Exaggerated Acetaldehyde Response after Ethanol Administration during Pregnancy and Lactation in Rats

Gordon, Barbara H. J.; Baraona, Enrique; Miyakawa, Happei; Finkelman, F.; Lieber, Charles S.

doi:10.1111/j.1530-0277.1985.tb05041.x

Cited by 24 publications

(12 citation statements)

References 19 publications

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“…Whether this was due to differences in the nutritional status of the animals or to the ethanol dose administered remains to be seen. However, we found that the metabolism of acetaldehyde after intravenous administration was somewhat retarded in the pregnant animals, in keeping with previous observations (15,26). It is possible that the oral dose of ethanol used in this study (4 g/kg) exceeded the maternal ability to metabolize this compound.…”

Section: Discussionsupporting

confidence: 78%

“…Ethanol is known to cross the placental bamer freely and to be distributed in fetal tissues (12)(13)(14). An exaggerated acetaldehyde response after ethanol administration has been described during pregnancy (15), but it is not certain that acetaldehyde crosses the placenta (15,16). In fact, whereas acetaldehyde administered at high dose to pregnant mice appears to induce teratogenic effects (17), fetal blood acetaldehyde concentrations are always lower than levels in maternal blood, even after high ethanol doses in pregnant rats (18,19).…”

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confidence: 99%

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Disposition of Ethanol and Acetaldehyde in Late Pregnant Rats and Their Fetuses

Zorzano

Herrera

1989

Pediatr Res

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ABSTRACT. The pattern of ethanol and acetaldehyde appearance in blood after an oral ethanol gavage (4 g/kg body wt) was not different at 12 or 21 days' gestation compared to virgin rats. Five min after maternal ethanol administration, concentrations of ethanol in fetal blood were lower than in maternal blood; however, at 15 min after ethanol administration, fetal and maternal blood levels were similar. Ethanol concentrations in fetal blood and amniotic fluid were already at equilibrium 5 min after ethanol administration. Acetaldehyde concentrations in fetal blood and in amniotic fluid were undetectable at all the times investigated, with the exception of fetuses from two pregnant rats studied 3 h after ethanol administration. Alcohol dehydrogenase activity in fetal liver and in placenta at late pregnancy was very low or undetectable, suggesting a very low rate of ethanol oxidation in vivo. After intravenous administration of acetaldehyde (10 mg/kg body wt), blood acetaldehyde concentrations were higher in pregnant than in virgin rats. Acetaldehyde concentrations in fetal blood and in amniotic fluid were similar to maternal blood at 2, 5, and 30 min after injection. When circulating concentrations of maternal and fetal acetaldehyde, obtained after either ethanol or acetaldehyde administration, were plotted, it was found that fetal blood concentrations of acetaldehyde were only detectable when maternal blood concentrations were greater than 80 pM. Concerning the acetaldehyde oxidation capacity, both the high and low affinity components of aldehyde dehydrogenase activity in fetal liver and placenta were very low as compared with maternal liver. However, aldehyde dehydrogenase activity in fetal liver was much higher than in placenta. It is proposed that ethanol present in the feto/placental unit is metabolized mainly by the maternal liver and that there is a threshold for acetaldehyde above which the capacity for acetaldehyde metabolism is surpassed. (Pediatr Res 25: 102-106,1989) In rodents, ethanol administration has been found to be teratogenic (1-3). The retarded growth and abnormalities in fetal development observed in the offspring of mothers who had consumed high doses of ethanol during pregnancy has been referred to as the fetal alcohol syndrome (4-7). The teratogenic actions of ethanol might be mediated by ethanol itself, by acetaldehyde, or by another as yet unknown metabolite synthesized as a consequence of ethanol ingestion (8).Received March 28, 1988; accepted September 15, 1988. Correspondence Prof. Emilio Herrera, Servicio de Bioquimica, Hospital Ramon y Cajal, Ctra. de Colmenar Km 9, 28034 Madrid, Spain.Supported by a grant from the CAYCIT of Spain.Although fetal effects of maternal ingestion of ethanol have been described (9-1 I), there is little information regarding the pharmacokinetics of ethanol or its toxic metabolite, acetaldehyde, during pregnancy. Ethanol is known to cross the placental bamer freely and to be distributed in fetal tissues (12)(13)(14). An exaggerated acetaldehyde response...

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Section: Discussionsupporting

confidence: 78%

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confidence: 99%

Disposition of Ethanol and Acetaldehyde in Late Pregnant Rats and Their Fetuses

Zorzano

Herrera

1989

Pediatr Res

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“…During gestational days 1 to 17, the levels did not differ. After delivery, the exaggerated acetaldehyde response to ethanol was increased, producing acetaldehyde concentrations 15-fold greater than in nonlactating controls [Gordon et al (1985)]. …”

