ABSTRACT This review article dealig with the subject of “The Cause and Prevention of Human Birth Defects” was prepared in celebration of the 40th anniversary of the Japanese Teratology Society. It begins with recollections of some of the important contributions of Japanese scientists in the fields of teratology and embryology and a summary of the many scientific and medical accomplishments of the past 50 years in the fields of teratology, genetics, developmental biology, epidemiology and genetics. The review includes a summary of the drugs, chemicals and physical agents that have been documented to result in congenital malformations and reproductive effects when pregnant women are exposed during pregnancy. The principles of teratology were also summarized and emphasize that 1) no teratogenic agent can be described qualitatively as a teratogen, since a teratogenic exposure must include not only the agent, but also the dose and the time in pregnancy when the exposure occurs. 2) Even agents that have been demonstrated to result in malformatins cannot produce every type of malformation. 3) Known teratogens can be presumptively identified by the spectrum of malformations they produce. 4) It is easier to exclude an agent as a cause of birth defects than to definitively conclude that it was responsible for birth defects. 5) When evaluating the risk of exposures, the dose is a crucial component in determining the risk. 6) Teratogenic agents follow a toxicological dose response curve. This means that each teratogen has a threshold dose, below which, there is no risk of teratogenensis, no matter when in pregnancy the exposure occurred. 7) The evaluation of a child with congenital malformations connot be adequately performed unless it is approached with the same scholarship and detail, as is any other complicated medical problem. 8) Each physician must recognize the consequences of providing erroneous reproductive risks to pregnant women exposed to drugs and chemicals during pregnancy or alleging that a child's malformations are due to an environmental agent without performing a complete and scholarly evaluation.
ABSTRACT The significant achievements of teratological research in Japan were traced from the beginning of the 20th century to the foundation of Japanese Teratology Society (JTS) in 1961 as a bird's-eye view of the prehistory of JTS. The activities of the leaders of foresight who contributed to establish the JTS and to consolidate its basis for future growth were introduced in chronological order; Japanese pioneers before 1945, early developing stage of research (1948–1954), study groups furnishing the basis of JTS (1955–1961), and the final step for JTS establishment (1960–1961).
Teratological research in Japan was initiated independent of foreign studies and had obtained original findings before World War II. The studies in Japan progressed with their main target the prevention of exogeneous malformations as a feasible approach from the standpoint of practical medicine. Accordingly, a close collaboration between experimental and clinical teratologists, one of the grand traditions of JTS, was in place even before the early stages of JTS foundation.
ABSTRACT The Japanese Teratology Society, previously called the Congenital Anomalies Research Association of Japan was officially founded on August 3,1961 in Tokyo. The first 25 years' history of the Society was reported in Congenital Anomalies in 1985 by myself. As I had served Secretary of the Society since the foundation and I am one of a few members who know the history of the founding era, the activities of the first five years of the Society are reviewed in more detail together with the work of Dr. Hideo Nishimura, Kyoto University through my personal view. A research meeting in Kyoto on February 25, 1961 was really the starting point of the Society. Then, the events of the Annual Meetings of the Society for five years, how newspapers reported them and what were the historically interesting problems in the lectures, symposia and free papers, and the changes in the numbers of members and their composition are presented. This review aims not only to record the important events in the early days of the Society but also hopefully to guide the younger researchers to achieve the final goal of prevention of congenital anomalies in the 21st century.
ABSTRACT A U.S.-Japan Seminar on was held in Tokyo on November 1–5, 1965 on “Epidemiological Studies into the Etiology of Congenital Malformations and Cancer.” It was convened by Dr. Hideo Nishimura of Kyoto University and Dr. Robert W. Miller of the National Cancer Institute (NCI). The main purposes were to introduce teratologists from the two countries to one another and to seek new areas of research. Among the assets for research in Japan were 1) Dr. Nishimura's collection of embryos for studies of normal intrauterine growth and for studies of congenital malformations among spontaneous miscarriages; 2) the availability of standard occupational records for information related to reproductive performance; 3) the family registry (koseki), useful for follow-up studies, vital events and evidence of consanguinity; 4) the Metropolitan Tokyo Children's Cancer Registry which soon after was extended to 5 more metropolitan areas; 5) the annual publication of autopsy summaries; 6) data from the (U.S.-Japan) Atomic Bomb Casualty Commission in Hiroshima and Nagasaki; 6) death-certificate diagnoses for migrants from Japan to the U.S. among whom studies of changes in cancer rates had been initiated at the NCI. Also in Japan 7% of marital partners were second-cousins or closer, of interest in studying genetic effects on the occurrence of cancer or congenital malformations. The seminar was followed by a workshop on methods in teratology held in Kyoto in 1968. These meetings led to progressive increases in the exchange of scientists and information.
ABSTRACT On the occasion of the fortieth anniversary of the establishment of the Japanese Teratology Society, this paper first describes how late Professor Hideo Nishimura's collection of human embryos greatly contributed to the standardization of the embryonic development of the Japanese, to the study of embryogenesis, and to the analysis of the etiology of congenital malformations. The collection now composes the main part of the Congenital Anomaly Research Center in Kyoto University and is opened for utilization by embryologists, teratologists and students. In this paper, emphasis is also placed on publications on teratology and embryology which were written by Japanese authors and published in our country, and which played an important role in guiding studies and research on teratology and embyology, and advancing education in human development in our country. Some of them are still available and are being used in these fields.
ABSTRACT Twenty years ago, the late Professor Hideo Nishimura identified some unsolved problems in teratology. His prediction concerning the future advances in this research area has in part become a reality by the year of 2001, but some difficult problems have still to be solved. We neither understand the causes and initiating mechanisms of a vast majority of birth defects nor have measures that can effectively prevent the birth of malformed babies. With the remarkable advances in molecular biology, the tune has come when we have the ability to elucidate the mechanisms of abnormal development and identify procedures to prevent human birth defects.
ABSTRACT Administration of acetazolamide to pregnant rodents leads to postaxial forelimb ectrodactyly, generally right-sided, in the offspring. We previously postulated that this uniquely localized malformation was caused by a reduction of intracellular PH(pHi) in the embryonic limb bud cells. The hypothesis is supported by numerous lines of evidence including the exacerbation of forelimb ectrodactyly by co-administration of amiloride. One action of amiloride is to inhibit the activity of Na+/H+ exchangers (NHEs), the major mechanism by which most eukaryotic cells regulate their internal pH. A mouse without this exchange mechanism should theoretically be hypersensitive to acetazolamide-induced postaxial forelimb ectrodactyly because the limb bud cells should be less able to recover from reduction of intracellular pH. To test this hypothesis we created a targeted knockout of NHE-1 (Na+/H+ Exchanger-1), to which we administered acteazolamide. The frequency and/or severity of forelimb ectrodactyly was no worse in NHE-1 null fetuses than in wild type or heterozygous littermates. We interpret this negative result to suggest that there are compensatory pathways by which embryonic cells can rid themselves of excess protons. We examined this idea by co-administration of acetazolamide and DIDS. This latter agent inhibits CI-/HCO3 exchange, a common mechanism for regulation of pHi against acidosis. Although malformation frequency and severity were high after this combination treatment, NHE-1 null embryos were not more affected with postaxial fore-limb ectrodactyly than their heterozygous and wild type littermates. We presume that embryonic limb bud cells possess another pathway through which they can regulate cytoplasmic proton concentration under acidotic conditions.