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PubMed2001

Stage-specific skeletal and visceral defects of the I(Kr)-blocker almokalant: further evidence for teratogenicity via a hypoxia-related mechanism.

BACKGROUND: As a class effect, potent I(Kr)-blockers have been shown to induce stage-specific external malformations. The aim of this study was to investigate whether I(Kr)-blockers also induce stage-specific visceral and skeletal defects and to further elucidate a proposed arrhythmia-hypoxia hypothesis. METHODS: Single oral doses of the selective I(Kr)-blocker almokalant (ALM) 25-150 micromol/kg, 7-14 dams/group, were given to Sprague-Dawley rats on gestation days (GD) 10-14, and the fetuses were examined for malformations on GD 21. One group was pretreated with the spin-trapping agent, alpha-phenyl-N-t-butylnitrone (PBN), given intraperitoneally 1 hr before ALM on GD 11. RESULTS: Cardiac ventricular septum defects and vascular malformations were observed after dosing on GD 10-11 and, to a lesser degree, on GD 12-13. Urogenital defects, absence/malposition of the postcaval lung lobe, and attenuated diaphragm were observed mainly on GD 10-11. Skeletal examination showed a high incidence of vertebral abnormalities on thoracic level on GD 10, on lower thoracic to caudal level on GD 11, and sternebral defects were observed all days. On GD 13 brachy-, oligo-, and syndactyly of the forepaw were induced, and of the hindpaw on GD 14. PBN reduced the incidence of both visceral and skeletal defects. CONCLUSIONS: The stage specificity of observed visceral and skeletal defects correlates well with what has been reported in the literature after temporary interruption of oxygen supply during the same stages of development. The protective effect by PBN present further evidence that the teratogenicity of potent I(Kr)-blockers is related to induction of hypoxia- reoxygenation injury due to embryonic cardiac arrhythmia.

Abnormalities, Drug-Induced↗
PubMed1975

Studies of the development of congenital anomalies in rats. III. Effects of inhibition of mitochondrial energy systems on embryonic development.

Pregnant rats were treated with various inhibitors of mitochondrial oxidative energy metabolism and with lowered oxygen tension, and the embryo fetuses examined for the occurrence of congenital malformations and for changes in enzymatic activities. Treatment with all agents tested resulted in the production of skeletal anomalies. Sodium phenobarbital was the most teratogenic of the drugs tested and produced a high incidence of malformations which included cleft palate, tail anomalies, spinal retroflexion, domed head, and facial hypoplasia. Diphenylhydantoin produced a low incidence of syndactyly and oligodactyly. In addition to its effects on fetal growth and development chloramphenicol appeared to interfere with implantation. Tissue preparations from embryos exposed to sodium phenobarbital and chloramphenicol showed markedly lowered levels of DPNH oxidase activity. Cytochrome oxidase activity was also markedly lowered in the preparations from chloramphenicol-exposed embryos. Enzyme activities in preparations from embryos exposed to malonate and diphenylhydantoin appeared unaffected, although the drugs are strong inhibitors of electron transport in vitro; the lack of apparent effect may be due to the fact that both drugs do not bind to the enzyme preparations and were diluted 100- to 200-fold during preparation and assay of the tissue homogenates.

Abnormalities, Drug-Induced↗
PubMed1976

Prenatal effects of Ochratoxin A in hamsters.

Pregnant golden hamsters were injected ip with 2.5-20 mg/kg ochratoxin A on one of gestation days 7-10. The largest dosages when given on day 7,8, or 9 increased prenatal mortality and on day 9 diminished fetal growth. Malformations, such as micrognathia, hydrocephalus, short tail, oligodactyly, syndactyly, cleft lip, micromelia, and heart defects occurred, but no skeletal malformations were noted. These results add to the prenatal effects of ochratoxin A previously reported in mouse, rat, and chicken embryos.

Abnormalities, Drug-Induced↗
PubMed1987

Inhibitory effect of caffeine on 5-azacytidine-induced digital malformations in the rat.

