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T W Sadler

Publications and source records attributed to T W Sadler.

At least 37 records · Page 2Linked to original sources
PubMed1994

Effects of the biguanide class of oral hypoglycemic agents on mouse embryogenesis.

The incidence of birth defects among offspring of mothers with non-insulin dependent diabetes mellitus (NIDDM) is 2-3-fold higher than among infants of non diabetics. Since mothers with NIDDM are frequently given oral hypoglycemic agents, including sulphonylureas and biguanides, to control their disease and since these agents have been associated with the occurrence of congenital malformations in humans and animals, the embryotoxic effects of the most commonly employed biguanides, metformin and phenformin, were evaluated in whole embryo culture. Neurulating mouse embryos were exposed to therapeutic concentrations (metformin 500-2,550 mg per day; phenformin 50-400 mg per day, respectively) of the compounds for 24-48 h. Concentrations of metformin in culture ranged from 0.15 to 1.8 mg/ml and phenformin from 2.5 x 10(-5) to 0.4 mg/ml. Cultures were terminated and scored for gross morphological alterations and total protein content. Metformin produced no alterations in embryonic growth and no major malformations. Approximately 10% of all embryos exposed to metformin regardless of dose, exhibited open cranial neuropores after 24 h of culture. However, this anomaly appeared to represent a delay in closure as opposed to an overt defect, since no embryos exposed to the highest concentration of the drug and cultured for 48 h showed open neural tubes. In contrast, phenformin produced dose dependent changes in incidence of malformations, protein content, and embryolethality. Malformations included neural tube closure defects, craniofacial hypoplasia, and reduction in size of the first and second visceral arches. Doses above 0.1 mg/ml produced embryolethality and all embryos were killed at the 0.4 mg/ml concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Diabetic teratogenesis. In vitro evidence for a multifactorial etiology with little contribution from glucose per se.

To determine the extent to which elevated glucose and 3-hydroxybutyrate (3OHB) concentrations contribute to the embryotoxic properties of diabetic serum, we tested the effects of serum from untreated or acutely insulin-treated diabetic rats on the development of mouse embryos during neurulation in vitro. Male Sprague-Dawley rats (n = 143) with streptozocin-induced diabetes for 1 week received infusions of insulin (n = 105) or saline (n = 38) for up to 120 min. The insulin-infused animals were exsanguinated when serum glucose concentrations fell to between 5.6 and 8.3 mM. Saline-infused animals were exsanguinated after a similar duration of infusion. Serum samples were tested for embryotoxic effects on 3-6 somite mouse embryos cultured in vitro for 24 h. Of embryos cultured in serum from untreated diabetic animals (glucose: 24 +/- 1 mM; 3OHB: 2.0 +/- 0.3 mM), 36% (31 of 87) exhibited gross malformations, mostly of the neural tube. Only 16% (10 of 62) of embryos grown in serum from acutely insulin-treated animals (glucose: 7.4 +/- 0.2 mM; 3OHB: 0.20 +/- 0.06 mM) were malformed. This rate that was less than half the rate caused by exposure to diabetic serum (P < 0.01), but a rate that remained much greater than the rate associated with culture in normal serum (0% in this study; < 2% historically). In vitro addition of glucose to serum from insulin-treated animals to re-establish hyperglycemia in the diabetic range (25 mM) resulted in a 17% (12 of 70) malformation rate, nearly identical to the 16% rate caused by normoglycemic serum from insulin-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗
PubMed1993

Postulated mechanisms underlying the development of neural tube defects. Insights from in vitro and in vivo studies.

In recent years, use of animal models has resulted in acquisition of a significant amount of new information regarding normal and abnormal neural tube development. Studies of mutant and of teratogen-exposed mice are complementary, with each providing insights that promise to advance our understanding of the other. Analysis of teratogen-exposed embryos is best suited for identifying susceptible developmental stages and vulnerable populations. Advances in molecular genetics, with the ability to identify gene products, their cell/tissue location, and, potentially, to understand their function, will make naturally occurring as well as man-made mutants invaluable for understanding the heterogeneous mechanisms that underly NTDs.

Animals↗
PubMed1993

Effects of altered maternal metabolism during gastrulation and neurulation stages of embryogenesis.

