Sulforaphane induces phase II detoxication enzymes in mouse skin and prevents mutagenesis induced by a mustard gas analog.

Mustard gas, used in chemical warfare since 1917, is a mutagenic and carcinogenic agent that produces severe dermal lesions for which there are no effective therapeutics; it is currently seen as a potential terrorist threat to civilian populations. Sulforaphane, found in cruciferous vegetables, is known to induce enzymes that detoxify compounds such as the sulfur mustards that react through electrophilic intermediates. Here, we observe that a single topical treatment with sulforaphane induces mouse epidermal levels of the regulatory subunit of glutamate-cysteine ligase, the rate-limiting enzyme in glutathione biosynthesis, and also increases epidermal levels of reduced glutathione. Furthermore, a glutathione S-transferase, GSTA4, is also induced in mouse skin by sulforaphane. In an in vivo model in which mice are given a single mutagenic application of the sulfur mustard analog 2-(chloroethyl) ethyl sulfide (CEES), we now show that therapeutic treatment with sulforaphane abolishes the CEES-induced increase in mutation frequency in the skin, measured four days after exposure. Sulforaphane, a natural product currently in clinical trials, shows promise as an effective therapeutic against mustard gas.

The gin epidemic: much ado about what?

While there is no doubt that the era of the 'gin epidemic' was associated with poverty and social unrest, the surge in gin drinking was localized to London and was a concomitant, not the cause, of these problems. The two main underlying social problems were widespread overcrowding and poverty. The former was related to an unprecedented migration of people from the country to London. The latter stemmed from an economic ideology called 'poverty theory', whose basic premise was that, by keeping the 'inferior order' in poverty, English goods would be competitive and would remain that way since workers would be completely dependent on their employers. Widespread overcrowding and poverty led to societal unrest which manifested itself in increased drunkenness when cheap gin became available after Parliament did away with former distilling monopolies that had kept prices high. Reformers ignored the social causes of this unrest and, instead, focused on gin drinking by the poor which they feared was endangering England's wealth and security by enfeebling its labour force, and reducing its manpower by decreasing its population. Part of this hostility was also related to gin itself. While drunkenness was often spoken of affectionately when it was induced by beer, England's national drink, gin was considered a foreign drink, and therefore less acceptable. These concerns were voiced less often after the passage of the Tippling Act of 1751, which resulted in an increase in gin prices and decreased consumption. However, the second half of the century was also a period in which England's military victory over the French gave it new wealth and power, which dispelled upper-class fears about an enfeebled and dissolute working class. It was also an era when new public health measures, such as mass inoculation against smallpox, and a decrease in the marrying age, led to a population increase that dispelled reformist fears about manpower shortages. The conclusion is that, while the lower cost of gin sparked the 'gin epidemic', the social unrest associated with this unprecedented surge in gin consumption was exacerbated, rather than caused, by the increase in drinking.

Gin Lane: did Hogarth know about fetal alcohol syndrome?

Medical historians have searched for evidence that the characteristics of fetal alcohol syndrome (FAS) were recognized long before its modern description in 1973. This search has often focused on the 'gin epidemic' in 18th century London, and especially William Hogarth's Gin Lane, which some authors allege reflects an awareness of the facial characteristics of the syndrome. While the 'gin epidemic' undoubtedly resulted in the increased birth of weak and sickly children, claims about Hogarth's awareness of the stigmata of the FAS are unfounded. The birth of weak and sickly children, and the high infant mortality rates associated with this period, long preceded the 'gin epidemic' and were primarily due to disease, starvation, exposure, and deliberate infanticide.

Fetal alcohol syndrome: the origins of a moral panic.

Since its discovery almost 30 years ago, the fetal alcohol syndrome (FAS) has been characterized in the USA, as a major threat to public health. In part because FAS resonated with broader social concerns in the 1970s and 1980s about alcohol's deleterious effect on American society and about a perceived increase in child abuse and neglect, it quickly achieved prominence as a social problem. In this paper, we demonstrate that, as concern about this social problem escalated beyond the level warranted by the existing evidence, FAS took on the status of a moral panic. Through examples taken from both the biomedical literature and the media about drinking during pregnancy, we illustrate the evolution of this development, and we describe its implications, particularly how it has contributed to a vapid public policy response.

