Previous studies show that aberrant tryptophan catabolism reduces maternal immune tolerance and adversely impacts pregnancy outcomes. Tryptophan depletion in pregnancy is facilitated by increased activity of tryptophan-depleting enzymes [i.e. the indolamine-2,3 dioxygenase (IDO)1 and IDO2) in the placenta. In mice, inhibition of IDO1 activity during pregnancy results in fetal loss; however, despite its important role, regulation of Ido1 gene transcription is unknown. The current study shows that the Ido1 and Ido2 genes are imprinted and maternally expressed in mouse placentas. DNA methylation analysis demonstrates that nine CpG sites at the Ido1 promoter constitute a differentially methylated region that is highly methylated in sperm but unmethylated in oocytes. Bisulfite cloning sequencing analysis shows that the paternal allele is hypermethylated while the maternal allele shows low levels of methylation in E9.5 placenta. Further study in E9.5 placentas from the CBA/J X DBA/2 spontaneous abortion mouse model reveals that aberrant methylation of Ido1 is linked to pregnancy loss. DNA methylation analysis in humans shows that IDO1 is hypermethylated in human sperm but partially methylated in placentas, suggesting similar methylation patterns to mouse. Importantly, analysis in euploid placentas from first trimester pregnancy loss reveals that IDO1 methylation significantly differs between the two placenta cohorts, with most CpG sites showing increased percent of methylation in miscarriage placentas. Our study suggests that DNA methylation is linked to regulation of Ido1/IDO1 expression and altered Ido1/IDO1 DNA methylation can adversely influence pregnancy outcomes.

In pancreatic islets, catabolism of tryptophan into serotonin and serotonin receptor 2B (HTR2B) activation is crucial for β-cell proliferation and maternal glucose regulation during pregnancy. Factors that reduce serotonin synthesis and perturb HTR2B signaling are associated with decreased β-cell number, impaired insulin secretion, and gestational glucose intolerance in mice. Albeit the tryptophan-serotonin pathway is dependent on vitamin B6 bioavailability, how vitamin B6 deficiency impacts β-cell proliferation during pregnancy has not been investigated. In this study, we created a vitamin B6 deficient mouse model and investigated how gestational deficiency influences maternal glucose tolerance. Our studies show that gestational vitamin B6 deficiency decreases serotonin levels in maternal pancreatic islets and reduces β-cell proliferation in an HTR2B-dependent manner. These changes were associated with glucose intolerance and insulin resistance, however insulin secretion remained intact. Our findings suggest that vitamin B6 deficiency-induced gestational glucose intolerance involves additional mechanisms that are complex and insulin independent.

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Endocrine disrupting chemicals (EDCs) can induce a myriad of adverse health effects. An area of active investigation is the multi- and transgenerational inheritance of EDC-induced adverse health effects referring to the transmission of phenotypes across multiple generations via the germline. The inheritance of EDC-induced adverse health effects across multiple generations can occur independent of genetics, spurring much research into the transmission of underlying epigenetic mechanisms. Epigenetic mechanisms play important roles in the development of an organism and are responsive to environmental exposures. To date, rodent studies have demonstrated that acquired epigenetic marks, particularly DNA methylation, that are inherited following parental EDC exposure can escape embryonic epigenome reprogramming. The acquired epimutations can lead to subsequent adult-onset diseases. Increasing studies have reported inter-individual variations that occur with epigenetic inheritance. Factors that underlie differences among individuals could reveal previously unidentified mechanisms of epigenetic transmission. In this review, we give an overview of DNA methylation and posttranslational histone modification as the potential mechanisms for disease transmission, and define the requirements for multi- and transgenerational epigenetic inheritance. We subsequently evaluate rodent studies investigating how acquired changes in epigenetic marks especially DNA methylation across multiple generations can vary among individuals following parental EDC exposure. We also discuss potential sources of inter-individual variations and the challenges in identifying these variations. We conclude our review discussing the challenges in applying rodent generational studies to humans.

Leukodystrophies are a broad spectrum of neurological disorders that are characterized primarily by deficiencies in myelin formation. Clinical manifestations of leukodystrophies usually appear during childhood and common symptoms include lack of motor coordination, difficulty with or loss of ambulation, issues with vision and/or hearing, cognitive decline, regression in speech skills, and even seizures. Many cases of leukodystrophy can be attributed to genetic mutations, but they have diverse inheritance patterns (e.g., autosomal recessive, autosomal dominant, or X-linked) and some arise from de novo mutations. In this review, we provide an updated overview of 35 types of leukodystrophies and focus on cellular mechanisms that may underlie these disorders. We find common themes in specialized functions in oligodendrocytes, which are specialized producers of membranes and myelin lipids. These mechanisms include myelin protein defects, lipid processing and peroxisome dysfunction, transcriptional and translational dysregulation, disruptions in cytoskeletal organization, and cell junction defects. In addition, non-cell-autonomous factors in astrocytes and microglia, such as autoimmune reactivity, and intercellular communication, may also play a role in leukodystrophy onset. We hope that highlighting these themes in cellular dysfunction in leukodystrophies may yield conceptual insights on future therapeutic approaches.