Transplacental lung carcinogenesis: molecular mechanisms and pathogenesis

Miller, Mark Steven

doi:10.1016/j.taap.2003.07.018

Cited by 34 publications

(23 citation statements)

References 113 publications

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“…The ratio of AHR-responsive/AHRnonresponsive offspring was somewhat lower (0.71) in litters from nonresponsive mothers treated with DBP (Table 2). This may indicate in utero toxicity in responsive pups exposed to a higher dose of DBP due to greater carcinogen bioavailability from the nonresponsive mothers, in agreement with results previously obtained with other PAHs (19,20,46). All mice surviving to 10 months of age that were exposed in utero to DBP exhibited hyperplasia, adenoma, adenoma with progression, and/or carcinoma of the lung compared with a 7% to 10% spontaneous incidence in offspring born to mothers given vehicle alone ( Table 3).…”

Section: Resultssupporting

confidence: 88%

“…Only 3 of 14 (21%) lung tumors from mice exposed to DBP in utero harbored Ki-ras mutations [1 G!T transversion in codon 12 (Cys), 1 G!A transition in codon 12 (Asp), and 1 G!C transversion in codon 13 (Arg)]. This incidence is much lower than previously observed (80%) in offspring from B6D2F1 Â D2 crosses exposed to 3-methylcholanthrene in utero (46)(47)(48). We also examined the expression of Rb, p16Ink4a, cyclin D1, and p19/ ARF in lung adenomas by real-time RT-PCR.…”

Section: Resultsmentioning

confidence: 78%

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In utero Exposure of Mice to Dibenzo[a,l]Pyrene Produces Lymphoma in the Offspring: Role of the Aryl Hydrocarbon Receptor

Loehr²,

Fischer³

et al. 2006

Cancer Research

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102

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Lymphoma and leukemia are the most common cancers in children and young adults; in utero carcinogen exposure may contribute to the etiology of these cancers. A polycyclic aromatic hydrocarbon (PAH), dibenzo [a,l]pyrene (DBP), was given to pregnant mice (15 mg/kg body weight, gavage) on gestation day 17. Significant mortalities in offspring, beginning at 12 weeks of age, were observed due to an aggressive T-cell lymphoblastic lymphoma. Lymphocytes invaded numerous tissues. All mice surviving 10 months, exposed in utero to DBP, exhibited lung tumors; some mice also had liver tumors. To assess the role of the aryl hydrocarbon receptor (AHR) in DBP transplacental cancer, B6129SF1/J (AHR b-1/d , responsive) mice were crossed with strain 129S1/SvIm (AHR d/d , nonresponsive) to determine the effect of maternal and fetal AHR status on carcinogenesis. Offspring born to nonresponsive mothers had greater susceptibility to lymphoma, irrespective of offspring phenotype. However, when the mother was responsive, an AHR-responsive phenotype in offspring increased mortality by 2-fold. In DBP-induced lymphomas, no evidence was found for TP53, B-catenin, or Ki-ras mutations but lung adenomas of mice surviving to 10 months of age had mutations in Ki-ras codons 12 and 13. Lung adenomas exhibited a 50% decrease and a 35-fold increase in expression of Rb and p19/ARF mRNA, respectively. This is the first demonstration that transplacental exposure to an environmental PAH can induce a highly aggressive lymphoma in mice and raises the possibility that PAH exposures to pregnant women could contribute to similar cancers in children and young adults. (Cancer Res 2006; 66(2): 755-62)

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 78%

In utero Exposure of Mice to Dibenzo[a,l]Pyrene Produces Lymphoma in the Offspring: Role of the Aryl Hydrocarbon Receptor

Loehr²,

Fischer³

et al. 2006

Cancer Research

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102

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“…In previous studies, using DBP or 3-methylcholanthrene in models, in which either the dam or the fetus were Ahr "nonresponsive" or "responsive," it was shown that the responsive dam reduced the risk to the fetus apparently by decreasing the bioavailability through enhanced maternal metabolism and clearance (7,8).…”

