The Role of Cholesterol in the Pathogenesis of Hypertension- Associated Nonalcoholic Steatohepatitis

Dietary cholesterol is a crucial risk factor for nonalcoholic steatohepatitis (NASH). Our recent studies indicated that high cholesterol intake was associated with the pathogenesis of hypertension-associated NASH. We developed a novel hypertensive rat model of NASH by feeding stroke-prone spontaneously hypertensive rats (SHRSP5/Dmcr) a high fat and cholesterol (HFC) diet. Histological features resembling human NASH were observed in this model. Furthermore, we investigated the kinetics of cholesterol in the rats fed an HFC diet and determined that suppression of bile acid (BA) detoxification led by HFC feeding results in cytotoxic BA accumulation in hepatocytes, which induces inflammatory response and liver damage. Sex differences in fibrogenesis were also observed in this model, and we found this was associated with a different ability in BA detoxification. Since SHRSP5/Dmcr rats are hypertensive, we investigated the role of hypertension in NASH progression by comparing NASH development among SHRSP5/Dmcr rats, spontaneously hypertensive rats and their original strain, Wistar Kyoto, with normal blood pressure. HFC diet induced more severe hepatic fibrosis in the hypertensive strains compared with the normotensive one. In conclusion, dietary cholesterol plays an essential role in the pathogenesis of NASH, and the combined action of cholesterol and hypertension further aggravates its progression

PPARα- and DEHP-Induced Cancers

Di(2-ethylhexyl)phthalate (DEHP) is a widely used plasticizer and a potentially nongenotoxic carcinogen. Its mechanism had been earlier proposed based on peroxisome proliferator-activated receptor α (PPARα) because metabolites of DEHP are agonists. However, recent evidence also suggests the involvement of non-PPARα multiple pathway in DEHP-induced carcinogenesis. Since there are differences in the function and constitutive expression of PPARα among rodents and humans, species differences are also thought to exist in the carcinogenesis. However, species differences were also seen in the lipase activity involved in the first step of the DEHP metabolism, which should be considered in DEHP-induced carcinogenesis. Taken together, it is very difficult to extrapolate the results from rodents to humans in the case of DEHP carcinogenicity. However, PPARα-null mice or mice with human PPARα gene have been developed, which may lend support to make such a difficult extrapolation. Overall, further mechanical study on DEHP-induced carcinogenicity is warranted using these mice

Effects of prenatal phthalate exposure on thyroid hormone levels, mental and psychomotor development of infants : The Hokkaido Study on Environment and Children's Health

Di (2-ethylhexyl) phthalate (DEHP) is commonly used phthalates and concerns of adverse effects of prenatal DEHP exposure on neonatal thyroid hormone (TH) and neurodevelopment are increasing. However, there is no report regarding association between prenatal DEHP exposure and infant neurodevelopment including TH levels in Japanese population. Thus the aim of present study was to evaluate the associations between prenatal DEHP exposure and mental and psychomotor development of infants 6 and 18 months along with investigating influence on neonatal free thyroxine (FT4) and thyroid stimulating hormone (TSH) levels in the prospective birth cohort study. Maternal blood samples collected between 23-41 weeks of gestation was analyzed for mono (2-ethylhexyl) phthalate (MEHP), metabolite of DEHP levels. Neonatal FT4 and TSH were obtained from mass screening data. Infant neurodevelopment was assessed by Bayley Scale of Infant Development second edition at 6 and 18 month of age. For the final analysis, 328 participants were included. The median levels of maternal MEHP was 10.6 ng/ml, neonatal TSH and FT4 was 2.20 μU/ml and 2.03 ng/ml, respectively. We did not find any associations between prenatal DEHP exposure and neonatal TH levels or infant mental and psychomotor development at 6 and 18 month. In this study, prenatal DEHP exposure did not show adverse effects on infant TH levels or mental and psychomotor development in early life stage. However, our previous study revealed negative effects of prenatal DEHP exposure on sex hormone levels, continuous investigation on neurodevelopment in later life in association with prenatal DEHP exposure is necessary

Prenatal di-2-ethylhexyl phthalate exposure and cord blood adipokine levels and birth size : The Hokkaido study on environment and children's health

Di-2-ethylhexyl phthalate (DEHP) is one of the most widely used phthalates. Metabolites of DEHP are detectable in majority of the population. Findings on adverse health outcomes, particularly birth weight in association with prenatal exposure to DEHP remain equivocal. Besides, there is insufficient evidence to address influence on metabolic function from epidemiological studies. Thus, our objective was to investigate cord blood adipokine levels and birth size in association with prenatal DEHP exposure in prospective birth cohort study. Mono-2-methylhexyl phthalate (MEHP), primary metabolite of DEHP was determined as exposure by using maternal blood sample of 3rd trimester. Leptin and adiponectin levels in cord blood were measured as markers of metabolic function. Birth weight and length were obtained from birth record. Association between maternal MEHP levels and cord blood adiponectin and leptin levels, birth weight and ponderal index (PI) were examined for 167 mother-child pairs who had both MEHP and cord blood adipokine measurements. The median MEHP level was 8.81 ng/ml and the detection rate was 100%. There was no sex difference in MEHP levels. Both leptin and adiponectin levels were higher in girls than in boys. MEHP level was positively associated with adiponectin level among boys and was negatively associated with leptin level among girls. MEHP level were negatively associated with PI only in girls and this could be due to decreased leptin level. This study suggested that prenatal DEHP exposure may be associated with cord blood adipokine and birth size. The influence potentially be sex-specific and could be more significant in girls