Department of Pharmacology and Toxicology
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Item Genetic variation in fatty acid amide hydrolase (FAAH): Associations with early drinking and smoking behaviors(Elsevier, 2022-11-11) Alsaafin, Alaa; Chenoweth, Meghan J; Sylvestre, Marie-Pierre; O'Loughlin, Jennifer; Tyndale, Rachel FBackground The endocannabinoid system is implicated in psychiatric disorders and drug dependence. Within this system, fatty acid amide hydrolase (FAAH) metabolizes endocannabinoids. Individuals with A-group genotypes (C/A or A/A) of a common FAAH variant (rs324420; C > A; Pro129Thr) have slower enzymatic activity compared to C-group individuals (C/C genotype). Slow FAAH activity is differentially associated with alcohol and nicotine use. Methods Among European-ancestry participants in the NDIT study (n = 249–607), genotype associations with past-year binge drinking in young adults were estimated in logistic regression models. In adolescents, hazard ratios (HR) were estimated from Cox proportional hazards models to assess the FAAH genotype group association with time to drinking initiation and attaining drinking frequency outcomes. HR were also used to assess genotype effect on time to smoking initiation and attaining early smoking milestones (e.g., first inhalation, ICD-10 dependence). Results Compared to those in the C-group, those in the A-group had higher odds of binge drinking at ages 20 (Odds ratio (OR) = 2.16, 95 % CI 1.36–3.42) and 30 (OR = 1.61, 95 % CI 1.10–2.36). Time to initiation of drinking and daily drinking was faster in adolescents in the A-group (HR = 1.39, 95 % CI 1.09–1.77 and HR = 2.24, 95 % CI 1.05–4.76, respectively). Time to smoking initiation was faster in the A-group (HR = 1.20, 95 % CI 1.04–1.39); however, time to smoking milestones among adolescent smokers was not consistently different for the A- versus C-groups (HR = 0.43 to 1.13). Conclusions Slow FAAH activity (A-group) was associated with greater risks for binge drinking, drinking initiation and escalation, and cigarette smoking initiation, but had little impact on the escalation in cigarette smoking behaviors.Item A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization(2022) Dilworth, David; Hanley, Ronan P; Ferreira de Freitas, Renato; Allali-Hassani, Abdellah; Zhou, Mengqi; Mehta, Naimee; Marunde, Matthew R; Ackloo, Suzanne; Carvalho Machado, Raquel Arminda; Khalili Yazdi, Aliakbar; Owens, Dominic D G; Vu, Victoria; Nie, David Y; Alqazzaz, Mona; Marcon, Edyta; Li, Fengling; Chau, Irene; Bolotokova, Albina; Qin, Su; Lei, Ming; Liu, Yanli; Szewczyk, Magdalena M; Dong, Aiping; Kazemzadeh, Sina; Abramyan, Tigran; Popova, Irina K; Hall, Nathan W; Meiners, Matthew J; Cheek, Marcus A; Gibson, Elisa; Kireev, Dmitri; Greenblatt, Jack F; Keogh, Michael-C; Min, Jinrong; Brown, Peter J; Vedadi, Masoud; Arrowsmith, Cheryl H; Barsyte-Lovejoy, Dalia; James, Lindsey I; Schapira, MatthieuNuclear receptor-binding SET domain-containing 2 (NSD2) is the primary enzyme responsible for the dimethylation of lysine 36 of histone 3 (H3K36), a mark associated with active gene transcription and intergenic DNA methylation. In addition to a methyltransferase domain, NSD2 harbors two proline-tryptophan-tryptophan-proline (PWWP) domains and five plant homeodomains (PHDs) believed to serve as chromatin reading modules. Here, we report a chemical probe targeting the N-terminal PWWP (PWWP1) domain of NSD2. UNC6934 occupies the canonical H3K36me2-binding pocket of PWWP1, antagonizes PWWP1 interaction with nucleosomal H3K36me2 and selectively engages endogenous NSD2 in cells. UNC6934 induces accumulation of endogenous NSD2 in the nucleolus, phenocopying the localization defects of NSD2 protein isoforms lacking PWWP1 that result from translocations prevalent in multiple myeloma (MM). Mutations of other NSD2 chromatin reader domains also increase NSD2 nucleolar localization and enhance the effect of UNC6934. This chemical probe and the accompanying negative control UNC7145 will be useful tools in defining NSD2 biology.Item Does genetic variation in a bitter taste receptor gene alter early smoking behaviours in adolescents and young adults?