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  • Prenatal caffeine ingestion induces aberrant DNA methylation and histone acetylation of steroidogenic factor 1 and inhibits fetal adrenal steroidogenesis.

Prenatal caffeine ingestion induces aberrant DNA methylation and histone acetylation of steroidogenic factor 1 and inhibits fetal adrenal steroidogenesis.

Toxicology (2014-04-11)
Jie Ping, Jian-fei Wang, Lian Liu, You-e Yan, Fang Liu, You-ying Lei, Hui Wang
ABSTRACT

Prenatal caffeine ingestion is one of the risk factors for intrauterine growth retardation (IUGR). Adrenal plays a pivotal role, mainly through steroidogenesis, in the regulation of intrauterine homeostasis and in fetal development and maturation. We have shown that prenatal caffeine ingestion can inhibit fetal adrenal corticosterone production, but the underlying mechanism is unknown. This study investigated the effects of prenatal caffeine ingestion on corticosterone and its associated synthesized enzymes (steroidogenic acute regulatory protein, StAR; 3β-hydroxysteroid dehydrogenase, 3β-HSD; cytochrome P450 cholesterol side chain cleavage, P450scc; P450c21; and P450c11) in the fetal adrenal in rats and further explored the underlying mechanism by analyzing the epigenetic modification and expression of the key transcription factor steroidogenic factor-1 (SF-1). The pregnant rats were intragastrically treated with 120 mg/kg.d caffeine from gestational day 11-20. The results showed that the IUGR rate was 51.2% after caffeine treatment. The contents of corticosterone and the mRNA levels of StAR, P450scc, P450c21, and P450c11 were decreased significantly in the fetal adrenal. Furthermore, caffeine reduced both the protein and the mRNA expression of SF-1 in the fetal adrenal. The epigenetic analysis showed that caffeine treatment can significantly enhance the mRNA expression of DNA methyltransferase (Dnmt) 1, Dnmt3a, histone deacetylases (Hdac) 1, and Hdac2. The detection of DNA methylation by bisulfite-sequencing PCR uncovered a notably increased total methylation rate in the SF-1 promoter. The ChIP assay showed decreased acetylation levels of H3K9 and H3K14 in the SF-1 promoter. In conclusion, prenatal caffeine ingestion is able to induce aberrant DNA methylation and histone acetylation of the SF-1 promoter in the rat fetal adrenal. These effects may contribute to the inhibition of the expression of SF-1 and its associated steroidogenic enzymes and the production of corticosterone during fetal development.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Caffeine, SAJ special grade, ≥98.5%
Supelco
Caffeine, Pharmaceutical Secondary Standard; Certified Reference Material
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Caffeine Melting Point Standard, Pharmaceutical Secondary Standard; Certified Reference Material
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Caffeine, anhydrous, tested according to Ph. Eur.
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Mettler-Toledo Calibration substance ME 18872, Caffeine, analytical standard, for the calibration of the thermosystem 900, traceable to primary standards (LGC)
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Caffeine, certified reference material, TraceCERT®
USP
Caffeine melting point standard, United States Pharmacopeia (USP) Reference Standard
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Caffeine, BioXtra
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Caffeine, powder, ReagentPlus®
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Caffeine, meets USP testing specifications, anhydrous
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Caffeine, Sigma Reference Standard, vial of 250 mg
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Corticosterone solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®
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Caffeine, anhydrous, 99%, FCC, FG
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Caffeine, United States Pharmacopeia (USP) Reference Standard
Caffeine, European Pharmacopoeia (EP) Reference Standard
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Caffeine solution, analytical standard, 1.0 mg/mL in methanol
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Corticosterone, ≥92%
Sigma-Aldrich
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Corticosterone, VETRANAL®, analytical standard
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Melting point standard 235-237°C, analytical standard
Supelco
Caffeine solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®
Caffeine for system suitability, European Pharmacopoeia (EP) Reference Standard