In summary, many congenital malformations are produced during gastrulation and neurulation stages of embryogenesis at a time when no definitive chorioallantoic placenta has been established. In rodents, altered maternal metabolism may have a direct impact on the embryo or an indirect impact via disruption of the nutritive function of the visceral yolk sac. If similar mechanisms operate in human embryos, these factors probably alter functions of the trophoblastic shell. In any case, it is crucial to remember that the metabolic status of the embryo is rapidly changing and during early stages of organogenesis may respond to alterations in nutrients quite differently during the first four weeks of gestation than at later stages of organogenesis and the fetal period.

Amino Acids↗
PubMed1993

Antisense attenuation of Wnt-1 and Wnt-3a expression in whole embryo culture reveals roles for these genes in craniofacial, spinal cord, and cardiac morphogenesis.

Wnt-1 and Wnt-3a proto-oncogenes have been implicated in the development of midbrain and hindbrain structures. Evidence for such a role has been derived from in situ hybridization studies showing Wnt-1 and -3a expression in developing cranial and spinal cord regions and from studies of mutant mice whose Wnt-1 genes have undergone targeted disruption by homologous recombination. Wnt-1 null mutants exhibit cranial defects but no spinal cord abnormalities, despite expression of the gene in these regions. The absence of spinal cord abnormalities is thought to be due to a functional compensation of the Wnt-1 deficiency by related genes, a problem that has complicated the analysis of null mutants of other developmental genes as well. Herein, we describe the attenuation of Wnt-1 expression using antisense oligonucleotide inhibition in mouse embryos grown in culture. We induce similar mid- and hindbrain abnormalities as those seen in the Wnt-1 null mutant mice. Attenuation of Wnt-1 expression was also associated with cardiomegaly resulting in hemostasis. These findings are consistent with the possibility that a subset of Wnt-1 expressing cells include neural crest cells known to contribute to septation of the truncus arteriosus and to formation of the visceral arches. Antisense knockout of Wnt-3a, a gene structurally related to Wnt-1, targeted the forebrain and midbrain region, which were hypoplastic and failed to expand, and the spinal cord, which exhibited lateral outpocketings at the level of the forelimb buds. Dual antisense knockouts of Wnt-1 and Wnt-3a targeted all brain regions leading to incomplete closure of the cranial neural folds, and an increase in the number and severity of outpocketings along the spinal cord, suggesting that these genes complement one another to produce normal patterning of the spinal cord. The short time required to assess the mutant phenotype (2 days) and the need for limited sequence information of the target gene (20-25 nucleotides) make this antisense oligonucleotide/whole embryo culture system ideal for testing the importance of specific genes and their interactions in murine embryonic development.

Animals↗
PubMed1993

Serotonin and cardiac morphogenesis in the mouse embryo.

The possible involvement of the neurotransmitter serotonin (5-HT) and its binding protein (SBP) in cardiac morphogenesis was studied using mouse whole embryo culture (together with immunocytochemistry or 3H-thymidine autoradiography) and a cell migration assay. Embryos were cultured before and during the period of endocardial cushion formation, embryonic (E) days 9-12, in the presence of 5-HT, the monoamine oxidase (MAO) inhibitor nialamide, or an uptake inhibitor (fluoxetine or sertraline). For the migration assay, cells from the outflow tracts of E12 embryos were dissociated and placed in a chemotaxis chamber together with different concentrations of 5-HT. E9 embryos cultured in the presence of 10 microM 5-HT and nialamide exhibited intense 5-HT immunoreactivity (5-HT IR) throughout the myocardium. This staining was greatly diminished by fluoxetine, sertraline, or the absence of nialamide. As morphogenesis proceeded, myocardial staining in embryos exposed to 5-HT became restricted to developing endocardial cushion forming regions and was more completely blocked by uptake inhibitors. No evidence for 5-HT synthesis by myocardium was found at any age studied using the precursor L-tryptophan. SBP was present in endocardial cushions in cultured and uncultured embryos. 3H-thymidine autoradiography demonstrated that both fluoxetine and sertraline inhibited proliferation of cardiac mesenchyme, endocardium, and myocardium. These effects were most pronounced when exposure began at E9 (prior to cushion formation). Dose-dependent effects of 5-HT on migration of outflow tract cells were also observed. Taken together, these results suggest that 5-HT may play a role in cardiac morphogenesis during endocardial cushion formation.

1-Naphthylamine↗
PubMed1993

Serotonin and morphogenesis. Transient expression of serotonin uptake and binding protein during craniofacial morphogenesis in the mouse.