The effect of caffeine on 5-azacytidine (5-AC)-induced digital malformations in rat fetuses was investigated. Caffeine suppressed all types of digital defects in the fore- and hindlimbs except for syndactyly induced by 1.0 mg/kg of 5-AC; it was still effective when administered 24 hours after 5-AC treatment. However, fetal mortality increased as the frequency of malformations decreased. While the malformation results support the view that caffeine inhibits the processes leading to malformation expression, the relation between its suppressive effect on malformations and its enhancing effect on fetal mortality is unclear.

Abnormalities, Drug-Induced↗
PubMed1987

Relative potency of four ethylene glycol ethers for induction of paw malformations in the CD-1 mouse.

Time-mated CD-1 mice were orally dosed on gestation day 11 (plug = 0) with distilled water (control) or one of four glycol ethers at a dose of 4 mmol/kg: ethylene glycol monomethyl ether (EGME, 304 mg/kg), ethylene glycol dimethyl ether (EGdiME, 361 mg/kg), diethylene glycol dimethyl ether (diEGdiME, 537 mg/kg), triethylene glycol dimethyl ether (triEGdiME, 713 mg/kg). Fetuses were collected on gestation day 18, weighed, and examined for gross external malformations. Fetuses were cleared and stained to examine paws. There were no signs of treatment-related maternal toxicity, and intrauterine survival was unaffected by glycol ether treatments. Fetal body weights were significantly reduced only in litters treated with EGdiME. There was no treatment-related pattern of gross external malformations other than paw defects. Only triEGdiME failed to produce a significant incidence of malformations. Paw defects were present in 87.5% of EGME-treated litters (68.5% of fetuses), 86.7% of EGdiME-treated litters (33.8% of fetuses), and 77.8% of diEGdiME-treated litters (39.7% of fetuses). Hindpaw defects predominated over forepaw, and syndactyly was the most common malformation. The incidences of oligodactyly and short digits were also significantly increased. The similarity of malformations produced by these methyl-substituted glycol ethers is proposed to be attributable to in vivo conversion to a common teratogen, methoxyacetic acid.

Animals↗
PubMed1989

Teratogenicity of 3,3-dimethyl-1-phenyltriazene in the rat: gross malformations including micrognathism.

3,3-Dimethyl-1-phenyltriazene (DMPT), an alkylating agent, has been reported to be teratogenic in chickens, mice, and rats. One of the most commonly affected structures is the mandible; however, a complete description and incidence rates of all malformations produced have not been published. Rats were treated on day 12 of gestation (day 0 = sperm in vaginal smear) with a single intraperitoneal injection of 30 mg DMPT/kg. Fetuses were examined on each subsequent day of gestation for external and skeletal abnormalities. Standard soft tissue examinations were performed on day-20 fetuses. A high percentage (greater than or equal to 80%) of treated litters contained numerous fetuses with micrognathism, cleft palates, syndactyly, adactyly, and misshapen digits and limbs. Lordosis, cerebellar and cerebral hypoplasia, decreased fetal size, and generalized delayed ossification were also observed. Dams exposed to DMPT had decreased food consumption and weight gains, although clinicopathologic and histopathologic evaluations failed to indicate other evidence of maternal toxicity. DMPT caused numerous permanent structural alterations that were not attributed to maternal toxicity.

Abnormalities, Drug-Induced↗
PubMed1992

Increased postimplantation loss and malformations among the F2 progeny of male rats chronically treated with cyclophosphamide.

