Tooth agenesis is one of the most common orodental anomalies that demonstrate phenotypic and genotypic heterogeneity with a prevalence of 2.5%-7%. Mutations in WNT10A have been proposed to be the most common cause of nonsyndromic tooth agenesis (NSTA). The aim of this study was to characterize the dental features and genetic variants of NSTA in a Thai population. We recruited 13 unrelated patients with NSTA who attended the Faculty of Dentistry, Chulalongkorn University, Thailand, from 2017 to 2019. All 13 underwent whole exome sequencing that identified likely pathogenic genetic variants, all in WNT10A, in five patients. All five patients had second premolar agenesis, while three also had absent or peg-shaped upper lateral incisors. Patient 1 possessed a novel heterozygous duplication, c.916_918dupAAC (p.Asn306dup) in WNT10A. Patients 2 and 3 harbored a heterozygous and homozygous c.637G > A (p.Gly213Ser) in WNT10A, respectively. Patients 4 possessed a heterozygous c.511C > T (p.Arg171Cys) in WNT10A. Patient 5 harbored a homozygous c.511C > T (p.Arg171Cys) in WNT10A and a novel heterozygous c.413A > T (p.Asn138Ile) in EDARADD, suggesting digenic inheritance. We recruited another 18 family members of these five patients. Out of 23 participants, homozygous WNT10A variants were identified in 2 patients and heterozygous variants in 17 individuals. Both homozygous patients had NSTA. Eight out of 17 heterozygous individuals (8/17) had NSTA or a peg-shaped lateral incisor, indicating a 47% penetrance of the heterozygous variants or 53% (10/19) penetrance of either homozygous or heterozygous variants in WNT10A. The frequencies of the c.511C > T in our in-house 1,876 Thai exome database, Asian populations, and non-Asian populations were 0.016, 0.005-0.033, and 0.001, respectively; while those of the c.637G > A were 0.016, 0.004-0.029, and 0.000, respectively. In conclusion, our study reports two novel variants with one each in WNT10A and EDARADD, expanding the genotypic spectra of NSTA. Second premolar

Pregnancy is a complex physiological state, in which the metabolism of endogenous as well as exogenous agents is ostensibly altered. One exogenous agent of concern is the hepatocarcinogen aflatoxin B1 (AFB1), a foodborne fungal toxin, that requires phase I metabolic oxidation for conversion to its toxic and carcinogenic form, the AFB1-8,9-exo-epoxide. The epoxide interacts with cellular targets causing toxicity and cell death; these targets include the covalent modification of DNA leading to mutations that can initiate malignant transformation. The main detoxification pathway of the AFB1-epoxide involves phase II metabolic enzymes including the glutathione-S-transferase (GST) family. Pregnancy can modulate both phase I and II metabolism and alter the biological potency of AFB1. The present work investigated the impact of pregnancy on AFB1 exposure in mice. A single IP dose of 6 mg/kg AFB1 was administered to pregnant C57BL/6 J mice at gestation day 14 and matched non-pregnant controls. Pregnant mice accumulated 2-fold higher AFB1-N7-guanine DNA adducts in the liver when compared with nonpregnant controls 6 h post-exposure. Enhanced DNA adduct formation in pregnant animals paralleled elevated hepatic protein expression of mouse CYP1A2 and mouse homologs of human CYP3A4, phase I enzymes capable of bioactivating AFB1. Although phase II enzymes GSTA1/2 showed decreased protein expression, GSTA3, the primary enzymatic protection against the AFB1-epoxide, was unaffected at the protein level. Taken together, our results reveal that pregnancy may constitute a critical window of susceptibility for maternal health, and provide insight into the biochemical factors that could explain the underlying risks.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.