This study describes the timecourse of expression of low-affinity serotonin uptake sites in the developing craniofacial region of the mouse embryo. Whole mouse embryos were incubated in the presence of various serotonergic compounds followed by immunocytochemical localization of serotonin (5-HT) and its binding protein. In the gestational day 9 embryo (3-5 somites), 5-HT uptake was observed in the myocardium of the heart, the visceral yolk sac and foregut. A specific and transient pattern of 5-HT uptake was observed in the hindbrain neuroepithelium from day 9.5-11, where it was localized in rhombomeres 2-5 in the day 9.5 embryo. By day 10, when rhombomeres were no longer evident, uptake was present in the dorso-lateral neuroepithelium surrounding the fourth ventricle (rhombic lip; cerebellar anlage). Uptake of 5-HT was initially observed in the surface epithelium of the craniofacial region at day 10 (20-25 somites) and was greatly increased at day 11. The invaginating lens, nasal placode epithelium and otocyst also took up 5-HT at day 11. During these stages a 45 kD serotonin-binding protein (SBP) was expressed in craniofacial mesenchyme, and became progressively restricted to regions subjacent to epithelial uptake sites. These staining patterns were shown to be specific for 5-HT and SBP by their absence in embryos stained using preabsorbed antisera. The timecourse of these patterns are correlated with critical events in craniofacial morphogenesis including (1) onset of inductive epithelial-mesenchymal interactions, (2) invagination and fusion of placodal structures, (3) presence of rhombomeres, and (4) regions of low proliferative activity.

Animals↗
PubMed1992

The role of the visceral yolk sac in hyperglycemia-induced embryopathies in mouse embryos in vitro.

The adverse developmental effects of hyperglycemia to rodent embryos have been shown using whole embryo culture. Although, a mechanism by which hyperglycemia-induced effects occur is unknown, recent work has focused on the visceral yolk sac as a potential target tissue. Therefore, we have evaluated the developmental effects of hyperglycemia in early head fold stage mouse embryos in vitro and assessed the histiotrophic function of the visceral yolk sac. As has been previously shown in rodents, hyperglycemia produced neural tube closure defects in a concentration dependent manner at 33, 50, and 67 mM glucose using a 44 h exposure period. However, exposure times between 6 and 12 h were sufficient to alter embryonic development when the glucose concentration was 50 or 67 mM. In contrast, early somite stage embryos (4-6 somite stage) appear to be less sensitive to dysmorphogenesis and a 48 h exposure to 67 mM glucose but not 33 or 50 mM also produced neural tube defects. Hyperglycemia (67 mM) did not alter the uptake of 35S-methionine and 35S-cysteine-labeled hemoglobin (35S-Hb) in the visceral yolk sac (VYS) in early headfold staged embryos. However, the accumulation of 35S in the embryo was reduced by 16-18% at glucose concentrations of 50 or 67 mM during the last 12 h of a 44 h exposure period. No effect on VYS uptake or embryonic accumulation of 35S-labeled products was observed at shorter exposure periods (12-24 and 24-36 h).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Serotonin as a regulator of craniofacial morphogenesis: site specific malformations following exposure to serotonin uptake inhibitors.

During craniofacial development in the mouse embryo (days 9-12 of gestation; plug day = day 1), transient expression of serotonin (5-HT) uptake in epithelial structures of this region correlates with critical morphogenetic events (Lauder et al., '88; Shuey, '91; Shuey et al., '89, '92). The purpose of the present investigation was to assess the possible functional significance of these uptake sites by examination of patterns of dysmorphology following exposure of embryos to selective 5-HT uptake inhibitors. Exposure of mouse embryos in whole embryo culture to sertraline, at a concentration (10 microM) which produced no evidence of general embryotoxicity, caused craniofacial malformations consistent with direct action at 5-HT uptake sites. Two other 5-HT uptake inhibitors, fluoxetine and amitriptyline, produced similar defects. The critical period of sertraline exposure occurred on days 10-11. The observed craniofacial defects were associated with decreased proliferation and extensive cell death in mesenchyme located 5-6 cell layers deep from the overlying epithelium. In contrast, the subepithelial mesenchymal layers showed normal or elevated levels of proliferation. From these results it appears that inhibition of 5-HT uptake into craniofacial epithelia may produce developmental defects by interference with serotonergic regulation of epithelial-mesenchymal interactions important for normal craniofacial morphogenesis.

