Relation of body mass index to frequency of recurrent preterm birth in women treated with 17-alpha hydroxyprogesterone caproate.

OBJECTIVE: The standard weekly dose of 17-alpha hydroxyprogesterone caproate (17OHP-C; 250 mg/wk) to reduce the risk of recurrent preterm birth was adopted without regard to patient characteristics. We examined the relationship between prepregnancy body mass index (BMI) and gestational age at birth after 17OHP-C prophylaxis. We hypothesized that rates of births before 32, 35, and 37 weeks of gestation would be increased in women with a BMI of 25 kg/m(2) or greater. STUDY DESIGN: A retrospective cohort study was conducted from a deidentified database of women treated with 17OHP-C for prior spontaneous preterm birth. The frequency of recurrent preterm delivery before 32, 35, and 37 weeks of gestation was investigated for women with a BMI less than 25 kg/m(2) compared with women with a BMI of 25 kg/m(2) or greater. The adjusted relative risk of preterm delivery was estimated through a modified Poisson regression approach. RESULTS: Of 390 women who met inclusion criteria, 60 (15.4%) delivered before 32 weeks, 89 (22.8%) before 35 weeks, and 156 (40.0%) before 37 weeks. A total of 174 women had a BMI less than 25 kg/m(2) (mean [SD], 21.2 [2.5]) and 216 had a BMI of 25 kg/m(2) or greater (mean [SD], 33.5 [6.7]). Risk of birth before 32 weeks was 1.7 times higher on average (adjusted relative risk, 1.7; 95% confidence interval, 1.05-2.77) in overweight women than in women with a BMI less than 25 kg/m(2), adjusting for age, race, smoking, and short cervix. There was no difference in the risk of preterm birth before 35 or 37 weeks. CONCLUSION: Among pregnant women receiving 17OHP-C prophylaxis for a prior preterm birth, recurrent preterm birth before 32 weeks was significantly more common in those women whose prepregnancy BMI was 25 kg/m(2) or greater than in women with BMI less than 25 kg/m(2). This observation is consistent with pharmacological studies suggesting that dosing regimens of 17OHP-C may affect efficacy.

Repeated gestational exposure of mice to chlorpyrifos oxon is associated with paraoxonase 1 (PON1) modulated effects in maternal and fetal tissues.

Chlorpyrifos oxon (CPO), the toxic metabolite of the organophosphorus (OP) insecticide chlorpyrifos, causes developmental neurotoxicity in humans and rodents. CPO is hydrolyzed by paraoxonase-1 (PON1), with protection determined by PON1 levels and the human Q192R polymorphism. To examine how the Q192R polymorphism influences fetal toxicity associated with gestational CPO exposure, we measured enzyme inhibition and fetal-brain gene expression in wild-type (PON1(+/+)), PON1-knockout (PON1(-/-)), and tgHuPON1R192 and tgHuPON1Q192 transgenic mice. Pregnant mice exposed dermally to 0, 0.50, 0.75, or 0.85 mg/kg/d CPO from gestational day (GD) 6 through 17 were sacrificed on GD18. Biomarkers of CPO exposure inhibited in maternal tissues included brain acetylcholinesterase (AChE), red blood cell acylpeptide hydrolase (APH), and plasma butyrylcholinesterase (BChE) and carboxylesterase (CES). Fetal plasma BChE was inhibited in PON1(-/-) and tgHuPON1Q192, but not PON1(+/+) or tgHuPON1R192 mice. Fetal brain AChE and plasma CES were inhibited in PON1(-/-) mice, but not in other genotypes. Weighted gene co-expression network analysis identified five gene modules based on clustering of the correlations among their fetal-brain expression values, allowing for correlation of module membership with the phenotypic data on enzyme inhibition. One module that correlated highly with maternal brain AChE activity had a large representation of homeobox genes. Gene set enrichment analysis revealed multiple gene sets affected by gestational CPO exposure in tgHuPON1Q192 but not tgHuPON1R192 mice, including gene sets involved in protein export, lipid metabolism, and neurotransmission. These data indicate that maternal PON1 status modulates the effects of repeated gestational CPO exposure on fetal-brain gene expression and on inhibition of both maternal and fetal biomarker enzymes.

Identifying safer anti-wear triaryl phosphate additives for jet engine lubricants.

Individuals aboard jet aircraft may be exposed to potentially toxic triaryl organophosphate anti-wear lubricant additives (TAPs) that are converted by cytochromes P450 into toxic metabolites. Consequences of exposure could be reduced by using less toxic TAPs. Our goal was to determine whether an in vitro assay for inhibition of butyrylcholinesterase (BChE) by bioactivated TAPs would be predictive of inhibition of serine active-site enzymes in vivo. The in vitro assay involved TAP bioactivation with liver microsomes and NADPH, followed by incubation with human BChE and measurement of BChE activity. Of 19 TAPs tested, tert-butylated isomers produced the least BChE inhibition. To determine the relevance of these results in vivo, mice were exposed to Durad 125 (D125; a commercial mixture of TAP esters) or to TAPs demonstrating low or no BChE inhibition when assayed in vitro. Inhibition of BChE by bioactivated TAPs in vitro correlated well with inhibition of other serine active-site enzymes in vivo, with the exception of brain acetylcholinesterase and neuropathy target esterase (NTE), which were not inhibited by any TAP tested following single exposures. A recombinant catalytic domain of NTE (rNEST) exhibited classical kinetic properties of NTE. The metabolite of tri-(o-cresyl) phosphate (ToCP), 2-(o-cresyl)-4H-1,3,2-benzodioxaphosphoran-2-one (CBDP), inhibited rNEST in vitro, but with an IC(50) value almost 6-times higher than for inhibition of BChE. Physiologically-relevant concentrations of the flavonoid naringenin dramatically reduced D125 bioconversion in vitro. The in vitro assay should provide a valuable tool for prescreening candidate TAP anti-wear additives, identifying safer additives and reducing the number of animals required for in vivo toxicity testing.

Behavioral Characterization of GCLM-Knockout Mice, a Model for Enhanced Susceptibility to Oxidative Stress.

Glutathione (GSH) is a major player in cellular defense against oxidative stress. Deletion of the modifier subunit of glutamate cysteine ligase (GCLM), the first and the rate-limiting enzyme in the synthesis of GSH, leads to significantly lower GSH levels in all tissues including the brain. GCLM-knockout (Gclm(-/-)) mice may thus represent a model for compromised response to oxidative stress amenable to in vitro and in vivo investigations. In order to determine whether the diminished GSH content would by itself cause behavioral alterations, a series of behavioral tests were carried out comparing young adult Gclm(-/-) with wild-type mice. Tests included the rotarod, acoustic startle reflex and prepulse inhibition of the startle reflex, open field behavior, and the platform reversal variant of the Morris Water Maze. Results showed no differences between Gclm(-/-) and wild-type mice in any of the neurobehavioral tests. However, more subtle alterations, or changes which may appear as animals age, cannot be excluded.