A Novel Defensive Mechanism against Acetaminophen Toxicity in the Mouse Lateral Nasal Gland: Role of CYP2A5-Mediated Regulation of Testosterone Homeostasis and Salivary Androgen-Binding Protein Expression

Zhou, Xin; Wei, Yuan; Xie, Fang; Laukaitis, Christina M.; Karn, Robert C.; Kluetzman, Kerri; Gu, Jun; Zhang, Qing Yu; Roberts, Dean W.; Ding, Xinxin

doi:10.1124/mol.110.070045

Cited by 12 publications

(6 citation statements)

References 37 publications

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“…2B ) included the female-biased OBP7, the male-biased MUP4, the male-only ESP1, the male-biased ESP38, and several male-biased secretoglobins (SCGB1B19, SCGB1B3, SCGB2A2—Mammaglobin, SCGB2B3, SCGB2B7). Secretoglobins are found in mammalian secretions and have important roles in the modulation of inflammation and tissue repair ( Jackson et al, 2011 ), are involved in removing toxins ( Zhou et al, 2011 ), and may have roles in chemical communication ( Karn & Laukaitis, 2015 ). Kallikrein 1-related peptidases were also significantly sexual dimorphic (i.e., female-biased KLK1B22, KLK1B1, and KLK1B3), however, this pattern (though significant) was not consistent across all the females tested.…”

Section: Resultsmentioning

confidence: 99%

On the tear proteome of the house mouse (Mus musculus musculus) in relation to chemical signalling

Stopková

Klempt

Kuntová

et al. 2017

PeerJ

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Mammalian tears are produced by lacrimal glands to protect eyes and may function in chemical communication and immunity. Recent studies on the house mouse chemical signalling revealed that major urinary proteins (MUPs) are not individually unique in Mus musculus musculus. This fact stimulated us to look for other sexually dimorphic proteins that may—in combination with MUPs—contribute to a pool of chemical signals in tears. MUPs and other lipocalins including odorant binding proteins (OBPs) have the capacity to selectively transport volatile organic compounds (VOCs) in their eight-stranded beta barrel, thus we have generated the tear proteome of the house mouse to detect a wider pool of proteins that may be involved in chemical signalling. We have detected significant male-biased (7.8%) and female-biased (7%) proteins in tears. Those proteins that showed the most elevated sexual dimorphisms were highly expressed and belong to MUP, OBP, ESP (i.e., exocrine gland-secreted peptides), and SCGB/ABP (i.e., secretoglobin) families. Thus, tears may have the potential to elicit sex-specific signals in combination by different proteins. Some tear lipocalins are not sexually dimorphic—with MUP20/darcin and OBP6 being good examples—and because all proteins may flow with tears through nasolacrimal ducts to nasal and oral cavities we suggest that their roles are wider than originally thought. Also, we have also detected several sexually dimorphic bactericidal proteins, thus further supporting an idea that males and females may have adopted alternative strategies in controlling microbiota thus yielding different VOC profiles.

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Section: Resultsmentioning

confidence: 99%

On the tear proteome of the house mouse (Mus musculus musculus) in relation to chemical signalling

Stopková

Klempt

Kuntová

et al. 2017

PeerJ

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“…The Cyp2f2-null mouse joins three other mouse models reported to target members of the Cyp2 gene clusters on mouse chromosome 7: the Cyp2g1-null/Cyp2a5-low model (Zhuo et al, 2004), the Cyp2a5-null model , and the Cyp2g1-null mouse model (Zhou et al, 2011). As with Cyp2a5-null and Cyp2g1-null models, the Cyp2f2-null mouse was generated on a B6 genetic background.…”

Section: Discussionmentioning

confidence: 99%

Generation and Characterization of aCyp2f2-Null Mouse and Studies on the Role of CYP2F2 in Naphthalene-Induced Toxicity in the Lung and Nasal Olfactory Mucosa

Wei

Winkle³

et al. 2011

J Pharmacol Exp Ther

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The CYP2F enzymes, abundantly expressed in the respiratory tract, are active toward many xenobiotic compounds, including naphthalene (NA). However, the precise roles of these enzymes in tissue-selective chemical toxicity have been difficult to resolve. A Cyp2f2-null mouse was generated in this study by disrupting the Cyp2f2 fourth exon. Homozygous Cyp2f2-null mice, which had no CYP2F2 expression and showed no changes in the expression of other P450 genes examined, were viable and fertile and had no in utero lethality or developmental deficits. The loss of CYP2F2 expression led to substantial decreases in the in vitro catalytic efficiency of microsomal NA epoxygenases in lung (up to ϳ160-fold), liver (ϳ3-fold), and nasal olfactory mucosa (OM; up to ϳ16-fold), and significant decreases in rates of systemic NA (300 mg/kg i.p.) clearance. The Cyp2f2-null mice were largely resistant to NA-induced cytotoxicity, when examined at 24 h after NA dosing (at 300 mg/kg i.p.), and to NA-induced depletion of total nonprotein sulfhydryl (NPSH), examined at 2 h after dosing, in the lungs. In contrast, the loss of CYP2F2 expression did not alleviate NAinduced NPSH depletion or tissue toxicity in the OM. Mouse CYP2F2 clearly plays an essential role in the bioactivation and toxicity of NA in the lung but not in the OM. The Cyp2f2-null mouse should be valuable for studies on the role of CYP2F2 in the metabolism and toxicity of numerous other xenobiotic compounds and for future production of a CYP2F1-humanized mouse.