1-Naphthylamine↗
PubMed1991

Activity profiles of developmental toxicity: design considerations and pilot implementation.

The available literature was searched for quantitative test results from both in vitro and in vivo assays for developmental toxicity for five model compounds: cyclophosphamide, methotrexate, hydroxyurea, caffeine, and ethylenethiourea. These compounds were chosen on the basis of their extensive utilization in a variety of assay systems for developmental toxicity as evidenced by their representation in the ETIC database (each generally has 100-500 citations encompassing multiple test systems). Nine cellular-based assays, six assays using whole embryos in culture, as well as Segment II and abbreviated exposure tests for mammalian test species are included in the database. For each assay, the critical endpoints were identified, each of which was then provided a three-letter code, and the criteria for extraction of quantitative information were established. The extracted information was placed into a computerized reference file and subsequently plotted such that the qualitative (positive/negative) and quantitative (e.g., IC50, highest ineffective dose (HID), lowest effective dose (LED] results across all test systems could be displayed. The information contained in these profiles can be used to compare qualitative and quantitative results across multiple assay systems, to identify data gaps in the literature, to evaluate the concordance of the assays, to calculate relative potencies, and to examine structure-activity relationships.

Animals↗
PubMed1991

Altered visceral yolk sac function produced by a low-molecular-weight somatomedin inhibitor.

A fraction from diabetic rat serum containing a low-molecular-weight (800-1000) somatomedin inhibitor (SI) alters growth and development in both neurulation and early limb bud staged mouse embryos in vitro. Previous studies suggested that an accumulation of serum proteins and morphological changes of the visceral yolk sac (VYS) were produced following exposure to the SI in early limb bud staged conceptuses. The morphological changes, characterized by the presence of large endosomes in the endodermal cells, suggested that the SI altered histiotrophic nutrition, whereby proteins are pinocytosed by the endodermal VYS cells and degraded to constituent amino acids. Therefore, the effects of the SI on pinocytosis and protein degradation by the VYS were evaluated using the whole embryo culture system. Results showed that the SI reduced fluid phase pinocytosis as determined by the uptake of [U-14C]sucrose, but that accumulation of [3H]leucine-labeled hemoglobin ([3H]Hb) by the VYS was greater following exposure to the SI than in controls. In contrast, the accumulation of 3H-labeled amino acids in the embryo (produced from the degradation of [3H]Hb by the VYS) was reduced by the SI. The extent of amino acid reduction in embryonic accumulation is dependent upon the concentration of SI in the culture medium and correlates with the incidence of malformations produced by the SI, i.e., high rates of malformations occur with large reductions in embryonic 3H-labeled amino acid accumulation. The apparent paradox of high [3H]Hb accumulation in the presence of decreased pinocytosis appears to be the result of altered processing of the [3H]Hb in the endodermal cells. The altered processing decreases the "elimination" of the proteins from the VYS and results in the decrease in 3H-labeled amino acid present in the embryo proper. Therefore, the SI appears to alter two processes of VYS histiotrophic function. (1) decreased pinocytosis and (2) altered protein processing, ultimately resulting in a decreased availability of substrates for the embryo. During the early stages of embryogenesis in the human, the trophoblast cells of the placenta are responsible for the transport of nutrients from the maternal to embryonic systems. Since these cells show high phagocytic and pinocytotic activities, the SI may also disrupt these processes in the chorioallantoic placenta and contribute to diabetes-induced embryopathies.

Animals↗
PubMed1991

Hypothermia: teratogenic and protective effects on the development of mouse embryos in vitro.