The role of dietary fat in alcohol's prenatal effects.

Pregnant rats were fed a control diet or high saturated fat diet (lard) for 6 weeks prior to breeding and continued to consume these diets during pregnancy. Beginning on gestation day 8, rats in each diet group were intubated with 5.5 or 0 g/kg alcohol. Rats in the 0 g/kg group were pair-fed to those in their respective 5.5 g/kg groups. Offspring were weighed at birth. On postnatal days 18 and 20, they were tested for passive avoidance learning and locomotor activity, respectively. Animals prenatally exposed to alcohol weighed less at birth and at weaning time (21 days of age) and required more trials to reach criterion in the passive avoidance test but did not differ in activity. Diet did not affect any of these measures significantly nor were there any significant interactions. We conclude that high saturated fat from lard does not influence alcohol's prenatal effects.

Was the fetal alcohol syndrome recognized by the Greeks and Romans?

Ancient Greek and Roman philosophers/scientists are frequently quoted as expressing an awareness of potential harm associated with drinking during pregnancy. However, the statements attributed to these authors were not made by them. Instead, they are interpretations, presented in the form of verbatim statements, of their views relating to procreation. Although they did have something to say about the role of alcohol in procreation, it was the effects of drinking on the male body at the time of conception, and especially alcohol's effects on male body temperature, that concerned them. A cold body at the time of conception was believed to enhance the likelihood of conceiving a female, which to the Greeks and Romans was a 'deformity'.

How do physicians define "light," "moderate," and "heavy" drinking?

Although widely used, terms associated with consumption of alcohol--such as "light," "moderate," and "heavy"--are unstandardized. Physicians conveying health messages using these terms therefore may impart confusing information to their patients or to other physicians. As an initial attempt to assess if informal standardization exists for these terms, the present study surveyed physicians for their definitions of such terms. Physicians operationally defined "light" drinking as 1.2 drinks/day, "moderate" drinking as 2.2 drinks/day, and "heavy" drinking as 3.5 drinks/day. Abusive drinking was defined as 5.4 drinks/day. There was considerable agreement for these operational definitions, indicating there is indeed an informal consensus among physicians as to what they mean by these terms. Gender and age did not influence these definitions, but self-reported drinking on the part of physicians was a factor. We also asked physicians for their opinions regarding the effects of "light," "moderate," and "heavy" drinking on health in general and specifically on health-related implications for pregnant women, and whether they felt their patients shared these beliefs.

Prevention of alcohol abuse-related birth effects--II. Targeting and pricing.

Current public health measures to reduce the occurrence of fetal alcohol abuse syndrome (FAAS) and alcohol abuse-related birth effects (AARBEs) have been ineffective, because they target alcohol consumption, rather than alcohol abuse. The present discussion contends that the most effective public health strategy for reducing FAAS and AARBEs is a combination of more specific public health messages that target alcohol abuse, coupled with higher taxes on alcohol beverages. Although alcohol consumption by alcohol abusers has been thought to be inelastic to price changes, recent studies have found that both heavy drinking and binge drinking are sensitive to alcohol price changes, and price elasticities are relatively high for heavy drinkers who are aware of the consequences of their drinking. Although price increases may have a disproportionate impact on lower socioeconomic groups, this article concludes that they are justifiable from both a utilitarian and a categorical imperative perspective.

Prevention of alcohol abuse-related birth effects--I. Public education efforts.

Maternal alcohol abuse during pregnancy can result in a pattern of anomalies in children called 'fetal alcohol syndrome' (FAS) and more recently, 'fetal alcohol abuse syndrome (FAAS)'. FAAS as well as individual alcohol-related anomalies, called 'alcohol abuse-related birth effects' (AARBEs), are widely considered to be totally preventable, because they stem from a behaviour that is presumably modifiable. However, current strategies to reduce their occurrence are more palliative than preventive, because their underlying premise, viz. that raising public awareness of the potential dangers of commonly used substances such as alcohol is enough to reduce their use, lacks empirical support. Moreover, in some cases they are also counter-productive. After considering the relevant literature, this review contends that 'universal' public education efforts will only be effective in reducing FAAS and AARBEs if they focus on the cause of these disorders, which is alcohol abuse rather than the currently open-ended message that any amount of alcohol consumption during pregnancy constitutes a danger to an unborn child. This argument lays the ground work for an alternative and more pragmatic strategy set forth in the following paper for preventing FAAS and AARBEs.

