Kimberley J. Woodcroft

PPARα Expression Protects Male Mice from High Fat–Induced Nonalcoholic Fatty Liver

Emerging evidence suggests that the lack of PPARα enhances hepatic steatosis and inflammation in Ppara-null mice when fed a high-fat diet (HFD). Thus, the aim of this study was to determine whether Ppara-null mice are more susceptible to nonalcoholic steatohepatitis (NASH) than their wild-type (WT) counterparts following short-term feeding with a HFD. Age-matched male WT and Ppara-null mice were randomly assigned to consume ad libitum a standard Lieber-DeCarli liquid diet (STD) (35% energy from fat) or a HFD (71% energy from fat) for 3 wk. Liver histology, plasma transaminase levels, and indicators of oxidative/nitrosative stress and inflammatory cytokines were evaluated in all groups. Levels of lobular inflammation and the NASH activity score were greater in HFD-exposed Ppara-null mice than in the other 3 groups. Biochemical analysis revealed elevated levels of ethanol-inducible cytochrome P450 2E1 and TNFα accompanied by increased levels of malondialdehyde as well as oxidized and nitrated proteins in Ppara-null mice. Elevated oxidative stress and inflammation were associated with activation of c-Jun-N-terminal kinase and p38 kinase, resulting in increased hepatocyte apoptosis in Ppara-null mice fed a HFD. These results, with increased steatosis, oxidative stress, and inflammation observed in Ppara-null mice fed a HFD, demonstrate that inhibition of PPARα functions may increase susceptibility to high fat-induced NASH.

Variation of dust endotoxin concentrations by location and time within homes of young children.

Ownby DR, Peterson EL, Williams LK, Zoratti EM, Wegienka GR, Woodcroft KJ, Joseph CLM, Johnson CC. Variation of dust endotoxin concentrations by location and time within homes of young children.
Pediatr Allergy Immunol 2010: 21: 533–540.
© 2010 John Wiley & Sons A/S

Maternal smoking during pregnancy, polymorphic CYP1A1 and GSTM1, and lung-function measures in urban family children☆

PURPOSE Understanding the interplay between genes and in-utero tobacco exposure in affecting child lung development is of great significance. In this study, we tested the hypothesis that tobacco-related lung-function reduction in children differs by maternal polymorphic genes Cytochrome P450 1A1 (CYP1A1) and Glutathione S-transferase Mu 1 (GSTM1). MATERIALS AND METHODS Data were collected among 370 children (6-10 years old, 81.6% African-Americans) and their biological mothers visiting a large childrens hospital. Study hypotheses were tested using multiple regression method. RESULTS Among the study sample, 143 mothers smoked throughout pregnancy and 72 smoked on a daily basis. Spirometric measures (mean±SD) included were: forced vital capacity (FVC)=1635±431 mL, forced expiratory volume in the first 1s (FEV1)=1440 ±360 mL, percent FEV1/FVC ratio=89±12, and forced expiratory flow between the 25% and 75% of FVC (FEF25-75)=1745±603 mL. In addition to a tobacco effect on FVC (-131 mL, 95% CI: -245, -17) and FEV1/FVC ratio (42, 95% CI: 1, 83), regression analysis controlling for covariates indicated that for the subsample of children whose mothers were CYP1A1⁎2A homozygous, maternal daily smoking was associated with -734 mL (95% CI: -1206, -262) reductions in FEV1 and -825 mL (95% CI: -909, -795) reductions in FVC; reduced smoking was still associated with -590 mL (95% CI: -629, -551) reductions in FVC. For children of mothers with GSTM1 deletion, persistent daily smoking was associated with -176 mL (95% CI: -305, -47) reductions in FVC. DISCUSSION AND CONCLUSIONS Maternal smoking during pregnancy was significantly associated with lung-function reduction in children, particularly for those whose mothers possessed the polymorphic CYP1A1*2A and GSTM1 deletion.

Prenatal antimicrobial use and early-childhood body mass index

Background/Objectives:Growing evidence suggests that antibiotic use is associated with childhood body mass index (BMI), potentially via mechanisms mediated by gut microbiome alterations. Less is known on the potential role of prenatal antimicrobial use in offspring obesity risk. We examined whether prenatal antibiotic or antifungal use was associated with BMI at the age of 2 years in 527 birth cohort participants.Methods/Subjects:Antimicrobial use was obtained from the prenatal medical record. Height and weight were measured at the age of 2 years. Overweight/obesity was defined as a BMI ⩾85th percentile.Results:A total of 303 (57.5%) women used antibiotics and 101 (19.2%) used antifungals during pregnancy. Prenatal antifungal use was not associated with child BMI at the age of 2 years. In the fully adjusted model, prenatal antibiotic use was associated with a 0.20±0.10 (P=0.046) higher mean BMI Z-score at the age of 2 years. Associations between prenatal antibiotic use and childhood BMI varied by trimester of exposure, with first or second-trimester exposure more strongly associated with larger BMI at the age of 2 years for both BMI Z-score (interaction P=0.032) and overweight/obesity (interaction P=0.098) after covariate adjustment.Conclusions:Prenatal antibiotic, but not antifungal, use is associated with larger BMI at the age of 2 years; associations were stronger for antibiotic exposures in earlier trimesters. Future studies examining whether these associations are due to alterations in the maternal and/or infant microbiome are necessary. Children who are overweight at the age of 2 years are at higher risk for being overweight as they age; prenatal antibiotic use is a potentially modifiable exposure that could reduce childhood obesity.

Subgroup differences in the associations between dog exposure during the first year of life and early life allergic outcomes

The effect of dog exposure on the risk of children developing allergic disease remains controversial. Many analyses have not considered that associations may vary within population subgroups.

Authors' reply: Cytokines and uterine leiomyoma - a novel trustful Pathway?

To the editor: We are grateful for the interest and support of Drs. Brito et al. in our recent publication. We agree with the authors’ statement that it is not clear whether the observed associations between cytokines and uterine leiomyomas in our publication are the result or a potential cause. As stated in our manuscript, the study design was cross-sectional and temporality could not be assessed. A longitudinal study with multiple measurements would indeed be beneficial to the study of the proposed hypothesis. We disagree, however, that working only with African American women may not permit appropriate investigation of an inflammatory hypothesis. Racial disparities do provide insight into research studies, but a thoughtful approach to design of studies of diseases with racial differences is also important. The study from which the samples were taken, the Study of Environment Lifestyles and Fibroids (SELF), only recruited African American women for specific reasons. In the United States, African American women tend to develop uterine leiomyomas at younger ages and undergo hysterectomy at younger ages for leiomyomas compared to White women. SELF was designed to examine risk factors for incident uterine leiomyomas. A study of incident uterine leiomyoma would be most successful by recruiting African American women in their 20’s and White women in their 30’s. Due to prohibitive costs of running what would have essentially been parallel studies, SELF focused on the population of women more severely affected by leiomyomas, African American women. We also think that studies of leiomyoma incidence are needed for women of varying races and ethnicities. However, incidence studies with ultrasound confirmation of leiomyoma status are very time-consuming and expensive – but perhaps not as expensive as associated leiomyoma morbidity and treatment and recovery costs. We are thrilled that discussions are underway to focus on understanding mechanisms that cause leiomyomas so that prevention strategies for uterine leiomyomas can be developed from that knowledge. The inflammation hypothesis has been proposed, and our published work was a first step in attempting to test this hypothesis. We look forward to others testing this hypothesis as well as proposing new and sound hypotheses to address this important and common public health problem.