(Wiley, 2022-03-16) Alsaafin, Alaa; Chenoweth, Meghan Jo-Ann; Sylvestre, Marie-Pierre; O'Loughlin, Jennifer; Tyndale, Rachel FynvolaVariation in the TAS2R38 taste receptor gene alters the ability to taste bitter compounds. We tested whether TAS2R38 variation influences early smoking behaviours in adolescence, a critical period of acquisition when taste may influence the natural course of tobacco use.Item Antidepressant use by the breastfeeding mother: Clinical and economic consequences(2006) Lee, AmyThere is a paucity of data on the consequences of antidepressant use in breastfeeding women, compared to leaving the depression untreated, making it difficult to weigh the risk and benefits of both options to mother and child. Thus, the health and healthcare costs of depressed, breastfeeding women treated with antidepressants (AD(+)), and their infants were compared to those forgoing pharmacotherapy (AD(-)), and to healthy women (COMP) for the first year postpartum. The validity of maternal report of healthcare utilization, and the reliability of report of infant feeding methods were also examined. Mother-infant pairs were interviewed over the first year postpartum. The Edinburgh Postnatal Depression Scale (EPDS), Short Form 36 (SF-36), and Functional Status II- Revised (FS-II(R)) were used to assess maternal depression, and maternal and infant well-being, respectively. Fifty-five, 34, and 60 AD(+), AD(-), and COMP women, respectively, completed the study. EPDS scores differed between the groups; (AD(+): 6.5, AD(-): 10.5, COMP: 3.7, p<0.01), suggesting more depressive symptomatology in AD(-). AD(+) scores were higher than COMP, suggesting inadequate treatment. SF-36 mental component scores (AD(+): 49.8, AD(-) 45.8, COMP: 55.5, p<0.01) indicated more functional impairment in AD(-) women. The annual average costs per mother-infant pair from the provincial ministry of health perspective differed between the groups (AD(+): $1488.36, AD(-): $2054.54, COMP: $1082.29, p<0.05). From the societal perspective, both depressed groups incurred greater costs compared to COMP (AD(+): $3730.48, AD(-): $4129.45, COMP:$2757.41, p<0.01). Although depressed groups incurred greater costs and had poorer outcomes compared to the COMP, AD(+) women were achieving better outcomes compared to AD(-) without incurring greater costs. Although remote risks of exposure to the nursed infant cannot be dismissed, given the clinical and economic benefits found in the study, postpartum women with depression should not be discouraged from pharmacotherapy, even while breastfeeding. Maternal self-report and report of infant health care utilization were compared to administrative records. No differences existed in agreement between data sources between reports by depressed mothers, and COMP mothers. Finally, maternal recall of infant feeding method over time was accurate for breastfeeding and formula feeding status, but less so for age when solids were introduced.Item Loss of hepatic aryl hydrocarbon receptor protein in adrenalectomized rats does not involve altered levels of the receptor's cytoplasmic chaperones(NRC Research Press, 2013-08-16) Lee, Chunja ; Grey, Anne K. Mullen ; Riddick, David S.The aryl hydrocarbon receptor (AHR) plays physiological roles and mediates adaptive and toxic responses to environmental pollutants. Adrenalectomized rats display decreased hepatic AHR protein levels, with no change in mRNA, and selectively impaired induction of cytochrome P450 1B1. This was similar to reported phenotypes for mice with hepatocyte-specific conditional deletion of AHR-interacting protein (AIP), a chaperone protein of the cytoplasmic AHR complex. In the current study, we demonstrated that adrenalectomy (ADX) and acute dexamethasone (DEX) treatment do not alter hepatic AIP mRNA or protein levels. Also, hepatic protein levels of the 90-kDa heat shock protein and p23 were not altered