Fetal alcohol syndrome: the 'American Paradox'.

Nearly all cases of fetal alcohol syndrome (FAS) identified in prospective epidemiological studies have been conducted in the United States of America. The very high incidence rate for FAS in the USA and the relatively low rate in other countries does not correspond to measures of alcohol consumption. By analogy with the 'French paradox', we have termed the high rate of FAS in the USA coupled with its relatively low level of alcohol consumption, the 'American paradox'.

Fetal alcohol syndrome. Hearing, speech, language, and vestibular disorders.

Fetal alcohol syndrome (FAS) refers to a pattern of anomalies that include craniofacial, CNS, growth, and various sensory anomalies. We have observed that FAS is associated with four kinds of hearing disorders: (1) developmentally delayed auditory function, (2) sensorineural hearing loss, (3) intermittent conductive hearing loss owing to recurrent serous otitis media, and (4) central hearing loss. As is the case with other syndromes associated with craniofacial anomalies and hearing impairments, speech and language pathologies also are common in FAS patients. Although auditory and vestibular systems arise from similar embryological tissue, vestibular dysfunction is variable in FAS. Early identification and intervention to treat hearing, language, and speech problems should improve the functional level of FAS in children.

What do physicians know and say about fetal alcohol syndrome: a survey of obstetricians, pediatricians, and family medicine physicians.

Pediatricians, obstetricians, and family practice physicians in Michigan were surveyed by mail for their knowledge and opinions about Fetal Alcohol Syndrome (FAS) and Fetal Alcohol Effects (FAE). Physicians said that about 67% of their patients raised questions about drinking during pregnancy but only 2% specifically referred to FAS or FAE. Most physicians were uncertain about whether their colleagues were sufficiently aware of FAS, whether FAS could be diagnosed at birth, or if physicians were acquainted with the syndrome's major criteria. However, most believed FAS was not being overdiagnosed and believed that making a diagnosis of FAS at birth could lead to improved treatment of an affected child. Physicians also believed that physician counseling was a more effective way of reducing the incidence of FAS/FAE than warning labels. Forty-one percent of the physicians placed the threshold for FAS at one to three drinks per day and 38% placed the threshold at one or fewer drinks a day. Thirty-five percent placed the estimated incidence of FAS at 1 to 2 per 1000 in the United States. We conclude that physicians are in relative agreement about the effects of drinking during pregnancy and the value of physician counseling but are misguided as to what constitutes a true risk level of drinking as far as the etiology of FAS is concerned.

Protecting fetuses from certain harm.

Deborah Mathieu's proposal for state intervention in the lives of pregnant substance abusers in order to prevent serious harm to their future children sparked a lively debate in this journal. The present discussion characterizes the three main arguments offered against her proposal as (a) the "uncertainty principle"--the inability to predict which fetuses will be affected, (b) the "father factor"--gender bias with respect to prenatal damage, and (c) "critical periods"--the vulnerability of the embryo/fetus at different times of pregnancy. Each of these arguments is examined in the specific context of fetal alcohol syndrome (FAS). Since the birth of a child with FAS is a virtual certainty if a woman has previously given birth to a child with FAS, since no father has ever sired a child with FAS unless his spouse is an alcoholic, and since the most damaging effects are those associated with exposure throughout and especially late in pregnancy, none of the arguments offered against Mathieu's proposal are relevant in this particularly narrow set of circumstances. While Mathieu's proposal seems pertinent in this situation, her proposal would be even more effective if modified as suggested here.

Acute treatment of paternal alcohol exposure produces malformations in offspring.

Male rats were intubated only once with either 6, 4, 2, or 0 g/kg alcohol. Food was removed from all animals for several hours after intubation. Males were bred with a single female until sperm was observed in the vaginal smear, for up to a maximum of 7 days after treatment. Females were sacrificed on gestation day 20. There were no significant effects on mating, fecundity, or litter size, but there were significant dose-response increases in "runts" and significant linear associations in the number of malformations in alcohol-sired offspring. A second study using the same methodology found similar results. The results indicate that a single acute treatment with alcohol just prior to breeding may have a significant effect on offspring.