Section: Acetaldehyde Formaldehyde and Breast Cancer Risksmentioning

confidence: 99%

Preventing hereditary cancers caused by opportunistic carcinogens

Friedenson¹

2011

Nat Prec

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ObjectivesPrevious studies reported inherited BRCA1/2 deficits appear to cause cancer by impairing normal protective responses to some carcinogens. Opportunistic carcinogens can exploit these deficits by causing chronic inflammation, constant cell death and replacement in a mutagenic environment, DNA crosslinking or double strand breaks. Some of the resulting cancers may be prevented if BRCA1/2 specific carcinogens are identified. MethodsThe literature was systematically searched for carcinogens capable of exploiting deficits in BRCA1/2 pathways. Search criteria were common exposure, available information, required BRCA1/2 pathway repairs, increased risks for any cancer, and effects on stem cells. ResultsFormaldehyde and acetaldehyde are closely related carcinogens and common pollutants that are everywhere. Alcohol metabolism also produces acetaldehyde. High levels of either carcinogen overwhelm normal detoxification systems, cause inflammation, inhibit DNA repair and produce DNA cross links as critical carcinogenic lesions. Searching model system studies revealed both carcinogens activate stem cells, BRCA1/2 pathways and connected BRCA1/2 pathways to myeloid leukemia. For example, the BRCA1-BARD1 complex is required for proper nucleophosmin functions. Nucleophosmin prevents a major subset of acute myeloid leukemia (AML). Next, these concepts were independently tested against risks for myeloid leukemia. Epidemiologic results showed that BRCA2 gene defects inherited on both chromosomes increased risks so dramatically that AML occurs in most children. Using data from 14 studies, known/potential heterozygous BRCA1/BRCA2 mutations increased risks for myeloid leukemias by at least 3 fold in 7 studies and by at least 50% in 12.Acetaldehyde occurs in breast milk. In model studies, excessive acetaldehyde/alcohol exposure affects estrogen metabolism and stimulates alternate alcohol detoxification pathways. These pathways can cause DNA cross linking by releasing oxygen species and activating procarcinogens. Acetaldehyde in rats' drinking water increased incidence of leukemias, lymphomas, pancreatic cancers and fibroadenomas. Human epidemiologic studies showed increased premenopausal breast cancer risks associated with persistent/high acetaldehyde levels related to alcohol metabolism genotype. ConclusionsAlthough it is difficult to prove direct causation, BRCA1/2 mutation carriers may reduce cancer risks by avoiding excessive formaldehyde and acetaldehyde. Broader genetic testing and pharmacologic/nutritional detoxification are possible.

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“…During gestational days 1 to 17, the levels did not differ. After delivery, the exaggerated acetaldehyde response to ethanol increased, producing acetaldehyde concentrations 15-fold greater than in nonlactating controls [Gordon et al (1985)]. …”

Section: Relative Risk Data Linking Acetaldehyde/alcohol and Leukemiasmentioning

confidence: 99%

Preventing hereditary cancers caused by opportunistic carcinogens

Friedenson¹

2011

Nat Prec

View full text Add to dashboard Cite

ObjectivesPrevious studies reported inherited BRCA1/2 deficits can cause cancer by impairing normal protective responses. Opportunistic carcinogens can exploit these deficits by causing chronic inflammation, constant cell death and replacement in a mutagenic environment, DNA crosslinking or double strand breaks. Some of the resulting cancers may be prevented if opportunistic carcinogens are identified. MethodsThe literature was systematically searched for carcinogens capable of exploiting deficits in BRCA1/2 pathways. Search criteria were common exposure, available information, required BRCA1/2 pathway repairs, increased risks for any cancer, and effects on stem cells. ResultsFormaldehyde and acetaldehyde are closely related carcinogens and common pollutants that seem everywhere. Alcohol metabolism also produces acetaldehyde. High levels of either carcinogen overwhelm normal detoxification systems, cause inflammation, inhibit DNA repair and produce DNA cross links as critical carcinogenic lesions. Searching model system studies revealed both carcinogens activate stem cells, BRCA1/2 pathways and connected BRCA1/2 pathways to myeloid leukemia. For example, the BRCA1-BARD1 complex is required for proper nucleophosmin functions. Nucleophosmin prevents a major subset of acute myeloid leukemia (AML). Next, these concepts were independently tested against risks for myeloid leukemia. Epidemiologic results showed that BRCA2 gene defects inherited on both chromosomes increased risks so dramatically that AML occurs in most children. Using data from 14 studies, known/potential heterozygous BRCA1/BRCA2 mutations increased risks for myeloid leukemias by at least 3 fold in 7 studies and by at least 50% in 12.Acetaldehyde occurs in breast milk. In model studies, excessive acetaldehyde/alcohol exposure affects estrogen metabolism and stimulates alternate alcohol detoxification pathways. These pathways can also cause DNA cross linking by releasing oxygen species and activating procarcinogens. Acetaldehyde in rats' drinking water increased incidence of leukemias, lymphomas, pancreatic tumors and fibroadenomas. Six human epidemiologic studies support an association between alcohol related genotype or alcohol consumption and early onset breast cancers, including those in BRCA1/2 mutation carriers. ConclusionsAlthough it is difficult to prove direct causation, BRCA1/2 mutation carriers may reduce cancer risks by avoiding excessive formaldehyde and acetaldehyde. Broader genetic testing and pharmacologic/nutritional detoxification are possible.

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Exaggerated Acetaldehyde Response after Ethanol Administration during Pregnancy and Lactation in Rats

Cited by 24 publications

References 19 publications

Disposition of Ethanol and Acetaldehyde in Late Pregnant Rats and Their Fetuses

Disposition of Ethanol and Acetaldehyde in Late Pregnant Rats and Their Fetuses

Preventing hereditary cancers caused by opportunistic carcinogens

Preventing hereditary cancers caused by opportunistic carcinogens

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