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Introduction

In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Help us improve our products. Sign up to take part. A Nature Research Journal. Twenty years after the thalidomide disaster in the late s, Blaschke et al. On the other hand, enantiomerically pure thalidomide remains in solution, affording the observed biological experimental results: the S -enantiomer is teratogenic, while the R -enantiomer is not.

Thalidomide is one of the most notorious drugs, responsible for a tragic global medical disaster of limb malformations in the late s 1 , 2 , 3 , 4 , 5 , 6 , 7. However, the increased number of limb malformations was later confirmed to be caused by thalidomide. Although thalidomide was banned in in Germany, and later worldwide, it has once again attracted clinical interest due to the discovery of its unique pharmacological action against a number of intractable diseases, such as leprosy, human immunodeficiency virus replication in acquired immune deficiency syndrome, and cancer 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , Thalidomide 1 possesses a single stereogenic carbon center and thus S - and R -enantiomers Fig.

Commercially, it was marketed as a racemate. In , Blaschke et al. This paper suggested that the thalidomide disaster could have been avoided if only R - 1 had been marketed instead of racemic 1. Thus, how can these results be rationalized in the light of the findings by Blaschke et al. Although several enantioselective biological studies on the metabolism of thalidomide have been reported 21 , the confirmation of the different biological activity of the pure thalidomide enantiomers has ultimately remained problematic. In , Handa and co-workers carried out a landmark biological study on thalidomide by identifying cereblon CRBN as a thalidomide-binding protein 22 , They found that thalidomide induces its teratogenic effects by binding to CRBN in zebrafish and chicks.

This report opened a new era for thalidomide in science and completely redirected the research on this drug 24 , 25 , 26 , In , Hakoshima, Handa, and co-workers, including two of the authors of the present study, finally put an end to the debate on the teratogenicity of S -thalidomide via structural and biochemical studies of the S - and R -enantiomers of thalidomide coordinated to CRBN The biochemical studies were carried out on deuterium-substituted enantiomers of thalidomide 29 to suppress any enantiomeric interconversion. The results revealed that the S -enantiomer of 1 displayed a fold stronger binding to CRBN and inhibition of self-ubiquitylation compared to the R -isomer.

The crystal structure of the thalidomide-binding domain of CRBN bound to each of the enantiomers revealed that both bind to the CRBN pocket, although the bound form of the S -enantiomer exhibits a more natural ring conformation of the six-membered glutarimide moiety. Thus, the report by Blaschke is absolutely correct, i. However, one question remains regarding the clear biological differences between the thalidomide enantiomers reported in , despite the observed racemization of thalidomide.

Why do animal experiments that use R - 1 not display teratogenicity if R - 1 readily racemizes in vivo? During our continuous studies on 1 and its derivatives 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , we noticed that the physicochemical properties of racemic 1 and its pure enantiomers are very different The term self-disproportionation of enantiomers SDE was introduced by Soloshonok in to describe the transformation of an enantiomerically enriched system through the formation of fractions with a different proportion of enantiomers relative to the original ratio 40 , 41 , 42 , 43 , 44 , 45 , Our investigation began by examining whether SDE would occur in a solution of 1.

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In these solutions, the progressive formation of a precipitate was observed. The use of 0. Next, experiments under conditions simulating biological media were carried out, i. Other ratios of R - and S - 1 were also examined in water and similar behavior was observed entries 9— In all cases, a substantial amount of precipitate was observed in the final solution, and the precipitate showed a low ee of 1 vide infra. Subsequently, we attempted to carry out the SDE of non-racemic thalidomide at a practical scale Fig. The filtrate and precipitate were dried separately by freeze drying.

The filtrate afforded R - 1 3. This experiment was repeated three times and similar results were obtained. Self-disproportionation of non-racemic thalidomide at practical scale; a DMSO 0. Then, we examined the solubility of enantiomeric and racemic 1. The solubility of 1 in water was determined by absorption spectroscopy. After filtering off all insoluble solids, the saturated water solution of 1 1. The water solubility of 1 was calculated using a calibration curve.

The water solubility of S - 1 Such differences in the solubility of the individual enantiomers and the racemate of thalidomide 1 are in good agreement with the differences in their X-ray crystal structures that have previously been reported by us 39 , The crystal structure of S - 1 shows two types of arrangements: a solvated monomer and a non-solvated homodimer of two S - 1 molecules with hydrogen-bonding at the glutarimide rings. On the other hand, a non-solvated heterodimer of R - and S -thalidomide molecules was obtained for racemic- 1. Obviously, the solvated monomer of S - 1 is more soluble than the other structures.