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“…In addition, we analyzed the Harderian gland (the source of heteroglobin that may mediate behavior in hamsters) (Dominguez 1995;Alvarez et al 2002); kidney, which was compromised in a uteroglobin (Ug) knockout (Zhang et al 1997); and liver, a major site of detoxification that might be affected by toxins that could not be bound and removed in an Abp knockout animal (Zhou et al 2011). H&E staining revealed no discernable structural differences across tissues, including submandibular gland (Figure 1), sublingual, lacrimal, parotid, Harderian, liver, kidney, and ovaries (female only) ( Figure S3), harvested from the three genotypes.…”

Section: Histological Assessment Of Tissue Structurementioning

confidence: 99%

“…Another knockout mouse project produced a Cyp2g1-null/ Cyp2a5-low mouse and showed that toxin metabolism in the LNG of the male treated with large amounts of APAP upregulated a27 and bg27 expression (Zhou et al 2011). This apparently quenched reactive APAP metabolites and thereby spared critical cellular proteins from inactivation.…”

Section: Overall Impact Of Knocking Out the Abp Genesmentioning

confidence: 99%

“…This suggests the possibility that ABP was preadapted to serve a pheromonal role in mice similar to the observation that long-chain hydrocarbons that protect the cuticle of Drosophila against desiccation have also been shown to act as pheromones involved in sexual isolation (Coyne and Charlesworth 1997). A different study evaluated toxin metabolism in the lateral nasal gland (LNG) of the male Cyp2g1-null/Cyp2a5-low mouse treated with large amounts of acetaminophen (APAP; Zhou et al 2011). The authors proposed that, through its critical role in testosterone metabolism, CYP2A5 regulates (1) the bioavailability of APAP and APAP-glutathione and (2) the expression of ABP, which can quench reactive APAP metabolites and thereby spare critical cellular proteins from inactivation.…”

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confidence: 99%

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Studies of an Androgen-Binding Protein Knockout Corroborate a Role for Salivary ABP in Mouse Communication

et al. 2017

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The house mouse Androgen-binding protein (Abp) gene family is comprised of 64 paralogs, 30 Abpa and 34 Abpbg, encoding the alpha (ABPA) and beta-gamma (ABPBG) protein subunits that are disulfide-bridged to form dimers in secretions. Only 14 Abp genes are expressed in distinct patterns in the lacrimal (11) and submandibular glands (3). We created a knockout mouse line lacking two of the three genes expressed in submandibular glands, Abpa27 and Abpbg27, by replacing them with the neomycin resistance gene. The knockout genotype (2/2) showed no Abpa27 or Abpbg27 transcripts in submandibular gland complementary DNA (cDNA) libraries and there was a concomitant lack of protein expression of ABPA27 and ABPBG27 in the 2/2 genotype saliva, shown by elimination of these two proteins from the saliva proteome and the loss of cross-reactive material in the acinar cells of the submandibular glands. We also observed a decrease in BG26 protein in the 2/2 animals, suggesting monomer instability. Overall, we observed no major phenotypic changes in the 2/2 genotype, compared with their +/+ and +/2 siblings raised in a laboratory setting, including normal growth curves, tissue histology, fecundity, and longevity. The only difference is that male and female C57BL/6 mice preferred saliva of the opposite sex containing ABP statistically significantly more than saliva of the opposite sex without ABP in a Y-maze test. These results show for the first time that mice can sense the presence of ABP between saliva targets with and without ABPs, and that they spend more time investigating the target containing ABP.

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A Novel Defensive Mechanism against Acetaminophen Toxicity in the Mouse Lateral Nasal Gland: Role of CYP2A5-Mediated Regulation of Testosterone Homeostasis and Salivary Androgen-Binding Protein Expression

Cited by 12 publications

References 37 publications

On the tear proteome of the house mouse (Mus musculus musculus) in relation to chemical signalling

On the tear proteome of the house mouse (Mus musculus musculus) in relation to chemical signalling

Generation and Characterization of aCyp2f2-Null Mouse and Studies on the Role of CYP2F2 in Naphthalene-Induced Toxicity in the Lung and Nasal Olfactory Mucosa

Studies of an Androgen-Binding Protein Knockout Corroborate a Role for Salivary ABP in Mouse Communication

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