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Characterization of the intergenerational impact of in utero and postnatal oxycodone exposure.

ABSTRACT: Prescription opioid abuse during and after pregnancy is a rising public health concern. While earlier studies have documented that offspring exposed to opioids in utero have impaired neurodevelopment, a significant knowledge gap remains in comparing the overall development between offspring exposed in utero and postnatally. Adding a layer of complexity is the role of heredity in the overall development of these exposed offspring. To fill in these important knowledge gaps, the current study uses a preclinical rat model mimicking oxycodone (oxy) exposure in utero (IUO) and postnatally (PNO) to investigate comparative and intergenerational effects in the two different treatment groups. While significant phenotypic attributes were observed with the two treatments and across the two generations, RNA sequencing revealed alterations in the expression of key synaptic genes in the two exposed groups in both generations. RNA sequencing and post validation of genes using RT-PCR highlighted the differential expression of several neuropeptides associated with the hypocretin system, a system recently implicated in addiction. Further, behavior studies revealed anxiety-like behaviors and social deficits that persisted even in the subsequent generations in the two treatment groups. To summarize, our study for the first time reveals a new line of investigation on the potential risks associated with oxy use during and after pregnancy, specifically the disruption of neurodevelopment and intergenerational impact on behavior.

SUBMITTER: Odegaard KE

PROVIDER: S-EPMC7511347 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Characterization of the intergenerational impact of in utero and postnatal oxycodone exposure.

Odegaard Katherine E KE Schaal Victoria L VL Clark Alexander R AR Koul Sneh S Gowen Austin A Sankarasubramani Jagadesan J Xiao Peng P Guda Chittibabu C Lisco Steven J SJ Yelamanchili Sowmya V SV Pendyala Gurudutt G

Translational psychiatry 20200923 1

Prescription opioid abuse during and after pregnancy is a rising public health concern. While earlier studies have documented that offspring exposed to opioids in utero have impaired neurodevelopment, a significant knowledge gap remains in comparing the overall development between offspring exposed in utero and postnatally. Adding a layer of complexity is the role of heredity in the overall development of these exposed offspring. To fill in these important knowledge gaps, the current study uses ...[more]

PMID: 32968044

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Project description:ObjectiveLow birth weight (LBW) is associated with increased risk of obesity, diabetes, and cardiovascular disease during adult life. Moreover, this programmed disease risk can progress to subsequent generations. We previously described a mouse model of LBW, produced by maternal caloric undernutrition (UN) during late gestation. LBW offspring (F(1)-UN generation) develop progressive obesity and impaired glucose tolerance (IGT) with aging. We aimed to determine whether such metabolic phenotypes can be transmitted to subsequent generations in an experimental model, even in the absence of altered nutrition during the second pregnancy.Research design and methodsWe intercrossed female and male F(1) adult control (C) and UN mice and characterized metabolic phenotypes in F(2) offspring.ResultsWe demonstrate that 1) reduced birth weight progresses to F(2) offspring through the paternal line (Cfemale -Cmale = 1.64 g; Cfemale -UNmale = 1.57 g, P < 0.05; UNfemale -Cmale = 1.64 g; UNfemale -UNmale = 1.60 g, P < 0.05), 2) obesity progresses through the maternal line (percent body fat: Cfemale -Cmale = 22.4%; Cfemale -UNmale = 22.9%; UNfemale -Cmale = 25.9%, P < 0.05; UNfemale -UNmale = 27.5%, P < 0.05), and 3) IGT progresses through both parental lineages (glucose tolerance test area under curve Cfemale -Cmale = 100; Cfemale -UNmale = 122, P < 0.05; UNfemale -Cmale = 131, P < 0.05; UNfemale -UNmale = 151, P < 0.05). Mechanistically, IGT in both F(1) and F(2) generations is linked to impaired beta-cell function, explained, in part, by dysregulation of Sur1 expression.ConclusionsMaternal undernutrition during pregnancy (F(0)) programs reduced birth weight, IGT, and obesity in both first- and second-generation offspring. Sex-specific transmission of phenotypes implicates complex mechanisms including alterations in the maternal metabolic environment (transmaternal inheritance of obesity), gene expression mediated by developmental and epigenetic pathways (transpaternal inheritance of LBW), or both (IGT).

Dataset Information

Characterization of the intergenerational impact of in utero and postnatal oxycodone exposure.

Publications

Characterization of the intergenerational impact of in utero and postnatal oxycodone exposure.

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