Hypothermia often occurs in association with clinical conditions involving severe hypoglycemia, but its effect on embryonic development has not been well evaluated. Thus, the whole embryo culture method was used to expose day 9 (neurulating) and day 10 (early limb bud stage) mouse embryos to physiologic levels of hypothermia (35 degrees C and 32 degrees C) for 4 and 24 hr. Embryos were evaluated after 24 hours for growth and malformations and compared with controls grown at 37 degrees C. Lactate production was measured in embryos cultured for 4 hr at 32 degrees C and compared with those cultured at 37 degrees C. A 4-hr exposure to hypothermia produced little effect morphologically but reduced the rate of lactate production at both embryonic stages. A 24-hr exposure to hypothermia at 35 degrees C or 32 degrees C produced growth retardation and dysmorphogenesis in embryos undergoing neurulation. Early limb bud stage embryos were less sensitive to this treatment, with growth retardation produced only at the lower temperature. Since hypothermia is commonly associated with severe hypoglycemia in cases of diabetic insulin overdose, day 9 (neurulating) mouse embryos were exposed concurrently to short periods of hypothermia and hypoglycemia and compared with embryos cultured in hypoglycemic medium at normal temperature. The results demonstrate that hypothermia partially protects embryos against the dysmorphogenic effects of hypoglycemia. A balance of metabolic rate and available substrate is discussed as a possible mechanism for this protective effect.

Animals↗
PubMed1991

Recovery by mouse embryos following teratogenic exposure to ketosis.

Previous studies have shown that the ketone body D,L,-beta-hydroxybutyrate was teratogenic to mouse embryos exposed in culture during the period of neurulation. Inhibition of closure of the cranial and caudal neuropores was the most frequently occurring defect and these abnormalities were thought to be the forerunner of anencephaly and spina bifida, respectively. However, additional studies demonstrated that embryos could recover morphologically from these effects if the ketone body was removed from the culture medium and if the recovery period was of sufficient duration. In an attempt to define further the phenomenon responsible for this recovery and to determine the extent of the recovery process, the present study examining the cross-sectional area, cell number, and mitotic index of cranial neuroepithelial cells was conducted in mouse embryos cultured from the early somite stage under one of the following conditions: 1) control medium for 60 h; 2) medium containing 32 mmol/l D,L,-beta-hydroxybutyrate for 24 h followed by culture in control medium for an additional 36 h (recovery group); 3) medium containing 32 mmol/l D,L,-beta-hydroxybutyrate for 60 h (continuously exposed group). The results indicate that although neural tube closure occurred in the recovery group, complete recovery was limited to the ventral regions of the forebrain and that the remainder of the prosencephalon as well as the rhombencephalon failed to undergo complete catch-up growth. Thus, cell numbers in these areas were approximately 70% of control values. Therefore, while the gross anatomical disturbances produced by the ketone body may be compensated for, histological alterations in the affected tissues remain. Ultimately, these data suggest that neurological deficits may be an outcome of ketone body exposure during the early stages of embryogenesis.

3-Hydroxybutyric Acid↗
PubMed1990

Biochemical basis for D,L,-beta-hydroxybutyrate-induced teratogenesis.

Previous investigations have demonstrated that a potential mechanism for D,L,-beta-hydroxybutyrate (BOHB)-induced teratogenesis in neurulating mouse embryos (5-6 somite stage) after 24 hours of exposure in vitro is mediated by an inhibition of the pentose phosphate pathway (PPP) (Hunter, et al. '87). Employing conceptuses of an earlier stage (2-3 somite stage), the biochemistry of BOHB-induced abnormalities was examined further by exposing embryos to 32 mM BOHB for 24 hour and comparing results with controls with respect to the rate of metabolism via the PPP, de novo pyrimidine biosynthesis (PB), and BOHB utilization. Moreover, the capability of these BOHB-exposed embryos to recover from such an insult was also assessed by transferring them to fresh control medium and allowing them to grow for an additional 36 hours. Both controls and BOHB-exposed embryos showed a progressive increase in rate of BOHB utilization between days 9 and 11.5 of gestation in vitro. Exposure to ketone body produced a 100% rate of neural tube defects and a 25.2% decrease in total embryonic protein content. In contrast to results obtained at the 5-6 somite stage, no inhibition of the PPP in whole conceptuses, embryos, or visceral yolk sacs was observed in the group exposed to BOHB at the 2-3 somite stage. Furthermore, a 7.5 mM D-ribose supplement, an intermediate in the PPP, was unable to rescue the younger embryos from BOHB-induced abnormalities and growth retardation. On the other hand, BOHB produced a 34.3% decrease in pyrimidine biosynthesis in the 2-3 somite embryos, but not in the visceral yolk sac. In addition, embryos recovered biochemically after being transferred to control medium, demonstrating a 25.5% overshoot in pyrimidine biosynthesis. Therefore, the mechanism of BOHB-induced teratogenesis appears to differ depending on the stage of embryonic development at the time of initial exposure.