Maternal alcohol consumption and spontaneous abortion.

This review examines the relationship between maternal alcohol consumption during pregnancy and spontaneous abortions. Although very high spontaneous abortion rates have been reported for alcoholic women, it is still uncertain if this is due to the direct effects of alcohol or the indirect effects of alcoholism-related disorders such as cirrhosis. The higher rates of spontaneous abortion among alcoholics may also be due to their higher pregnancy rates. Studies in animals indicate that blood alcohol levels > 200 mg/dl can directly precipitate spontaneous abortion. The association between lower levels of maternal alcohol consumption and spontaneous abortion is much less clear. There is a definite effect of study site in these latter studies: those conducted in North America nearly always report statistically significant associations; those conducted in Europe or Australia nearly always report no significant associations. The reason for this difference is not related to differences in alcohol consumption. Possible explanations for this geographical difference include difference in the socioeconomic status of the women being studied and artefacts associated with the designs used to study these relationships.

Was the fetal alcohol syndrome recognized in the ancient Near East?

One of the most frequently cited examples of ancient prescience concerning the potential dangers of drinking during pregnancy is the story of Samson in the Biblical Book of Judges. The present article examines the relevant passages from this and other related Biblical texts for indications that the ancient Hebrews were indeed aware of alcohol's potential to harm the fetus. This examination was then broadened to include a survey of later Talmudic literature relating to drinking during pregnancy, and literature from Sumerian, Hittite, and Egyptian cultures contemporary with those found in the Bible. No evidence was found for concern in the ancient Near East about any possible harm.

Prenatal high saturated fat diet modifies behavioral effects of prenatal alcohol exposure in rats.

Pregnant rats were fed a control diet, a high saturated fat diet, or a high polyunsaturated diet lacking in vitamin E and zinc, for 6 weeks prior to breeding and continued to consume these diets during pregnancy. Beginning on gestation day 8, rats in each diet group were intubated with 5.3 or 0 g/kg alcohol. Rats in the 0 and 3 g/k group were pair fed to those in their respective 5 g/kg groups. A fourth group received one of the three diets ad lib, and was not intubated. On postnatal day 20, offspring were tested for locomotor activity and head-dipping behavior. Animals prenatally exposed to alcohol were more active and made more head dips than pair-fed controls, but only if their mothers consumed the control diet. Alcohol had an opposite effect on offspring whose mothers consumed the high saturated fat diet, and had no effect on animals consuming the high polyunsaturated/no vitamin E or zinc diet. These preliminary results suggest that dietary fat may modify the behavioral effects of prenatal alcohol exposure. This effect may be the result of the stabilizing effect of saturated fats on cell membranes which increases their resistance to perturbation by alcohol.

Alcohol-induced changes in blood gases, glucose, and lactate in pregnant and nonpregnant rats.

The effects of alcohol and pregnancy on venous blood pH, gases (pO2, pCO2), bicarbonate (HCO-3), and glucose and lactate were examined in pregnant and nonpregnant female rats using anaerobic analytical methods of blood collection. Baseline measurements were obtained prior to treatment and then at 30 min, 1, 2, and 4 h after gastric intubation with 0, 2, 4, or 6 g/kg of alcohol. Alcohol produced a metabolic acidosis, increases in blood glucose and lactate concentrations, and an increase in blood oxygen concentration. Gestation days 18-19 (0.8 gestation) of pregnancy were associated with a slight alkalosis, a decrease in oxygen concentration, no effect on glucose concentrations, and an increase in lactate concentrations compared with nonpregnancy. The only significant interaction between alcohol and pregnancy occurred for pO2 and O2C, wherein alcohol increased both of these parameters in nonpregnant animals only. These results indicate that the rat's pH response to acute alcohol infusion is unique because alcohol does not produce any significant changes in blood pH in other animal models. This change was similar in both pregnant and nonpregnant animals. Except for changes in blood oxygen content, the pregnant and nonpregnant female rat's response to alcohol were also similar as well.