Case-control study of nutritional and environmental factors and the risk of oral clefts in Thailand.

BACKGROUND: One infant in 700 is born with an oral cleft. Prior studies suggest low micronutrient status is associated with an increased risk of oral clefts. Environmental factors such as passive smoke exposure or supplement use may also affect oral cleft risk. We examined nutrition and environmental related risk factors for oral clefts. METHODS: We conducted a case-control study in Northeast Thailand in 2012 to 2013. We enrolled 95 cases and 95 controls. We recruited cases with a nonsyndromic cleft lip with or without a cleft palate (CL±P) less than 24 months old. Cases were matched to controls on age and place of conception. We collected survey data, a food frequency questionnaire, and measured zinc concentrations in toenail trimmings. We calculated descriptive statistics by case and control status. We used conditional logistic regression to estimate unadjusted and adjusted associations, 95% confidence intervals (CIs), and p-values. RESULTS: Any liver intake (adjusted OR [aOR] for ≥1/week versus none), 10.58; 95%CI, 1.74-64.37, overall p = 0.02) and the presence of food insecurity (aOR, 9.62; 95% CI, 1.52-61.05; p = 0.02) in the periconceptional period increased CL±P risk. Passive smoke exposure increased the risk of CL±P (aOR, 6.52; 95% CI, 1.98-21.44; p < 0.01). Toenail zinc concentrations were not associated with CL±P risk. CONCLUSION: Our findings add to a growing body of knowledge of environmental risk factors for oral clefts from low- and middle-income countries. Our findings on liver are contradictory to prior results. Large multisite studies are needed to identify environmental and genetic risk factors for oral clefts. Birth Defects Research (Part A) 106:624-632, 2016. © 2016 Wiley Periodicals, Inc.

Unique monooxygenation pattern indicates novel flavin-containing monooxygenase in liver of rainbow trout.

Vertebrate flavin-containing monooxygenases (FMOs) have only been isolated from mammalian organisms. However, many FMO substrates include pesticides which may adversely affect fish and other aquatic organisms residing in adjacent waterways to treated fields. Although FMO activities have been identified in fish, the exact isoform profile is uncertain. Utilizing prochiral methyl tolyl sulfides (MTS) and isoform-selective antibodies, an attempt was made to identify specific FMO isoforms which may be involved in sulfoxidation reactions which have been shown to bioactivate thioether pesticides, such as aldicarb. Rainbow trout hepatic microsomes treated with detergent to eliminate cytochrome P450 contributions catalyzed the formation of the sulfoxide of MTS in 75% S enantiomeric excess. These catalytic results contrast activities of the five other FMO isoforms including FMO1 (> 98% R) and FMO3 (50% R). Benzydamine N-oxidation was also observed as were methimazole, thiourea, and aldicarb sulfoxidation reactions. Antibodies to FMO1 recognized a single protein of 60 kDa in trout liver microsomes, while anti-FMO3 antibodies only slightly reacted with a 55-kDa microsomal protein. These results indicate a novel isoform profile in rainbow trout liver implicating either a mixture of competing FMO isoforms or a FMO1-like isoform displaying unique catalytic activity.

Innovations in preclinical biology: ex vivo engineering of a human kidney tissue microperfusion system.

Kidney disease is a public health problem that affects more than 20 million people in the US adult population, yet little is understood about the impact of kidney disease on drug disposition. Consequently there is a critical need to be able to model the human kidney and other organ systems, to improve our understanding of drug efficacy, safety, and toxicity, especially during drug development. The kidneys in general, and the proximal tubule specifically, play a central role in the elimination of xenobiotics. With recent advances in molecular investigation, considerable information has been gathered regarding the substrate profiles of the individual transporters expressed in the proximal tubule. However, we have little knowledge of how these transporters coupled with intracellular enzymes and influenced by metabolic pathways form an efficient secretory and reabsorptive mechanism in the renal tubule. Proximal tubular secretion and reabsorption of xenobiotics is critically dependent on interactions with peritubular capillaries and the interstitium. We plan to robustly model the human kidney tubule interstitium, utilizing an ex vivo three-dimensional modular microphysiological system with human kidney-derived cells. The microphysiological system should accurately reflect human physiology, be usable to predict renal handling of xenobiotics, and should assess mechanisms of kidney injury, and the biological response to injury, from endogenous and exogenous intoxicants.