3-Hydroxybutyric Acid↗
PubMed1990

Phenylalanine and its metabolites induce embryopathies in mouse embryos in culture.

The aim of this study was to determine the teratogenicity of phenylalanine (Phe) and Phe metabolites in neurulating mouse embryos. Therefore, the system of whole embryo culture was employed and D9 (neurulating) mouse embryos were exposed to Phe, phenylethylamine (PEA), phenylpyruvic acid (PPA), phenylacetic acid (PAA), 2-OH phenylacetic acid (2-OH PAA), and phenyl-lactic acid (PLA) at concentrations ranging from 0.01 mM to 10 mM for 24 hours. After 24 hours, embryos were examined for morphological abnormalities and protein content by the Lowry method. Phe at 1 and 6 mM concentrations was not teratogenic; however, 10 mM inhibited cranial neural tube closure in 82% of the embryos. PEA was the most toxic factor and concentrations of 1 and 10 mM were embryo-lethal, whereas neural tube closure defects (NTDs) were observed in 67% of the embryos at 0.1 mM. 2-OH PAA was the second most toxic metabolite with concentrations of 1 and 10 mM producing NTDs in 10 and 100% of the embryos, respectively. PLA and PAA produced no NTDs at concentrations of 1 mM, 60% at 5 mM, and 100% at 10 mM. Finally, PPA produced approximately 50% NTDs at both 1 mM and 10 mM concentrations. PLA, PAA, 2-OH PAA, and PPA produced a significant reduction in embryonic protein, and PEA and 2-OH PAA reduced yolk sac protein values. PEA, 2-OH PAA, PPA, PAA, and PLA also produced craniofacial abnormalities, i.e., incomplete expansion of the forebrain, collapse of the optic vesicle, and hypoplasia of the mandible and/or the maxilla.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Embryopathic effects of short-term exposure to hypoglycemia in mouse embryos in vitro.

The effect of short-term hypoglycemia was studied at two stages of development in postimplantation mouse embryos in vitro. Day 8 (gastrulating) mouse embryos were placed in hypoglycemic medium (60, 80, 100, or 110 mg/dl glucose) for 4 hours in which normoglycemia (120 to 150 mg/dl glucose) was restored for the remaining 44 hours of culture. Day 9 (neurulating) mouse embryos were exposed to hypoglycemia (20, 40, 60, or 80 mg/dl glucose) for 2, 4, 6, or 24 hours followed by normoglycemia for the remainder of 24 hours. At the end of culture embryos were evaluated for growth and malformations and compared with controls grown in normoglycemic medium. The results show that a 50% reduction in glucose for as little as 2 hours causes dysmorphogenesis in neurulating mouse embryos, whereas longer exposure times, more severe levels of hypoglycemia, or both are required to affect growth. Furthermore, gastrulating embryos are more sensitive to short periods of hypoglycemia than those undergoing neurulation.

Animals↗
PubMed1989

Role of the mouse visceral yolk sac in nutrition: inhibition by a somatomedin inhibitor.

A low molecular weight somatomedin inhibitory serum fraction (SI), obtained from streptozotocin-induced diabetic rats, causes morphological abnormalities and growth reduction in mouse embryos grown in whole embryo culture (WEC). These abnormalities are thought to be caused, at least in part, by a failure of the visceral yolk sac (VYS) to properly degrade proteins, a process that normally provides the conceptus with amino acids and peptides for de novo protein synthesis (histiotrophic nutrition). To test this hypothesis, embryos exposed to the SI were provided with a mixture of ten essential amino acids (supplemented group) in an attempt to circumvent SI-induced VYS dysfunction. Results showed that 82.4% (14/17) of embryos in the amino acid-supplemented group exhibited improved growth and development compared to those embryos exposed to medium containing the SI alone (unsupplemented group). Supplemented embryos showed greater expansion of the brain regions, improved visceral arch development, and increased protein content compared to nonsupplemented SI-treated embryos. However, these parameters were still reduced compared to controls. VYSs from both the unsupplemented and amino acid-supplemented groups were identical with respect to alterations in morphology and increased protein content compared to VYSs from conceptuses cultured in control medium (with or without amino acid supplementation). The improvement in embryonic growth and development due to amino acid supplementation in spite of VYS abnormalities supports the hypothesis that nutritional deprivation is one aspect of SI-induced teratogenesis.

Amino Acids↗