Contrasting effects of different maternal diets on sexually dimorphic gene expression in the murine placenta

Abstract

Diet during pregnancy influences the future health of a woman's offspring, with outcomes differing depending on the child's sex. Because the placenta buffers the fetus from the mother, we examined the impact of diet and fetal sex on placental gene expression in mice fed either a very-high-fat, low-fat, chow diet of intermediate caloric density. At day 12.5 of pregnancy, placental RNA was extracted and analyzed by microarray. The expression of 1,972 genes was changed more than 2-fold (P < 0.05) in comparisons across diet in at least one of the three groups. Female placentae demonstrated more striking alterations in gene expression in response to maternal diet than male placentae. Notably, each diet provided a distinctive signature of sexually dimorphic genes, with expression generally higher in genes (651 out of 700) from female placentae than those from male placentae. Several genes normally considered as characteristic of kidney function were affected by diet, including genes regulating ion balance and chemoreception. The placenta also expressed most of the known olfactory receptor genes (Olfr), which may allow the placenta to sense odorant molecules and other minor dietary components, with transcript levels of many of these genes influenced by diet and fetal sex. In conclusion, gene expression in the murine placenta is adaptive and shaped by maternal diet. It also exhibits pronounced sexual dimorphism, with placentae of females more sensitive to nutritional perturbations than placentae of males.

Fig. 1.

(A) Heat map based on maternal diet effects on placental gene expression. Placentae from dams on the C diet are well separated from the placentae of conceptuses from dams on the LF and VHF diets. Despite the differences in caloric density between two defined diets, the gene regulation patterns in placentae of LF and VHF conceptuses were more like each other than like those in placentae of C conceptuses. Gene tree clustering on 1,972 genes, whose expression was changed by >2-fold with P < 0.05, is able to distinguish placentae from dams on the LF and VHF diets. (B) Heat map based on fetal sex effects on placental gene expression. Placentae gene expression patterns of male conceptuses clearly clustered separately from the placentae of females, when data on the total regulated genes (with 2-fold differences) across all dietary groups are compared (P < 0.05). Samples marked with an asterisk are those from the left as opposed to the right uterine horn. The close grouping of these with the other samples suggests that uterine implantation site has no affect on placental gene expression patterns.

Fig. 2.

Venn diagrams of placental gene expression patterns influenced by maternal diet and fetal sex. (A–D) Diagrams comparing the placental genes that were up-regulated (A and B) and down-regulated (C and D) in female and male conceptuses from dams on the LF and VHF diet after subtracting from the C diet group. (E) Diagram comparing the number of differentially expressed genes in female and male placentae in the LF group versus the VHF group (≥2-fold; P < 0.05, for a total of 200 autosomal and 11 sex chromosomal genes). (F and G) Sexually dimorphically expressed genes in at least one of the three diet groups (≥2-fold; P < 0.05, for a total of 736 autosomal and sex chromosome genes). The up-regulated genes that overlap in the male placentae of all diet groups were Ddx3y (represented by two probes) and Eif2s3y. The down-regulated genes that overlap in the male placentae of all diet groups were Xist (represented by three probes), Klk7, Crabp1, and Rimklb (4933426K21Rik).