Session: SAT 389-413-Signaling and Transcriptional Control in Endocrine Systems
Poster Board SAT-399
From population data, we know that male pregnancies have a 10% higher risk of preterm delivery, more placental pathologies, and are more likely to have altered genitalia at birth in response to phthalate exposure in utero. Human chorionic gonadotropin (hCG) is a candidate mediator. This placental hormone is higher in female vs. male pregnancies as early as 5 wks. In the first trimester, hCG binds to the luteinizing hormone receptor of the testis, stimulating differentiation of Leydig cells and initiating testosterone synthesis. In a birth cohort analysis, we found an association of phthalate exposure and sex-specific differences in hCG expression and showed a similar relationship by dosing human trophoblasts in vitro. Thus, we postulated that the placenta is a source of essential signals for fetal sexual differentiation.
Methods: We assembled microarray data from 72 placentas; 35 were males and 37 were females based on levels of a ribosomal Y-linked protein, RPS4Y1. All were collected with informed consent from pregnancy terminations or following delivery. They included basal plates from normal, preterm and preeclamptic pregnancies (14-40 wks); freshly isolated villous cytotrophoblasts (vCTBs) and chorionic membrane (cm) CTBs (6-8 wks); and freshly isolated and cultured (40 h) vCTBs (15-20 wks). The microarray data were acquired by using an Affymetrix platform. Data were normalized before analysis, which involved fitting multivariate regression models for each gene to isolate sex effects. This yielded a list of raw p-values, which were adjusted for multiple testing to give false discovery rate (FDR) p-values. The FDR p-values and fold differences were entered into Ingenuity Pathway Analysis.
Results: The most highly differentially expressed (DE) genes were encoded on the Y chromosome. Fold differences reached 135. vCTBs dosed with mono-n-butyl phthalate (MnBP) had the largest differences, which also included genes involved in renal/urological development. The sex difference was estimated independently of the MnBP dose effects. In the basal plate, the upregulated DE list included X-linked steroidogenic genes. They were downregulated in isolated CTBs, suggesting a maternal source for the basal plate signals, which may differ in male vs. female pregnancies. In the cmCTBs, the DE genes by sex were regulators of embryonic development, supporting the theory of an environmental-maternal-placental-fetal signaling axis that is perhaps more vulnerable to perturbation in males vs. females.
Nothing to Disclose: JJA, LZ, SF
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