Maternal oxycodone treatment causes pathophysiological changes in the mouse placenta

• Published in: Placenta (Eastbourne) Vol. 100; pp. 96 - 110
• Main Authors: Green, Madison T., Martin, Rachel E., Kinkade, Jessica A., Schmidt, Robert R., Bivens, Nathan J., Tuteja, Geetu, Mao, Jiude, Rosenfeld, Cheryl S.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.10.2020
• Subjects: Analgesic; Analgesics, Opioid - adverse effects; Animals; DOHaD; Drug abuse; Female; Male; Mice; Opioid; Oxycodone - adverse effects; Placenta - drug effects; Placenta - metabolism; Placental lactogens; Pregnancy; Pregnancy Rate; Reproduction; Sex Ratio; Sexual dimorphism; Transcriptome - drug effects; Trophoblast; Trophoblast giant cells; Trophoblast giant cells; Drug abuse; Reproduction; Analgesic; DOHaD; Opioid; Trophoblast; Placental lactogens; Sexual dimorphism
• ISSN: 0143-4004; 1532-3102
• DOI: 10.1016/j.placenta.2020.08.006

Pregnant women are increasingly being prescribed and abusing opioid drugs. As the primary communication organ between mother and conceptus, the placenta may be vulnerable to opioid effects but also holds the key to better understanding how these drugs affect long-term offspring health. We hypothesized that maternal treatment with oxycodone (OXY), the primary opioid at the center of the current crisis, deleteriously affects placental structure and gene expression patterns. Female mice were treated daily with 5 mg OXY/kg or saline solution (Control, CTL) for two weeks prior to breeding and until placenta were collected at embryonic age 12.5. A portion of the placenta was fixed for histology, and the remainder was frozen for RNA isolation followed by RNAseq. Maternal OXY treatment reduced parietal trophoblast giant cell (pTGC) area and decreased the maternal blood vessel area within the labyrinth region. OXY exposure affected placental gene expression profiles in a sex dependent manner with female placenta showing up-regulation of many placental enriched genes, including Ceacam11, Ceacam14, Ceacam12, Ceacam13, Prl7b1, Prl2b1, Ctsq, and Tpbpa. In contrast, placenta of OXY exposed males had alteration of many ribosomal proteins. Weighted correlation network analysis revealed that in OXY female vs. CTL female comparison, select modules correlated with OXY-induced placental histological changes. Such associations were lacking in the male OXY vs. CTL male comparison. Results suggest OXY exposure alters placental histology. In response to OXY exposure, female placenta responds by upregulating placental enriched transcripts that are either unchanged or downregulated in male placenta. Such changes may shield female offspring from developmental origins of health and disease-based diseases. •Placental cells bathed by maternal blood are vulnerable to circulating opioids.•Maternal oxycodone (OXY) treatment reduces parietal trophoblast giant cells.•Maternal OXY exposure induces sex-specific placenta transcript changes.•Placental-specific transcripts are enriched in female placenta exposed to OXY.