Cyclophosphamide, administered to the male rat, produces increased pre- and postimplantation loss in the progeny as well as an increase in the numbers of malformed and growth retarded fetuses. The purpose of this study was to determine whether the adverse effects of chronic paternal cyclophosphamide exposure are transmissible to the next generation, the F2 progeny. Adult male rats were treated by gavage daily with saline or with cyclophosphamide (3.4 or 5.1 mg/kg) for 4 or 18 weeks and mated. The male and female offspring in each treatment group (F1 generation) were randomly mated. The resulting pregnant females were killed on day 20 of gestation to evaluate progeny outcome in the F2 generation. There was a significant increase in postimplantation loss among the offspring of the group whose fathers had been treated with cyclophosphamide at a dose of 5.1 mg/kg/day. Exposure to a dose of 5.1 mg/kg/day of cyclophosphamide also resulted in an F2 generation with a significantly decreased mean fetal weight per litter and a significant increase in the number of malformed fetuses. The malformations observed among the F2 progeny included open eyes, omphalocele, generalized edema, syndactyly, gigantism, and dwarfism. Thus, exposure of the father to cyclophosphamide does result in a specific and heritable alteration in the fertility of the surviving "apparently normal" F1 progeny. Interestingly, the adverse consequences of exposure of male rats to cyclophosphamide are similar in the F2 generation to those previously reported for the F1 progeny.

Animals↗
PubMed1992

Pathogenesis of ethanol-induced limb reduction defects in mice.

Acute administration of dosages of 2.5, 2.8, or 2.9 g/kg of ethanol to pregnant C57BL/6J mice on gestational day 9 1/4 resulted in major malformations of the forelimb including postaxial ectrodactyly, preaxial syndactyly, and reduction defects involving intermediate digits. The incidence and severity of these defects was positively correlated with dosage. Sidedness of the defects was also dose-dependent. In affected embryos, excessive amounts of cell death were notable within 5-9 hr of treatment initiation in selected cell populations. Cell death was primarily distributed in two regions of the developing limb bud--a ventrodistal ectodermal cell population (apical ectodermal ridge) and a proximal mesenchymal cell population. The patterns of cell death observed appear to be pathogenically related to the limb defects noted at later stages. In particular, it would appear that the deficiencies in the apical ectodermal ridge resulting from ethanol-induced cell death can account for virtually all the subsequent limb defects.

Abnormalities, Drug-Induced↗
PubMed1993

Evaluation of congenital limb reduction defects in upstate New York.

Limb reduction defects (LRD), reported to the Congenital Malformations Registry in upstate New York between 1983-1987, were investigated in terms of LRD classification, parental demographics, and LRD characteristics. After excluding LRD with chromosome abnormalities, we followed guidelines developed by the European Congenital Anomaly Surveillance Consortium (EUROCAT) to classify 271 LRD into six groups based on similar patterns of embryological failure. The descriptive analysis indicated a prevalence of 0.45 per 1,000 births (stable over 5 years) for LRD diagnosed during the first 2 years of life. Among 271 LRD cases, 95 were classified as terminal transverse (35.1%), 71 as split limbs (26.2%), 36 as preaxial (13.3%), 32 as postaxial (11.8%), 26 as intercalary (9.6%), and 11 as multiple types (4.1%). In cases with multiple limb involvement (28.4%), two thirds had the same type of LRD in each limb. The multiple types and preaxial groups showed the most distinctive characteristics: they had the highest frequency of suspected syndromes, other birth defects, and syndactyly compared to the other LRD. There were no significant differences in the distribution of demographic variables among different LRD types. Consideration of the incidence and characteristics of LRD by classifying them into these distinct subgroups may be useful for evaluating possible mechanisms of malformation.

Abnormalities, Multiple↗
PubMed1993

Mouse placenta: hemodynamics in the main maternal vessel and histopathologic changes induced by 2-methoxyethanol and 2-methoxyacetic acid following maternal dosing.

