DEHP exposure alters carcinoembryonic antigen family member transcript levels and modulates responses to activin A in the murine placenta

Abstract

Introduction

Activin A affects placental decidualisation and trophoblast growth and invasion. Levels increase during pregnancy, peaking at parturition, while premature elevation is a hallmark of several pregnancy disorders. We examined the impact of unopposed/elevated activin A bioactivity in the inhibin α knockout (Inha KO) mouse placenta which lacks competitive inhibition by inhibin A. We also investigated whether simultaneous exposure to the endocrine disruptor, diethyl-hexyl phthalate (DEHP), which impairs normal placental function and affects activin A signalling in other organs, exacerbates morphological and transcriptional effects.

Methods

Litters of Inha WT, Het and KO fetuses were collected at E15.5 from time-mated Inha heterozygous pregnant mice randomly assigned to three groups: untreated, corn oil (Vehicle) or DEHP 500 mg/kg/day, from E12.5–14.5 (n = 2–17). Gross and histological placental morphology was analysed, and bulk RNA-sequencing conducted.

Results

Placentae of Inha WT, Het and KO fetuses exhibited no gross morphological differences or differentially expressed genes. However, WT males compared to WT females displayed significantly increased placenta size and labyrinth area. DEHP exposure significantly increased fetal resorption at E15.5 but yielded limited differences in placental morphology. Sex- and genotype-specific transcript alterations in DEHP-exposed placentae included four carcinoembryonic antigen family transcripts (Ceacam13, Gm5155, Psg18, Psg-ps1) and four additional trancripts (Cts3, Ssr4, Sec11c, Taf7l) altered in all genotypes.

Discussion

Despite minimal morphological changes, transcriptomic differences suggest that spongiotrophoblast cells and syncytiotrophoblast giant cells are DEHP exposure targets, with carcinoembryonic antigen family transcripts susceptible to its effects. Additionally, DEHP modulates placental gene transcript levels when activin A is unopposed in vivo.