In Utero Exposure to Δ9-Tetrahydrocannabinol Leads to Postnatal Catch-Up Growth and Dysmetabolism in the Adult Rat Liver.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Lipogenesis*; Dronabinol/*toxicity ; Dyslipidemias/*pathology ; Hallucinogens/*toxicity ; Liver/*pathology ; Prenatal Exposure Delayed Effects/*pathology; Animals ; Animals, Newborn ; Dyslipidemias/chemically induced ; Female ; Liver/drug effects ; Male ; Pregnancy ; Prenatal Exposure Delayed Effects/chemically induced ; Rats ; Rats, Wistar

The rates of gestational cannabis use have increased despite limited evidence for its safety in fetal life. Recent animal studies demonstrate that prenatal exposure to Δ9-tetrahydrocannabinol (Δ9-THC, the psychoactive component of cannabis) promotes intrauterine growth restriction (IUGR), culminating in postnatal metabolic deficits. Given IUGR is associated with impaired hepatic function, we hypothesized that Δ9-THC offspring would exhibit hepatic dyslipidemia. Pregnant Wistar rat dams received daily injections of vehicular control or 3 mg/kg Δ9-THC i.p. from embryonic day (E) 6.5 through E22. Exposure to Δ9-THC decreased the liver to body weight ratio at birth, followed by catch-up growth by three weeks of age. At six months, Δ9-THC-exposed male offspring exhibited increased visceral adiposity and higher hepatic triglycerides. This was instigated by augmented expression of enzymes involved in triglyceride synthesis (ACCα, SCD, FABP1, and DGAT2) at three weeks. Furthermore, the expression of hepatic DGAT1/DGAT2 was sustained at six months, concomitant with mitochondrial dysfunction (i.e., elevated p66shc) and oxidative stress. Interestingly, decreases in miR-203a-3p and miR-29a/b/c, both implicated in dyslipidemia, were also observed in these Δ9-THC-exposed offspring. Collectively, these findings indicate that prenatal Δ9-THC exposure results in long-term dyslipidemia associated with enhanced hepatic lipogenesis. This is attributed by mitochondrial dysfunction and epigenetic mechanisms.