The two main maternal vessels that are a major, if not the entire, source of maternal blood for the mouse placenta are unique in possessing intraluminal valvular projections. The morphologic configuration of these projections suggests their potential to converge, diverge, and rotate blood currents flowing under systolic pressure. The intravascular occurrence of circular fibrin bodies composed of concentric fibrin strands coagulated from the plasma and almost no blood cellular elements in these strands lends credence to this concept. Histopathologic changes in the extraembryonic and embryonic tissues induced by an intraperitoneal injection of 250 or 500 mg/kg of 2-methoxyethanol, or its metabolite, 2-methoxyacetic acid, via oral gavage were determined 48 hr after dosing CD-1 mice on day 11 of pregnancy. Both compounds caused 1) marked congestion and dilatation, associated with or without fibrinous occlusions, of the main maternal vessel of the placenta, 2) serosanguinous exudation and maternal hemorrhages from the placental periphery, 3) necrosis and desquamation involving the mesometrial surface or peripheral edge of the placenta, 4) translabyrinthine embryonic hemorrhage into the maternal circulation, and 5) embryonic hemorrhages into the exocoelomic, amniotic, and pericardial cavities. These lesions signify a disordered maternal circulation in the placenta suggestive of potentially serious pathologic effects. These lesions may play a role in the resorption, reduction in fetal body weight, and syndactyly or oligodactyly attributed to 2-methoxyethanol and 2-methoxyacetic acid.

Acetates↗
PubMed2006

Metopic suture in fetuses with Apert syndrome at 22-27 weeks of gestation.

OBJECTIVES: To examine the possible association of skull deformity and the development of the cranial sutures in fetuses with Apert syndrome. METHODS: Three-dimensional (3D) ultrasound was used to examine the metopic and coronal sutures in seven fetuses with Apert syndrome at 22-27 weeks of gestation. The gap between the frontal bones in the transverse plane of the head at the level of the cavum septi pellucidi was measured and compared to findings in 120 anatomically normal fetuses undergoing routine ultrasound examination at 16-32 weeks. RESULTS: In the normal group, the gap between the frontal bones in the metopic suture at the level of the cavum septi pellucidi, decreased significantly with gestation from a mean of 2.2 mm (5th and 95th centiles: 1.5 mm and 2.9 mm) at 16 weeks to 0.9 mm (5th and 95th centiles: 0.3 mm and 1.6 mm) at 32 weeks. In the seven cases with Apert syndrome, two-dimensional ultrasound examination demonstrated the characteristic features of frontal bossing, depressed nasal bridge and bilateral syndactyly. On 3D examination there was complete closure of the coronal suture and a wide gap in the metopic suture (15-23 mm). CONCLUSION: In normal fetuses, cranial bones are believed to grow in response to the centrifugal pressure from the expanding brain and proximity of the dura to the suture is critical in maintaining its patency. In Apert syndrome, the frontal bossing may be a mere consequence of a genetically predetermined premature closure of the coronal suture. Alternatively, there is a genetically predetermined deformation of the brain, which in turn, through differential stretch of the dura in the temporal and frontal regions, causes premature closure of the coronal suture and impaired closure of the metopic suture.

Acrocephalosyndactylia↗
PubMed1999

A novel human gene encoding an F-box/WD40 containing protein maps in the SHFM3 critical region on 10q24.

We report the cloning and characterization of a new human gene, Dactylin, encoding a novel member of the F-box/WD40 protein family. The Dactylin gene comprises nine exons distributed in more than 85 kb of genomic DNA and encoding a protein with four WD40 repeats and an F-box motif. Northern blot analysis demonstrates a single 2.8 kb transcript in brain, kidney, lung and liver. FISH hybridization localized Dactylin to 10q24.3. Using an Msc I SNP identified in the first exon of the gene, we were able to assign Dactylin within the critical region for Split Hand Split Foot malformation (SHFM3) that has been mapped to 10q24. The SHFM3 phenotype includes absence or hypoplasia of the central digital rays, a deep median cleft and syndactyly of the remaining digits. Recent studies have demonstrated the importance of F-box/WD40 proteins in the regulation of developmental processes, by a mechanism of specific ubiquitinization and subsequent proteolysis of target proteins belonging to the Wnt, Hh and NF-kappaB signaling pathways. The chromosomal location of Dactylin and its putative function as an F-box/WD40 repeat protein, likely to be involved in key signaling pathways crucial for normal limb development, make it a promising candidate gene for SHFM3.

Amino Acid Sequence↗
PubMed1999

Paired-related homeobox genes cooperate in handplate and hindlimb zeugopod morphogenesis.