Moreover, the homodimer of S - 1 should be more soluble than the heterodimer of racemic 1 , as the latter is more closely packed on account of two intermolecular hydrogen bonds. The SDE of S - 1 can be explained in the same way. The results by Blaschke et al. First, the acidic hydrogen atom at the asymmetric center of enantiomerically pure R - 1 epimerizes under physiological conditions, resulting in the formation of enantiomerically poor R - 1 e.

Such enantiomer mixtures of thalidomide with low ee spontaneously undergo a SDE to provide enantiopure R - 1 and racemic 1. This hypothesis is also supported by the fact that the oral absorption of racemic thalidomide is slower than that of the individual thalidomide enantiomers 50 , Since the report by Blaschke et al. Finally, we carried out similar experiments using non-racemic fluoro-thalidomide 2 30 , 37 , which is a non-racemized bioisostere of thalidomide 1.

Compound 2 exhibits potent anti-tumor activity against the human multiple myeloma cell line H 38 , while it is non-teratogenic We thus briefly optimized the conditions for SDE of non-racemic 2 in water cf. Self-disproportionation of non-racemic 2 in water. A substantial amount of precipitate was also observed. In summary, we have disclosed the SDE of non-racemic thalidomide 1 in water and phosphate buffer solution. The SDE of non-racemic 1 induces a spontaneous separation into dissolved and precipitating components based on the differences in solubility of the different structures of 1 , i.

Since the SDE of non-racemic fluoro-thalidomide 2 was also observed, this phenomenon may also occur in other chiral drugs 52 , Thus, chiral drugs with low enantiomeric purity should be used only with extreme care due to potential SDE processes in biological systems. R - 1 , S - 1 , and S - 2 were prepared according to previously reported methods 31 , Water 1. A mixture of S - 1 2. The thus obtained precipitate was filtered off and the enantiomeric excess of the filtrate was determined by HPLC. Water The filtrate and precipitate were dried by freeze drying.

R - 1 was detected both in the filtrate 3. Calibration curves were prepared by plotting the UV absorbance of aqueous solutions of 1 0. After removing the resulting insoluble solid by filtration, the saturated aqueous solution 1. The solubility of 1 in water was calculated using the calibration curves. Burley, D. Thalidomide and congenital abnormalities. Lancet , — Lenz, W. We are interested in manuscripts that utilize or evaluate birth defects surveillance data, use birth defects surveillance data in analytical epidemiological investigations, or apply these data to prevention or intervention programs.

Manuscripts may come from a single state, or from collaborative efforts and activities including both multi-state and international collaborations. If your idea falls outside the topical areas listed above, we would still like to talk with you about it. We also request that each manuscript be accompanied by a cover letter including the names, addresses and telephone number or email address for at least two potential reviewers uninvolved with the current work who might be willing to provide an objective and unbiased review.

Please send your manuscript by Friday, November 1, to the following address and contact person:. Exposure to chemical compounds was evaluated one month before pregnancy and during the first trimester. In this study, mothers of controls resided more frequently in urban areas and worked as liberal or administrative professionals.

A strong association was detected between orofacial clefts and exposure to solvents OR: 7.

Behavioral-Functional Teratology

Exposure to glycol ether during the first trimester of pregnancy was associated with the occurrence of clefts, with an OR of 1. Such associations were not altered when stratified by maternal age, area of residence, and socioeconomic status. Glycol ether is associated with increased incidence of spontaneous abortion and decreased fertility and is a common ingredient in products widely used in domestic cleaning activities Correa et al.

Bianchi et al. In the health field, some associations were shown, albeit inconclusive, with exposure to anesthetic gas and contact with cytostatic drugs without the definition of a specific biological model. However, a strong association was mentioned between cleft lip and maternal occupation in the leather and shoemaking industry OR: 3. Moderate associations were also found for hairdressers OR: 2.

Cleft palate showed a particularly high and statistically significant association with the leather industry OR: 5. The leather industry involves intense exposure to solvents, especially aliphatic hydrocarbons, chlorinated hydrocarbons, and other aromatic solvents, although it is generally not possible to precisely measure the intensity, degree, and duration of the worker's overall exposure. Despite these findings, the study's power was limited, and it was not possible to rule out biases ocurence.

