Genome-wide gene expression profiling of low-dose, long-term exposure of human osteosarcoma cells to bisphenol A and its analogs bisphenols AF and S.
The bisphenols AF (BPAF) and S (BPS) are structural analogs of the endocrine disruptor bisphenol A (BPA), and are used in common products as a replacement for BPA. To elucidate genome-wide gene expression responses, estrogen-dependent osteosarcoma cells were cultured with 10 nM BPA, BPAF, or BPS, for 8 h and 3 months. Genome-wide gene expression was analyzed using the Illumina Expression BeadChip. Three months exposure had significant effects on gene expression, particularly for BPS, followed by BPAF and BPA, according to the number of differentially expressed genes (1980, 778, 60, respectively), the magnitude of changes in gene expression, and the number of enriched biological processes (800, 415, 33, respectively) and pathways (77, 52, 6, respectively). 'Embryonic skeletal system development' was the most enriched bone-related process, which was affected only by BPAF and BPS. Interestingly, all three bisphenols showed highest down-regulation of genes related to the cardiovascular system (e.g., NPPB, NPR3, TXNIP). BPA only and BPA/BPAF/BPS also affected genes related to the immune system and fetal development, respectively. For BPAF and BPS, the 'isoprenoid biosynthetic process' was enriched (up-regulated genes: HMGCS1, PDSS1, ACAT2, RCE1, DHDDS). Compared to BPA, BPAF and BPS had more effects on gene expression after long-term exposure. These findings stress the need for careful toxicological characterization of BPA analogs in the future.
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: anja.fic@ffa.uni-lj.si.
A
A
Fic
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: simona.jurkovic@ffa.uni-lj.si.
S Jurković
SJ
Mlakar
Faculty of Medicine, Institute of Biochemistry, Centre for Functional Genomics and Bio-Chips, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia. Electronic address: peter.juvan@mf.uni-lj.si.
P
P
Juvan
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: vid.mlakar@ffa.uni-lj.si.
V
V
Mlakar
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: janja.marc@ffa.uni-lj.si.
J
J
Marc
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: marija.sollner@ffa.uni-lj.si.
M Sollner
MS
Dolenc
Occupational and Environmental Medicine, Faculty of Medicine, Lund University, S-221 85 Lund, Sweden. Electronic address: karin.broberg@ki.se.
K
K
Broberg
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: lucija.peterlin@ffa.uni-lj.si.
L Peterlin
LP
Mašič
D001559:Benzhydryl Compounds / Q000633:toxicity*; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D012516:Osteosarcoma / Q000235:genetics*; D010636:Phenols / Q000633:toxicity*; D013450:Sulfones / Q000633:toxicity*; D000098831:Bisphenol S Compounds; D000098826:Bisphenol A Compounds; D005466:Fluorocarbons
D001559:Benzhydryl Compounds; D010636:Phenols; D013450:Sulfones; C543008:bisphenol S; D000098831:Bisphenol S Compounds; C006780:bisphenol A; D000098826:Bisphenol A Compounds; C583074:bisphenol AF; D005466:Fluorocarbons
BPA analogs; BPAF; BPS; Microarray; Osteosarcoma cells