Maternal opioid use disorder: Placental transcriptome analysis for neonatal opioid withdrawal syndrome

Radhakrishna, Uppala; Nath, Swapan K.; Vishweswaraiah, Sangeetha; Uppala, Lavanya V.; Forray, Ariadna; Muvvala, Srinivas; Mishra, Nitish K.; Southekal, Siddesh; Guda, Chittibabu; Govindamangalam, Hiranjith; Vargas, Derek; Gardella, William G.; Crist, Richard C.; Berrettini, Wade H.; Metpally, Raghu; Bahado‐Singh, Ray O.

doi:10.1016/j.ygeno.2021.08.001

Cited by 13 publications

(10 citation statements)

References 53 publications

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“…Although we observed placental perturbations from THC exposure, the underlying mechanisms for these observations are not well understood. Maternal environmental exposures ranging from pregnancy nutrition, to opioids and smoking have all been associated with an altered placental transcriptome, including changes linked to neurodevelopmental disorders [66][67][68][69][70] . THC exerts its effects via receptors of the endocannabinoid system, which plays a critical role in mediating placental and fetal development [11][12][13][14][15]71 .…”

Section: Discussionmentioning

confidence: 99%

Chronic prenatal delta-9-tetrahydrocannabinol exposure adversely impacts placental function and development in a rhesus macaque model

Roberts

Schabel

Boniface

et al. 2022

Sci Rep

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Cannabis use in pregnancy is associated with adverse perinatal outcomes, which are likely mediated by the placenta. However, the underlying mechanisms and specific vasoactive effects of cannabis on the placenta are unknown. Our objective was to determine the impact of chronic prenatal delta-tetrahydrocannabinol (THC, main psychoactive component of cannabis) exposure on placental function and development in a rhesus macaque model using advanced imaging. Animals were divided into two groups, control (CON, n = 5) and THC-exposed (THC, n = 5). THC-exposed animals received a THC edible daily pre-conception and throughout pregnancy. Animals underwent serial ultrasound and MRI at gestational days 85 (G85), G110, G135 and G155 (full term is ~ G168). Animals underwent cesarean delivery and placental collection at G155 for histologic and RNA-Seq analysis. THC-exposed pregnancies had significantly decreased amniotic fluid volume (p < 0.001), placental perfusion (p < 0.05), and fetal oxygen availability (p < 0.05), all indicators of placental insufficiency. Placental histological analysis demonstrated evidence of ischemic injury with microinfarctions present in THC-exposed animals only. Bulk RNA-seq demonstrated that THC alters the placental transcriptome and pathway analysis suggests dysregulated vasculature development and angiogenesis pathways. The longer-term consequences of these adverse placental findings are unknown, but they suggest that use of THC during pregnancy may deleteriously impact offspring development.

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Section: Discussionmentioning

confidence: 99%

Chronic prenatal delta-9-tetrahydrocannabinol exposure adversely impacts placental function and development in a rhesus macaque model

Roberts

Schabel

Boniface

et al. 2022

Sci Rep

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“…In agreement with our findings, others have found the following canonical pathways to be significantly dysregulated in the placenta of neonatal opioid withdrawal syndrome-affected pregnancies: endocannabinoid neuronal synapse pathway, calcium signaling, CREB signaling in neurons, synaptogenesis signaling pathway, and the opioid signaling pathway. 119 Disease and Function pathway analysis correlated DEG with increased nociception, sensation and sensory system development and decreased learning, memory, and cognition in prenatally methadone-exposed offspring. In line with our findings, experimental animal models have found that prenatal opioid exposure is associated with decreased levels of neurotransmitters, 120–122 decreased neurogenesis, 123 , 124 impairments in somatosensory circuit function/compromised sensory adaptation to repeat tactile stimuli, 125 and altered myelination, 126 , 127 brain connectivity, and brain network topology.…”

Section: Discussionmentioning

confidence: 99%

Opioid-induced dysbiosis of maternal gut microbiota during gestation alters offspring gut microbiota and pain sensitivity

