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BACKGROUND: Current evidence suggests an increased risk for cancer mortality in those with low aryl hydrocarbon receptor repressor (AHRR) DNA methylation (DNAm) levels. Therefore, AHRR DNAm could identify a more "fragile" group at risk for cancer mortality than questionnaire-based evaluations. Given this, the aim was to identify "fragile" groups at risk of cancer mortality by integrating questionnaire-based smoking indices and leukocyte AHRR DNAm levels in the Japanese population. METHODS: The target population was 795 participants without a clinical history who underwent a health checkup in 1990. They were followed for up to 30 years for mortality. The AHRR DNAm levels in leukocytes were measured by the pyrosequencing method. HRs for cancer mortality were calculated using a Cox proportional hazards model. RESULTS: Significantly higher HRs for all-cancer mortality were observed in low AHRR DNAm groups regardless of smoking intensity [pack-years <20: 3.69 (1.46-9.37); pack-years ≥20: 2.13 (1.11-4.09)]. Compared with current smokers, significantly lower HRs for all-cancer mortality were observed in the group with high AHRR DNAm regardless of years since quitting [YSQ ≤10: 0.13 (0.02-0.96); YSQ >10: 0.28 (0.08-0.98)]. Even for YSQ greater than 10, there was no significant mortality risk reduction in the low AHRR DNAm group. CONCLUSIONS: The population with low AHRR DNAm levels had a higher risk of cancer mortality even with low smoking exposure. Furthermore, no significant risk reduction was observed in former smokers with low AHRR DNAm levels. IMPACT: AHRR DNAm levels in leukocytes may help identify groups at risk for cancer mortality overlooked by questionnaire-based smoking indices.

Global fructose consumption is on the rise; however, maternal high-fructose intake may have adverse effects on offspring. We previously demonstrated that excessive fructose intake by rat dams altered steroidogenic gene transcription in the hippocampus of offspring. Herein, we examined how maternal high-fructose intake influences the regulation of adrenal glucocorticoid levels in offspring. Rat dams received 20% fructose solution during gestation and lactation. After weaning, the offspring were provided normal water. Maternal high-fructose intake did not alter mRNA expression levels of adrenal corticosterone-synthesizing and corticosterone-inactivating proteins or the circulating adrenocorticotropic hormone levels of offspring at postnatal day (PD) 21; however, it increased circulating corticosterone levels and decreased mRNA and protein levels of adrenal 5α-reductase type 1 and 11β-hydroxysteroid dehydrogenase type 2 in offspring at PD160. Furthermore, maternal high-fructose intake enhanced DNA methylation of the adrenal 5α-reductase 1 promoter region in PD160 offspring. Thus, maternal high-fructose intake was found to affect adrenal steroid hormone clearance in adult offspring - at least in part - through epigenetic mechanisms.