Reproduction. 2020 Jan;159(1):27-39. (PMID: 31689235)
J Dev Orig Health Dis. 2016 Apr;7(2):132-43. (PMID: 26810380)
Biochim Biophys Acta. 2012 May;1821(5):747-53. (PMID: 22009142)
Free Radic Biol Med. 2008 Apr 1;44(7):1259-72. (PMID: 18242193)
Am J Physiol Renal Physiol. 2009 Dec;297(6):F1697-705. (PMID: 19828676)
Ann Intern Med. 2005 Nov 15;143(10):722-8. (PMID: 16287793)
PLoS One. 2012;7(3):e33370. (PMID: 22442686)
N Engl J Med. 1976 Aug 12;295(7):349-53. (PMID: 934222)
Pediatr Res. 2021 Apr 20;:. (PMID: 33879850)
Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11806-11. (PMID: 22761311)
Forensic Sci Int. 2012 May 10;218(1-3):92-6. (PMID: 22036306)
Obstet Gynecol. 2017 Oct;130(4):e205-e209. (PMID: 28937574)
ACS Chem Neurosci. 2012 May 16;3(5):349-55. (PMID: 22860202)
Liver Int. 2012 Aug;32(7):1079-92. (PMID: 22429485)
Hepatology. 2011 Jan;53(1):209-18. (PMID: 20890893)
Horm Res Paediatr. 2013;79(2):103-9. (PMID: 23466642)
J Pharmacol Exp Ther. 1972 Feb;180(2):446-53. (PMID: 5010682)
Sci Rep. 2018 Nov 20;8(1):17081. (PMID: 30459314)
BMJ. 1993 Dec 11;307(6918):1524-7. (PMID: 8274921)
Drug Alcohol Depend. 2019 Mar 1;196:14-20. (PMID: 30658220)
PLoS One. 2009 Jul 01;4(7):e6110. (PMID: 19568427)
Toxicology. 2017 Feb 1;376:94-101. (PMID: 27234314)
PLoS One. 2017 Jul 28;12(7):e0182256. (PMID: 28753672)
Arch Toxicol. 2019 Mar;93(3):649-658. (PMID: 30659320)
J Hepatol. 2016 Oct;65(4):784-790. (PMID: 27235307)
Reprod Toxicol. 2020 Jun;94:84-91. (PMID: 32325173)
Reprod Sci. 2019 Sep;26(9):1173-1180. (PMID: 30453824)
J Nutr. 2008 Jan;138(1):60-6. (PMID: 18156405)
Int J Obes Relat Metab Disord. 2001 May;25(5):735-40. (PMID: 11360158)
Clin Chem. 2011 Oct;57(10):1406-14. (PMID: 21836075)
Psychopharmacology (Berl). 2011 Nov;218(2):443-57. (PMID: 21667074)
Free Radic Biol Med. 2019 Jan;130:592-600. (PMID: 30248445)
Hepatology. 2013 Oct;58(4):1497-507. (PMID: 23299992)
Am J Physiol Endocrinol Metab. 2005 Apr;288(4):E663-73. (PMID: 15562247)
Mol Ther Nucleic Acids. 2020 Sep 4;21:751-763. (PMID: 32781430)
Aging Cell. 2019 Apr;18(2):e12895. (PMID: 30609251)
Cell Mol Life Sci. 2018 Sep;75(18):3313-3327. (PMID: 29936596)
Biochim Biophys Acta. 2016 Sep;1861(9 Pt A):1005-1014. (PMID: 27249207)
Hepatology. 2005 Jan;41(1):64-71. (PMID: 15690483)
Toxicol Appl Pharmacol. 2014 Feb 15;275(1):1-11. (PMID: 24368177)
Proc Natl Acad Sci U S A. 2015 Nov 10;112(45):E6185-94. (PMID: 26494286)
Nat Genet. 2000 May;25(1):87-90. (PMID: 10802663)
Hepatology. 2004 Dec;40(6):1387-95. (PMID: 15565570)
PLoS One. 2018 Jun 13;13(6):e0198490. (PMID: 29897997)
Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13018-23. (PMID: 9789033)
PLoS Biol. 2010 Jun 29;8(6):e1000412. (PMID: 20613859)
Life Sci. 2003 Mar 7;72(16):1859-70. (PMID: 12586223)
CMAJ. 2011 Oct 18;183(15):E1127-34. (PMID: 21911558)
Obstet Gynecol. 2016 Oct;128(4):713-723. (PMID: 27607879)
Methods Mol Biol. 2012;829:231-42. (PMID: 22231817)
Methods Enzymol. 2013;528:99-110. (PMID: 23849861)
Exp Physiol. 2015 Jul 1;100(7):755-8. (PMID: 26076765)
J Physiol Sci. 2014 Sep;64(5):347-55. (PMID: 24994532)
Sci Rep. 2019 May 20;9(1):7588. (PMID: 31110286)