by ADX or acute DEX treatment. These results suggest that the loss of rat hepatic AHR protein following ADX cannot be explained by changes in the levels of the receptor’s cytoplasmic chaperone proteins.Item Aryl hydrocarbon receptor-dependence of dioxin's effects on constitutive mouse hepatic cytochromes P450 and growth hormone signaling components(NRC Research Press, 2012-09-14) Lee, Chunja ; Riddick, David S.The aryl hydrocarbon receptor (AHR) has physiological roles in the absence of exposure to exogenous ligands and mediates adaptive and toxic responses to the environmental pollutant, 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD). A readily metabolized AHR agonist, 3-methylcholanthrene, disrupts expression of mouse hepatic growth hormone (GH) signaling components and suppresses cytochrome P450 2D9 (Cyp2d9), a male-specific gene controlled by pulsatile GH via signal transducer and activator of transcription 5b (STAT5b). Using TCDD as an essentially non-metabolized AHR agonist and Ahr -/- mice as the preferred model to determine the AHR-dependence of biological responses, we now show that two mouse hepatic STAT5b target genes, Cyp2d9 and major urinary protein 2 (Mup2), are suppressed by TCDD in an AHR-dependent manner. TCDD also decreased hepatic mRNA levels for GH receptor, Janus kinase 2, and STAT5a/b with AHR-dependence. Without inducing selected hepatic inflammatory markers, TCDD caused AHR-dependent induction of Cyp1a1 and NADPH-cytochrome P450 oxidoreductase (Por) and suppression of Cyp3a11. In vehicle-treated mice, basal mRNA levels for CYP2D9, CYP3A11, POR, serum amyloid protein P, and MUP2 were influenced by Ahr genetic status. We conclude that AHR activation per se leads to dysregulation of hepatic GH signaling components and suppression of some, but not all, STAT5b target genes.Item Glucocorticoid and adrenalectomy effects on the rat aryl hydrocarbon receptor pathway depend on the dosing regimen and post-surgical time(Elsevier, 2009-07-16) Grey, Anne K. Mullen ; Riddick, David S.The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the effects of aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3-methylcholanthrene (MC); the prototypical response is induction of drug-metabolizing enzymes. Factors that regulate AHR levels in vivo are poorly understood and it is also not clear how AHR levels affect aromatic hydrocarbon responsiveness. Our interest in pituitary-dependent regulation of AHR levels was prompted by two findings from our laboratory: (1) hypophysectomized rats have reduced hepatic levels of AHR protein; and (2) glucocorticoids increase AHR expression and aromatic hydrocarbon responsiveness in rodent hepatoma cells. To study whether adrenalectomy and glucocorticoids contribute to hormone-dependent regulation of the hepatic AHR pathway, male adrenalectomized (ADX) or SHAM-ADX rats were treated with dexamethasone (DEX) or vehicle. AHR protein was depleted by 50-60% at four days after ADX, but was not altered by DEX treatment. To assess whether the observed AHR depletion affected aromatic hydrocarbon responsiveness, the induction of hepatic cytochrome P450 1B1 (CYP1B1) mRNA by MC was measured as an AHR-mediated adaptive response. MC-induced hepatic CYP1B1 mRNA was reduced by 50% in ADX rats relative to SHAM-ADX. Exogenous glucocorticoid treatment (DEX – 1.5 mg/kg) induced hepatic AHR nuclear translocator (ARNT) mRNA by up to 9-fold at 3 and 6 h after dosing, with no corresponding change in ARNT protein levels. These data demonstrate that: (1) adrenal-dependent factors contribute to the physiological maintenance of hepatic AHR protein levels; (2) the depletion of hepatic AHR protein in ADX rats coincided with a diminished adaptive response to MC; and (3) exogenous glucocorticoid treatment increases hepatic ARNT mRNA levels regardless of adrenal status. This model is useful for studying the mechanisms of AHR and ARNT regulation and for further characterization of the impact of AHR protein depletion on the response to aromatic hydrocarbons in vivo.