Section: Discussionmentioning

confidence: 99%

“…However, an increasing number of carcinogens have been shown to be effective transplacentally in animal models, including arsenic (3), 4-(methynitrosamino)-1-(3-pyridyl)-1-butanone (4), 3′-azido-3′-deoxythymidine (5), and cooked food mutagens such as 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (6) and polycyclic aromatic hydrocarbons (PAH; ref. 7). These data, in addition to the fact that human epidemiologic studies correlate maternal chemical exposure with cancer in children (1,2), highlight the importance of understanding the mechanism(s) of transplacental carcinogenesis.…”

mentioning

confidence: 96%

Fetal MouseCyp1b1and Transplacental Carcinogenesis from Maternal Exposure to Dibenzo(a,l)pyrene

Castro

Baird

Pereira

et al. 2008

Cancer Prevention Research

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Dibenzo(a,l)pyrene (DBP) is among the most potent carcinogenic polycyclic aromatic hydrocarbons. Previously, we showed that DBP administration to pregnant mice resulted in high mortality of offspring from an aggressive T-cell lymphoma. All mice that survive to 10 months of age exhibit lung tumors with high multiplicity. Recombinant cytochrome P450 (cyp) 1b1 from mice and the homologue 1B1 in humans exhibit high activity toward the metabolic activation of DBP. Targeted disruption of the cyp1b1 gene protects against most DBP-dependent cancers. Mice heterozygous for the disrupted cyp1b1 allele were used to examine the effect of cyp1b1 gene dosage on DBP transplacental carcinogenesis. Dams were treated with 1 or 15 mg/kg of DBP or 50 mg/kg of benzo(a)pyrene. Cyp1b1-null offspring did not develop lymphoma, whereas wild-type and heterozygous siblings, born to dams given the high dose of DBP, exhibited significant mortalities between 10 and 30 weeks of age. At 10 months, all groups had lung adenomas or carcinomas [9.5%, 40.3%, 25.6%, and 100% incidences for controls, benzo(a)pyrene, 1 and 15 mg/kg DBP, respectively]. Cyp1b1 status did not alter benzo(a)pyrene-dependent carcinogenesis. At 1 mg/kg DBP, cyp1b1 status altered the incidence of lung tumors (19.0, 27.8, and 28.6% for nulls, heterozygous, and wild-type, respectively). At 15 mg/kg, tumor multiplicities in cyp1b1 wild-type (9.3) and heterozygous (9.5) offspring were nearly twice that of cyp1b1-null siblings (5.0). These data confirm that cyp1b1 bioactivation of DBP occurs in fetal target tissues, following transplacental exposure, with the thymus and lung as primary and secondary targets, respectively.

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“…Cigarette smoke is rich in polynuclear aromatic hydrocarbons (PAHs) (e.g., benzo[a]pyrene). They may accumulate in the human placenta, cross the placental barrier during pregnancy, and produce genotoxicity to the developing conceptus (Autrup and Vestergaard, 1996;Gladden et al, 2000;Miller, 2004). However, effects of maternal cigarette smoke on fetal and placental development assessed by weights of the neonate and placenta at delivery, and the overall placental metabolism of exposure substrates were variable ranging from significantly reduced to apparently normal (Sanyal et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Differential metabolism of benzo[α]pyrene in vitro by human placental tissues exposed to active maternal cigarette smoke

Sanyal

2007

Birth Defects Research Pt B

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Transplacental lung carcinogenesis: molecular mechanisms and pathogenesis

Cited by 34 publications

References 113 publications

In utero Exposure of Mice to Dibenzo[a,l]Pyrene Produces Lymphoma in the Offspring: Role of the Aryl Hydrocarbon Receptor

In utero Exposure of Mice to Dibenzo[a,l]Pyrene Produces Lymphoma in the Offspring: Role of the Aryl Hydrocarbon Receptor

Fetal MouseCyp1b1and Transplacental Carcinogenesis from Maternal Exposure to Dibenzo(a,l)pyrene

Differential metabolism of benzo[α]pyrene in vitro by human placental tissues exposed to active maternal cigarette smoke

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