Orofacial clefts were the birth defects with the strongest association to this exposure, particularly in assembly lines working with leather OR: 6. Thus, different studies conducted in different population groups and distinct time periods show the association between oral clefts and exposure to a heterogeneous group of solvents Table 2. The action of these chemical agents has already been described in the literature on risk factors for other diseases, like some neoplastic diseases, including non-Hodgkin lymphomas, leukemias, and pancreatic tumors Ojajarvi et al.

These findings tend to ensure the biological plausibility of their possible involvement in disturbing cell division mechanisms. Since the s there has been a dramatic rise in the use of agricultural inputs, including herbicides, insecticides, and fungicides. Such chemical substances are found throughout the environment and are manufactured specifically to be toxic to certain organisms, while some are known or suspected to be teratogenic, mutagenic, or carcinogenic in animals. Even so, relatively little attention has been paid to hundreds of chemical formulations and their effects on the health of populations.

This ecological study displayed the peculiar limitations of generalizing data, but shows independent effects of exposure to these products for the occurrence of clefts. The study should not be considered definitive, but it did raise a hypothesis for further investigation. Known sources of pesticide exposure include maternal farm work, maternal residence in farming areas, and maternal gardening. Shaw et al.

With regard to gardening exposure, professional application of pesticides produced an OR of 3. Although the results show a moderately increased risk in some cases, they do not present a clear pattern of association with exposure to specific pesticides. Croen et al. Areas were classified according to mean environmental contamination air, biota, oil, surface water, water springs, and specific chemical contaminants. A relative risk of over 2. The observed associations may have been influenced by other, uncontrolled chemical sources like occupation, industrial emissions, pesticides, and water contamination not associated with the target waste sites.

Thus, despite difficulty in measuring toxic environmental agents, the studies suggest that environmental contamination is associated with the occurrence of malformations. With regard to orofacial clefts Table 3 , the most extensively identified association was between the use of anticonvulsivant drugs and cleft lip with or without cleft palate, especially with the use of diphenylhydantoin, phenobarbital, and multi-drug therapy Castilla et al.

Various authors observed a two-fold risk of birth defects among children of epileptic mothers undergoing this form of prolonged treatment during pregnancy Hill et al. Meanwhile, a case-control study by Rosenberg et al. Their controls were children with malformations, with the purpose of reducing potential recall bias. Their results suggest that the use of diazepam during the first trimester of pregnancy did not increase the risk of oral clefts. The investigation estimated relative risks, controlling for potential confounders, on the order of 1.


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Hill et al. The most frequent report was the use of anti-convulsive drugs during the pre-gestational period. A study by Loffredo et al. The authors found an association between these and family history especially those involving the palate, with a relative risk of 2.

Dolovich et al. Analyzing case-control studies, despite the severity of malformations, a reduced but significant association was observed, on the order of 1. In these studies, the magnitude of association was not altered by using healthy as compared to malformed children as controls, suggesting that recall bias did not have a strong effect on the determination of excess observable risk.


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A case-control study considered the following potential confounding variables during pregnancy: smoking, hyperthermia, maternal use of anti-epileptic drugs, benzodiazepines, metronidazol, and sex hormones. Evidence of corticosteroid teratogenicity in humans is limited and has resulted in inconsistent recommendations, particularly during early pregnancy. They observed increased risk of cleft lip with or without cleft palate OR: 4. However, multivariate analysis showed no evidence of the control of this exposure by other potential confounders. There is evidence of reduced risk for the occurrence of a series of malformations clefts, cardiac defects, limb reduction, urinary tract defects, and cerebral defects, among others based on vitamin supplementation before pregnancy and during early pregnancy Werler et al.

Mothers were interviewed about vitamin use during the two months prior to the last menstrual period and over the course of the trimesters. When cases were compared to non-malformed controls, there was a significant reduction in the risk of cleft palate only with vitamin supplementation during the first month OR: 0. Although not significant, there was also a reduced risk of cleft lip with or without cleft palate with vitamin supplementation at any time in the first trimester or prior to the last menstrual period.

Calculating the combination of ORs for the time intervals related to the target malformation, once again the use of multivitamin supplements at least 2 water-soluble and 2 fat-soluble types appeared to be a statistically significant protective factor OR: 0.

The results were not substantially modified when compared with malformed controls.


