Transmission of Metabolic Dysfunction Across Generations

Abstract

Recent human and animal studies investigating the roles of the genome, epigenome, and environmental cues have identified associations between offspring predisposition to life-long obesity/metabolic disease and epigenetic modifications such as DNA methylation. This review explores the mechanisms by which maternal exposures impair the health of not only the next generation but also potentially future generations of offspring.

FIGURE 1.

Interactions of DNA methylation and histone modifications A: closed chromatin has CpG methylation (46) generated by DNA methyltransferase (DNMT) and histone methylation at H3K9, H4K20, and H2A/H4R3, with recruitment of histone deacetylase (HDAC) and methyltransferase (HMT) by methylated CpG by means of MeCP2. Transcription factors (TFs) are inhibited from binding, and gene expression is silenced. B: open, unmethylated chromatin does not recruit HDAC and HMT, and H4K3 methylation blocks DNMT binding. TFs bind unmethylated chromatin, recruiting histone acetyltransferase (HAT), which promotes transcriptional activation.

FIGURE 2.

Metabolic influence of oxidative stress on DNA and histone methylation To maintain the correct amount of S-adenosylmethionine (SAM), the main substrate used by DNA methyltransferases (DNMTs) and histone methyltransferases (HMTs), homocysteine (Hcy) produced by methylation reactions must be recycled for continuous synthesis of SAM. This occurs through interplay between the folate and methionine cycles. An excess of reactive oxygen species (ROS) can inhibit methyl adenosyltransferase and increase demand for reduced glutathione produced in the transsulfuration pathway that competes for homocysteine, limiting Hcy entry into the methionine cycle. Note that several reactions implicated directly and indirectly in the synthesis of SAM require micronutrients as enzyme cofactors (arrow dashed lines). 5-CH3THF, methyl-tetrahydrofolate; aKG, alfa-ketogluta-rate; CH2THF, methylene-tetrahydrofolate; Cys, cysteine; DHF, dihydrofolate; DMG, di-methylglyoxime; DNMTs, DNA methyltrans-ferase; GSSG, glutathione oxidized; MAT, S-methionine adenosyltransferase; Met, methionine; MTHR, methylene-tetrahydrofolate reductase; MTR, 5-methyltetrahydrofolate-homocysteine methyltransferase; SAH, S-adenosylhomo-cysteine; THF, tetrahydrofolate.

FIGURE 3.

Transgenerational transmission To be considered transgenerational transmission after a maternal exposure such as a high-fat/high-sugar (HF/HS) diet in this example, the inherited traits must be apparent in the F3 generation since the F1 embryo and F2 primordial germ cells are directly exposed to a given environmental factor in utero. In such cases, a change must occur in the germline to allow the effect to persist through three generations. As an example, EM images are shown of skeletal muscle of three generations of mice following the F0 mother's exposure to a HF/HS diet (69).