J Neonatal Perinatal Med. 2019;12(2):179-187. (PMID: 30584173)
J Nutr. 2003 Oct;133(10):3085-90. (PMID: 14519789)
Br J Nutr. 2010 Oct;104(8):1139-47. (PMID: 20540820)
J Biol Chem. 2008 Dec 5;283(49):34283-93. (PMID: 18838380)
Biomed Res Int. 2020 Jul 18;2020:7402645. (PMID: 32733952)
J Hepatol. 2012 Oct;57(4):837-43. (PMID: 22641095)
J Appl Toxicol. 2017 Dec;37(12):1517-1526. (PMID: 28681937)
Cells. 2019 Oct 22;8(10):. (PMID: 31652636)
Psychopharmacology (Berl). 1976 Nov 24;50(3):285-91. (PMID: 826975)
J Dev Orig Health Dis. 2018 Dec;9(6):566-572. (PMID: 29310731)
J Biol Chem. 2015 Apr 3;290(14):8711-21. (PMID: 25666611)
BMC Gastroenterol. 2012 Jul 06;12:84. (PMID: 22770479)
Diabetes Care. 2007 Oct;30(10):2638-40. (PMID: 17536073)
EMBO J. 2014 Apr 1;33(7):668-85. (PMID: 24469251)
BMC Pregnancy Childbirth. 2020 Dec 11;20(1):771. (PMID: 33308186)
Nature. 1999 Nov 18;402(6759):309-13. (PMID: 10580504)
J Clin Invest. 2011 Feb;121(2):604-12. (PMID: 21245576)
Annu Rev Nutr. 1997;17:77-99. (PMID: 9240920)
Cad Saude Publica. 2003 Sep-Oct;19(5):1241-56. (PMID: 14666206)
Exp Gerontol. 2010 Aug;45(7-8):466-72. (PMID: 20064600)
Mol Metab. 2020 Dec;42:101083. (PMID: 32956848)
Congenit Anom (Kyoto). 2011 Dec;51(4):167-73. (PMID: 22103455)
J Dev Orig Health Dis. 2021 May 28;:1-5. (PMID: 34047687)
Nat Neurosci. 2004 Jun;7(6):585-6. (PMID: 15146190)
J Biol Chem. 2004 Jun 11;279(24):25689-95. (PMID: 15078873)
Neurotoxicol Teratol. 2005 Mar-Apr;27(2):221-9. (PMID: 15734273)
Endocrinology. 2015 Sep;156(9):3069-76. (PMID: 26151354)
FEBS Open Bio. 2017 Jun 05;7(7):1009-1016. (PMID: 28680813)
Cell. 2005 Jul 29;122(2):221-33. (PMID: 16051147)
Free Radic Biol Med. 2020 May 20;152:116-141. (PMID: 32156524)
J Clin Endocrinol Metab. 2015 Dec;100(12):4425-33. (PMID: 26414963)
Free Radic Biol Med. 2012 Jan 1;52(1):59-69. (PMID: 22064361)
Mol Endocrinol. 2011 May;25(5):785-98. (PMID: 21372147)
Addiction. 1997 Nov;92(11):1553-60. (PMID: 9519497)
Complement Ther Clin Pract. 2006 Feb;12(1):27-33. (PMID: 16401527)
Prostaglandins Leukot Essent Fatty Acids. 2003 Feb;68(2):113-21. (PMID: 12538075)
BMJ Open. 2016 Apr 05;6(4):e009986. (PMID: 27048634)
Cell Metab. 2013 Apr 2;17(4):475-90. (PMID: 23562074)
J Pediatr. 2016 Jun;173:122-130.e1. (PMID: 26995700)
Int J Mol Sci. 2019 Mar 26;20(6):. (PMID: 30917489)
Obes Rev. 2008 Mar;9 Suppl 1:95-9. (PMID: 18307708)
Sci Rep. 2020 Jan 17;10(1):544. (PMID: 31953475)
Cell Physiol Biochem. 2017;42(2):537-550. (PMID: 28578322)
Hypertens Res. 2010 Jun;33(6):638-43. (PMID: 20379184)
Eur J Cardiovasc Prev Rehabil. 2004 Feb;11(1):3-8. (PMID: 15167200)
PLoS One. 2016 Nov 2;11(11):e0165432. (PMID: 27806128)
Obes Res. 2005 Apr;13(4):687-92. (PMID: 15897477)

CRU1126 Canada CAPMC CIHR; G-19-0026343 Canadian Heart and Stroke Foundation; CGS-D Natural Sciences and Engineering Research Council

Keywords: intrauterine growth restriction; liver; metabolism; miR-203a-3p; miR-29a/b/c; mitochondria; oxidative stress; triglycerides; Δ9-tetrahydrocannabinol

0 (Hallucinogens)
7J8897W37S (Dronabinol)

Date Created: 20210724 Date Completed: 20210730 Latest Revision: 20210730

20221213

PMC8305322

10.3390/ijms22147502

34299119