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  7. In this study, timing appears to be important for studying clefts; consistent with the embryological phenomenon, the greatest protective action against cleft lip occurs during the peri-conceptional period and for cleft palate during the second lunar month of pregnancy. Hayes et al. Analysis of the data produced an odds ratio of 1.

    The literature thus provides evidence that vitamin supplementation containing folic acid during pre-conception may reduce the risk of such malformations. However, this phenomenon has not been observed in all populations, suggesting the existence of genetic regulation in this phenomenon Finnell et al.

    Introduction

    Various lines of experimental research demonstrate the biological plausibility of the use of folic acid in reducing the occurrence of orofacial clefts. The first evidence is from animal studies with the reduction of these malformations in litters submitted to folic acid-rich diets Jordan et al. Given the possibility that fetal deficiency in both the transport and metabolism of folic acid places the fetus at increased risk for this malformation, and that maternal folic acid supplementation is not effective in all individuals, it is important to identify potential candidate genes for regulating this process Finnell et al.

    In the s, Peterson studied cases of live births and detected an association between oral contraceptive use during pregnancy and various malformations, with a relative risk of 1. Classical studies highlighted the association between diethylstilbestrol DES , a synthetic non-steroid compound with estrogen action widely used in the s, and the development of rare types of vaginal tumors in adolescents whose mothers had been exposed to DES during the respective pregnancies and more frequently with vaginal adenosis and cervical pseudopolyps Herbst et al.

    TERATOLOGY

    However, there are doubts concerning the teratogenic capacity of more typical forms of hormone use, like progesterone and contraceptives, specifically in relation to non-genital congenital lesions Castilla, et al. Nora et al. Their study showed a strong association RR: 8.

    Evidence of a strong association was obtained for cases of congenital cardiac malformation RR: 5. Increased frequency of neural tube defects combining both the use of oral contraceptives and other forms of hormone exposure associated with treatment of threatened abortion, hormone failure, anti-cancer treatment, and pregnancy tests, among others have been described Greenberg et al.

    On the other hand, Shardein contends that there is a series of limitations to the studies published on the teratogenic effect of oral contraceptive OC use, and that there is no justification for the prevailing concept on the induction of non-genital congenital malformations by OC use. The same is not true for the case of central nervous system malformations. According to the author, the risk effects appear to be non-specific, and in the case of orofacial clefts the association is controversial.

    In relation to neural tube defects, Kricker et al. A meta-analysis by Bracken attempted to estimate the risk of congenital malformations related to early OC exposure during pregnancy. Again, there was a lack of association between OC use and birth defects OR: 0. Another meta-analysis by Raman-Wilms et al. After finding an OR of 1. Exposure to sex hormones was defined as occurring in the first trimester of pregnancy. Studying the set of selected abnormalities, OC and combined estrogen use, excluding progestogens, proved to significantly increase the risk of birth defects.

    In the case of cleft lip with or without cleft palate, prenatal exposure to progestogens and other combinations excluding estrogens produced an OR of 5. However, when this exposure was controlled for possible confounders vaginal bleeding, malformations in first-degree relatives, history of abortion , the association decreased in magnitude OR: 1. Thus, this study's findings do not support the teratogenic effect of hormone exposure, indicating that if there is a risk for non-genital congenital defects it is small.

    Hemminki et al. They did not show a risk effect for neoplasia either in mothers or children , but they did identify a slight risk effect for the occurrence of malformations. This study thus supports the hypothesis that hormone therapy using estrogens or progestogens during the first trimester of pregnancy may be associated with these outcomes. James comments that high hormone concentration at the time of conception may partially determine the offspring's sex.

    The author thus analyzed the sex ratio of healthy siblings of patients with CLP, noting a trend towards a higher sex ratio among siblings of individuals with CLP as compared to siblings of individuals with cleft lip only. The author further concluded indirectly that the influence of maternal hormone imbalance may be demonstrated in the occurrence of these malformations, as well as the sex determination of offspring from other pregnancies. Genetic and epidemiological studies have failed to demonstrate a single genetic mechanism in the occurrence of CLP, even while demonstrating heavy family clustering.

    Segregation analyses provide inconsistent evidence for the existence of a single genetic control pattern, multi-factorial inheritance, or both mechanisms involved in the development of this malformation Maestri et al. Genetic analysis and specific tissue expression studies support the theory that specific variants of alleles in the TGF a gene participate actively in the craniofacial development mechanism Shiang et al.

    Jara et al.