generally accepted that ER-mediated signaling plays key roles in neurogenesis [ 5 , 6 , 7 ], neurodevelopment [ 8 ], and neuroprotection [ 9 , 10 , 11 ], and its impairment may lead to a predisposition to neurodegenerative diseases [ 12 , 13 ] and mood disorders [ 14 ]. However, the application of estrogens as neuroprotectants in humans presents numerous limitations, mainly due to detrimental side effects triggered by the activation of classical ERs in peripheral tissues.…”