NIH Swiss dams adapted long term to a diet very high in fat (VHF) produce a predominance of sons, while dams on a low fat (LF) diet produce proportionately more daughters. Our hypothesis is that changes in sex ratio occur through competition between conceptuses, and specifically between their placentae in attempts to gain resources from the dam during the post-implantation period. Here, we have compared patterns of autosomal gene expression within d 12.5 placentae of viable fetuses derived from dams that had been maintained on the VHF, LF, and a control (C) chow-based (Purina 5015) diet between 5 and 50 wks of age. Sex of fetuses was determined by X/Y fluorescent in situ hybridization. Placental RNA was isolated and processed for microarray analysis from one female and one male conceptus that had implanted adjacent to each other within the central zone of the uterine horns. After first and second strand cDNA preparation, cRNA target material was prepared and hybridized to Agilent Whole Genome 4×44K arrays. Slides were scanned on an Agilent G2565 Microarray Scanner, and data analyzed with Agilent Feature Extraction and GeneSpring GX v7.3.1 software. Comparisons were made between diet groups within the same sex and between males and females (6 VHF, 6 LF, and 8 C, comprising 10 males and 10 females). Genes displaying a 2-fold or greater change in expression with a P value <0.05 were considered to be differentially regulated. When overall patterns of gene expression were examined, marked differences were observed between the C, VHF, and LF placentae, with each group forming distinct heat map clusters. Importantly, even when gene expression from the X- and Y-chromosomes was ignored, there was pronounced sexual dimorphism within all diet groups, with 246, 315, and 349 genes differentially regulated within the C, VHF, and LF groups, respectively. Curiously, there was little overlap in sexually dimorphic gene expression across groups, although more similarity was evident between the C and LF groups than in the C and VHF and the LF and VHF comparisons. Sexually dimorphic genes within the C group included estrogen receptor-α (70 % down-regulated in males; P < 0.02) suggesting that females might be more responsive to 17β-estradiol and estrogenic toxicants than males. In contrast, androgen receptor was down-regulated in VHF males by 73% compared to VHF females (P<0.02). Additional genes up-regulated in C females versus C males included Fgf2, Ets1, HoxA11, Klk1, serotonin receptor Htr2β, Ren1 & Ren2 (renins), several olfactory receptors, such as Olfr1381, and Ceacam18. Quantitative real time PCR confirmed the microarray results. These data show that there are a relatively large number of autosomal genes which are regulated in a sexually dimorphic manner in the placenta. Genes that are differentially expressed between sons and daughters within the placenta are strongly influenced by maternal diet. It remains to be seen to what extent sexually dimorphic gene expression within the placenta controls sex ratio of offspring born. Supported by NIH Grant HD 44042. (poster)