Abu,

Singh,

Tao

et al. 2023

Gut Microbes

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There has been a rapid increase in neonates born with a history of prenatal opioid exposure. How prenatal opioid exposure affects pain sensitivity in offspring is of interest, as this may perpetuate the opioid epidemic. While few studies have reported hypersensitivity to thermal pain, potential mechanisms have not been described. This study posits that alterations in the gut microbiome may underly hypersensitivity to pain in prenatally methadone-exposed 3-week-old male offspring, which were generated using a mouse model of prenatal methadone exposure. Fecal samples collected from dams and their offspring were subjected to 16s rRNA sequencing. Thermal and mechanical pain were assessed using the tail flick and Von Frey assays. Transcriptomic changes in whole brain samples of opioid or saline-exposed offspring were investigated using RNA-sequencing, and midbrain sections from these animals were subjected to qPCR profiling of genes related to neuropathic and inflammatory pain pathways. Prenatal methadone exposure increased sensitivity to thermal and mechanical pain and elevated serum levels of IL-17a. Taxonomical analysis revealed that prenatal methadone exposure resulted in significant alterations in fecal gut microbiota composition, including depletion of Lactobacillus , Bifidobacterium , and Lachnospiracea sp and increased relative abundance of Akkermansia, Clostridium sensu stricto 1 , and Lachnoclostridium . Supplementation of the probiotic VSL#3 in dams rescued hypersensitivity to thermal and mechanical pain in prenatally methadone-exposed offspring. Similarly, cross-fostering prenatally methadone-exposed offspring to control dams also attenuated hypersensitivity to thermal pain in opioid-exposed offspring. Modulation of the maternal and neonatal gut microbiome with probiotics resulted in transcriptional changes in genes related to neuropathic and immune-related signaling in whole brain and midbrain samples of prenatally methadone-exposed offspring. Together, our work provides compelling evidence of the gut-brain-axis in mediating pain sensitivity in prenatally opioid-exposed offspring.

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“…These effects are exceedingly difficult to elucidate in daily clinical care practice as additional factors including maternal metabolism, and placental and fetal interaction further influence the overall fetal exposure and change the severity of NOWS. 28,31 Finally, we are not reporting neuro-developmental outcomes in our study subjects, but future studies are planned to assess this in our on-going MSA project.…”

Section: Discussionmentioning

confidence: 99%

Assessing Neonatal Opioid Withdrawal Syndrome Severity as a Function of Maternal Buprenorphine Dose and Umbilical Cord Tissue Concentrations

et al. 2022

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Background: Infants born to mothers with opioid use disorder (OUD) and prenatally treated with buprenorphine have a significantly lower incidence of neonatal opioid withdrawal syndrome (NOWS), its treatment duration, and hospital length of stay compared with methadone. However, risk of NOWS remains and clinicians continue to lack an objective methodology to predict NOWS severity among these infants. Objective: The purpose of this study was to assess the relationship between buprenorphine exposure, umbilical cord tissue (UCT) concentrations, and NOWS development and severity. Methods: A single-center retrospective observational cohort study from March 2018 through June 2020 of newborns exposed to buprenorphine in utero. Associations between quantified buprenorphine exposure, neonatal UCT concentrations, NOWS diagnosis, and severity were made using regression analyses. Results: A total of 24 mothers and 25 neonates were included. Length of maternal buprenorphine therapy (months) positively correlated to norbuprenorphine ( r2 = 0.234, P = 0.019) and buprenorphine + norbuprenorphine UCT concentrations ( r2 = 0.203, P = 0.031). A positive relationship was seen between active metabolite concentrations and cumulative morphine dose (mg/kg) for treatment of severe NOWS ( r2 = 0.471, P = 0.007). A 0.36 ng/g buprenorphine + norbuprenorphine UCT (CI = 0.002-0.72, P = 0.049) equated in a 1-point increase in modified peak Finnegan score. Conclusion and Relevance: Buprenorphine and norbuprenorphine UCT concentrations can allow for quantification of in utero fetal exposure and demonstrate an association with a longer duration of exposure with the severity and treatment of NOWS in exposed infants.

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Maternal opioid use disorder: Placental transcriptome analysis for neonatal opioid withdrawal syndrome

Cited by 13 publications

References 53 publications

Chronic prenatal delta-9-tetrahydrocannabinol exposure adversely impacts placental function and development in a rhesus macaque model

Chronic prenatal delta-9-tetrahydrocannabinol exposure adversely impacts placental function and development in a rhesus macaque model

Opioid-induced dysbiosis of maternal gut microbiota during gestation alters offspring gut microbiota and pain sensitivity

Assessing Neonatal Opioid Withdrawal Syndrome Severity as a Function of Maternal Buprenorphine Dose and Umbilical Cord Tissue Concentrations

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