Sex-related differences in murine hepatic transcriptional and proteomic responses to TCDD

Journal Article · Wed Apr 15 04:00:00 EDT 2015 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2015.02.012· OSTI ID:22465735

Prokopec, Stephenie D.; Watson, John D. ^[1]; Lee, Jamie ^[1]; Pohjanvirta, Raimo ^[2]

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1. Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto (Canada)
2. Laboratory of Toxicology, National Institute for Health and Welfare, Kuopio Finland (Finland)

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant that produces myriad toxicities in most mammals. In rodents alone, there is a huge divergence in the toxicological response across species, as well as among different strains within a species. But there are also significant differences between males and females animals of a single strain. These differences are inconsistent across model systems: the severity of toxicity is greater in female rats than males, while male mice and guinea pigs are more sensitive than females. Because the specific events that underlie this difference remain unclear, we characterized the hepatic transcriptional response of adult male and female C57BL/6 mice to 500 μg/kg TCDD at multiple time-points. The transcriptional profile diverged significantly between the sexes. Female mice demonstrated a large number of altered transcripts as early as 6 h following treatment, suggesting a large primary response. Conversely, male animals showed the greatest TCDD-mediated response 144 h following exposure, potentially implicating significant secondary responses. Nr1i3 was statistically significantly induced at all time-points in the sensitive male animals. This mRNA encodes the constitutive androstane receptor (CAR), a transcription factor involved in the regulation of xenobiotic metabolism, lipid metabolism, cell cycle and apoptosis. Surprisingly though, changes at the protein level (aside from the positive control, CYP1A1) were modest, with only FMO3 showing clear induction, and no genes with sex-differences. Thus, while male and female mice show transcriptional differences in their response to TCDD, their association with TCDD-induced toxicities remains unclear. - Highlights: • Differences exist between the toxicity phenotypes to TCDD in male and female mice. • TCDD-mediated transcriptomic differences were identified between the sexes. • Resistant female mice displayed a large, early-onset, transcriptomic response. • Sensitive male mice displayed a large, late-onset, transcriptomic response. • Fmo2, Fmo3 and Nr1i3 were induced across the time-course in only male mice.

• OSTI ID: 22465735
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 284; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ADULTS
APOPTOSIS
CELL CYCLE
DIOXIN
GENES
GUINEA PIGS
HYDROCARBONS
LIPIDS
LIVER
MESSENGER-RNA
METABOLISM
MICE
PHENOTYPE
RATS
RECEPTORS
SEX
STRAINS
TOXICITY
TRANSCRIPTION FACTORS