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. 2013 Nov;143(11):1698-708.
doi: 10.3945/jn.112.172148. Epub 2013 Sep 18.

Expression of the placental transcriptome in maternal nutrient reduction in baboons is dependent on fetal sex

Laura A Cox  1 , Cun Li, Jeremy P Glenn, Kenneth Lange, Kimberly D Spradling, Peter W Nathanielsz, Thomas Jansson
Affiliations

Expression of the placental transcriptome in maternal nutrient reduction in baboons is dependent on fetal sex

Laura A Cox et al. J Nutr. 2013 Nov.

Abstract

Maternal undernutrition increases the risk of perinatal complications and predisposes offspring to obesity, diabetes, and cardiovascular disease later in life. Emerging evidence suggests that changes in placental function play a role in linking altered maternal nutrition in pregnancy to the subsequent development of adult disease. The susceptibility for disease in response to an adverse intrauterine environment differs distinctly between boys and girls, with girls typically having better outcomes. Here, we tested the hypothesis that regulation of the placental transcriptome by maternal nutrient reduction (NR) is dependent on fetal sex. We used a nonhuman primate model of NR in which maternal global food intake was reduced by 30% in baboons starting at gestational day (GD) 30. At GD 165 (term = GD 183), placental genome expression profiling of 6 control (n = 3 females, 3 males) and 6 nutrient restricted (n = 3 females, 3 males) fetuses was carried out followed by bioinformatic analysis. Surprisingly, there was no coordinated placental molecular response to decreased nutrient availability when analyzing the data without accounting for fetal sex. In contrast, female placentas exhibited a highly coordinated response that included upregulation of genes in networks, pathways, and functional groups related to programmed cell death and downregulation of genes in networks, pathways, and functional groups associated with cell proliferation. These changes were not apparent in the male placentas. Our data support the concept that female placentas initiate complex adaptive responses to an adverse intrauterine environment, which may contribute to increased survival and better pregnancy outcomes in girls.

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Conflict of interest statement

Author disclosures: L. A. Cox, C. Li, J. P. Glenn, K. Lange, K. D. Spradling, P. W. Nathanielsz, and T. Jansson, no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Top-ranking networks for gene expression differences in female (A) and male (B) offspring of CTR and NR female baboons. Genes are denoted by gene IDs, green indicates downregulated, red indicates upregulated, gray indicates no difference in gene expression in NR compared with CTR, and white denotes the lack of quality signal on the array. ACTB, actin, beta; ACTL6B, actin-like protein 6B; ARPC2, actin related protein 2/3 complex, subunit 2, 34kDa; ARPC4, actin related protein 2/3 complex, subunit 4, 20kDa; ATP2B2, ATPase, Ca++ transporting, plasma membrane 2; CALD1, caldesmon 1; CAPN1, calpain 1, (mu/I) large subunit; CCNE1, cyclin E1; CDKN2C, cyclin-dependent kinase inhibitor 2C (p18, inhibits CDK4); CHD4, chromodomain helicase DNA binding protein 4; COL4A6, collagen, type IV, alpha 6; Creb, c-AMP response element-binding protein; CTBP2, C-terminal binding protein 2; CTR, control; DAB2IP, DAB2 interacting protein; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; F actin, fibrous actin; FHL3, four and a half LIM domains 3; FLII, flightless I homolog (Drosophila); FLT1, fms-related tyrosine kinase 1; GDA, guanine deaminase; GSN, gelsolin; HBE1, hemoglobin, epsilon 1; KLC1, kinesin light chain 1; KLHL17, kelch-like family member 17; KRT8, keratin 8; MAPK8IP3, mitogen-activated protein kinase 8 interacting protein 3; MKL1, megakaryoblastic leukemia (translocation) 1; MSN, moesin; MTA1, metastasis associated 1; MYCN, v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (avian); MYH9, myosin, heavy chain 9, non-muscle; MYO5A, myosin VA (heavy chain 12, myoxin); NEK6, NIMA-related kinase 6; NR, nutrient reduction; NUP93, nucleoporin 93kDa; OSGIN1, oxidative stress induced growth inhibitor 1; PBRM1, polybromo 1; PHLDA1, pleckstrin homology-like domain, family A, member 1; PI3K, phosphoinositide 3-kinase; PKLR, pyruvate kinase, liver and RBC; PLEC, plectin; PLSCR1, phospholipid scramblase 1; PP2A, protein phosphatase 2; PPP2R3A, protein phosphatase 2, regulatory subunit B'', alpha; PSMB7, proteasome (prosome, macropain) subunit, beta type, 7; PTGFRN, prostaglandin F2 receptor inhibitor; PTPN1, protein tyrosine phosphatase, non-receptor type 1; SBF1, SET binding factor 1; SERPINH1, serpin peptidase inhibitor, clade H (heat shock protein 47), member 1, (collagen binding protein 1); Shc, Src (sarcoma) homology 2 domain-containing transforming protein 1; SHROOM3, shroom family member 3; SLC1A5, solute carrier family 1 (neutral amino acid transporter), member 5; SLC6A4, solute carrier family 6 (neurotransmitter transporter, serotonin), member 4; SREBF1, sterol regulatory element binding transcription factor 1; SSH2, slingshot protein phosphatase 2; TINAGL1, tubulointerstitial nephritis antigen-like 1; TNNT3, troponin T type 3 (skeletal, fast); TPM3, tropomyosin 3; UCK2, uridine-cytidine kinase 2.
FIGURE 2
FIGURE 2
qRT-PCR validation of PPARγ (A), PRG2 (B), TP53 (C), and HIST3H3 (D) gene expression in female and male offspring of CTR and NR female baboons. The y-axis shows mRNA expression relative to both human 18S and MRPL48 endogenous CTR. Bars denote SEM. *Different from CTR, P < 0.05. CTR, control; HIST3H3, histone cluster 3 H3; MRPL48, mitochondrial ribosomal protein L48; NR, nutrient reduction; PPARγ, peroxisome proliferator-activated receptor γ PRG2, proteoglycan 2; TP53, tumor protein 53.
FIGURE 3
FIGURE 3
BAX/CASP3 immunoreactivity in male placenta of CTR female baboons, n = 3 (A,G); male placenta of NR female baboon, n = 3 (B,H); preabsorbed negative CTR (C,I); female placenta of CTR female baboon, n = 4 (D,J); female placenta of NR female baboon, n = 3 (E,K); and summary of results expressed as fraction percent of area stained (F,L). Green staining, nuclei; black staining, BAX/CASP3. Data are means ± SEMs. *Different from CTR, P < 0.05. Microbar applies to all images. BAX, BCL2-associated X protein; CASP3, caspase 3; CTR, control; NR, nutrient reduction.
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