In utero oxidative stress epigenetically programs antioxidant defense capacity and adulthood diseases

Abstract

Significance: Maternal health and diet during gestation are critical for predicting fetal outcomes, both immediately at birth and in adulthood. While epigenetic modifications have previously been tightly linked to carcinogenesis, recent advances in the field have suggested that numerous adulthood diseases, including those characteristic of metabolic syndrome, could be programmed in utero in response to maternal exposures, and these "programmable" diseases are associated with epigenetic modifications of vital genes.

Recent advances: While little is currently known about the epigenetic regulation of the antioxidant (AOX) defense system, several studies in animals show that AOX defense capacity may be programmed in utero, making it likely that the critical genes involved in this pathway are epigenetically regulated, either by DNA methylation or by the modification of histone tails.

Critical issues: This article presents the most current knowledge of the in utero regulation of the AOX defense capacity, and will specifically focus on the potential epigenetic regulation of this system in response to various in utero exposures or stimuli. The ability to appropriately respond to oxidative stress is critical for the health and survival of any organism, and the potential programming of this capacity may provide a link between the in utero environment and the tendency of certain individuals to be more susceptible toward disease stimuli in their postnatal environments.

Future directions: We sincerely hope that future studies which result in a deeper understanding of the in utero programming of the epigenome will lead to novel and effective therapies for the treatment of epigenetically linked diseases.

FIG. 1.

Sources of ROS during pregnancy. Under standard conditions, pregnancy is a time of elevated oxidative stress. However, numerous physiological and environmental stressors can further increase ROS production and oxidative stress, which can be detrimental for both the mother and the fetus. IUGR, intrauterine growth restriction; ROS, reactive oxygen species.

FIG. 2.

Maternal HF diet and the offspring's AOX defense system. Studies have suggested that a maternal HF contributes to numerous diseases in the offspring, including nonalcoholic liver disease, and this may be accompanied by a dysregulation of the AOX defense system in the offspring. The exact mechanism behind these observations remains undefined and is likely complicated and multi-faceted. Potentially, a maternal HF diet dysregulates maternal lipid metabolism, which increases maternal oxidative stress. The increased ROS produced during maternal lipid peroxidation are sensed by the placenta, which either increases its own ROS production, or transports maternal peroxidation products to the offspring. This is also accompanied by an increased transport of free fatty acids from the mother to the fetus. The excess fatty acids may lead to endogenous ROS production, and these, along with those from the mother, initially activate the AOX defense system. However, it is possible that with time, and under a chronic ROS burden, the AOX system no longer functions at capacity, which leads to oxidative damage and eventual tissue damage. AOX, antioxidant; HF, high fat; NEFA, non-esterified fatty acids; TG, triglycerides.

FIG. 3.

Epigenetic modifications. The two most common epigenetic modifications include DNA methylation and histone modifications. Methylation of the DNA strand and CG dinucleotides is considered an inhibitor of transcription, while histone modifications can either activate or inhibit gene transcription. Covalent modifications to the tails of histones regulate transcription by either loosening or tightening the DNA helix, and include acetylation (Ac), methylation (Me), sumoylation (S), phosphorylation (P), and ubiquitination (Ub).

FIG. 4.

Epigenetic regulation of hepatic Pon1 by maternal HF diet. Although the direct mechanism behind the regulation of the AOX system remains unknown, unpublished data from our lab suggests that a maternal HF diet can induce epigenetic changes in the fetal epigenome and affect AOX genes, including hepatic Pon1. We observed that fetal livers of offspring whose mothers consumed an HF diet during gestation but did not develop obesity (image represents OR-CD [Obese Resistant] rats from Charles River Laboratories) had increased TG and TBARS, which was accompanied by the increased mRNA expression of the Pon1 gene, a hepatic antioxidant. Chromatin immunoprecipitation, a technique utilized to test proteins associated with the chromatin, showed that the Pon1 promoter was enriched with H3K4Me2 as well as H4Ac, both of which are associated with active transcription and act by loosening the DNA to allow for the binding of various transcription factors. H3K4Me2, dimethylated histone H3 at Lysine residue 4; H4Ac, acetylation of histone H4.