The closely related homeobox genes prx-1 and prx-2 are expressed in lateral plate and limb bud mesoderm, but targeted inactivation of these genes failed to demonstrate a limb phenotype. Here we report that mice carrying compound mutations in prx-1 and prx-2 have severe limb deformities. In the forelimb autopod, pre- and postaxial polydactyly were found most commonly, but also syndactyly, oligodactyly, and abnormal digit placement affecting posterior elements were observed. In the hindlimb, preaxial polydactyly with variable expressivity was seen in all cases. Extreme distal digit duplications were seen in both the fore- and hindlimbs. prx-1; prx-2 double-mutant mice also displayed extreme shortening and impaired ossification of the hindlimb zeugopods. Integrity of the forelimb apical ectodermal ridge was abnormal as determined by expression of FGF8 and BMP4. Expression of msx-1 and msx-2, markers for BMP signaling pathways, was absent in regions of the posterior handplates, while expression of Shh and patched was unaffected. The mutant phenotypes were dosage dependent, since prx-1 -/-; prx-2 +/- mice also displayed severe limb abnormalities. These data suggest that prx-1 and prx-2 cooperatively regulate handplate and hindlimb zeugopod morphogenesis through BMP-mediated signaling pathways.

Animals↗
PubMed1999

Essential roles of retinoic acid signaling in interdigital apoptosis and control of BMP-7 expression in mouse autopods.

We previously reported that mice lacking the RARgamma gene and one or both alleles of the RARbeta gene (i.e., RARbeta+/-/RARgamma-/- and RARbeta-/-/RARgamma-/- mutants) display a severe and fully penetrant interdigital webbing (soft tissue syndactyly), caused by the persistence of the fetal interdigital mesenchyme (Ghyselinck et al., 1997, Int. J. Dev. Biol. 41, 425-447). In the present study, these compound mutants were used to investigate the cellular and molecular mechanisms involved in retinoic acid (RA)-dependent formation of the interdigital necrotic zones (INZs). The mutant INZs show a marked decrease in the number of apoptotic cells accompanied by an increase of cell proliferation. This marked decrease was not paralleled by a reduction of the number of macrophages, indicating that the chemotactic cues which normally attract these cells into the INZs were not affected. The expression of a number of genes known to be involved in the establishment of the INZs, the patterning of the autopod, and/or the initiation of apoptosis was also unaffected. These genes included BMP-2, BMP-4, Msx-1, Msx-2, 5' members of Hox complexes, Bcl2, Bax, and p53. In contrast, the mutant INZs displayed a specific, graded, down-regulation of tissue transglutaminase (tTG) promoter activity and of stromelysin-3 expression upon the removal of one or both alleles of the RARbeta gene from the RARgamma null genetic background. As retinoic acid response elements are present in the promoter regions of both tTG and stromelysin-3 genes, we propose that RA might increase the amount of cell death in the INZs through a direct modulation of tTG expression and that it also contributes to the process of tissue remodeling, which accompanies cell death, through an up-regulation of stromelysin-3 expression in the INZs. Approximately 10% of the RARbeta-/- /RARgamma-/- mutants displayed a supernumerary preaxial digit on hindfeet, which is also a feature of the BMP-7 null phenotype (Dudley et al., 1995, Genes Dev. 9, 2795-2807; Luo et al., 1995, Genes Dev. 9, 2808-2820). BMP-7 was globally down-regulated at an early stage in the autopods of these RAR double null mutants, prior to the appearance of the digital rays. Therefore, RA may exert some of its effects on anteroposterior autopod patterning through controlling BMP-7 expression.

Animals↗
PubMed2002

Laminin alpha 5 is required for lobar septation and visceral pleural basement membrane formation in the developing mouse lung.

Laminin alpha/beta/gamma heterotrimers are the major noncollagenous components of all basement membranes. To date, five alpha, three beta, and three gamma chains have been identified. Laminin alpha 5 is expressed early in lung development and colocalizes with laminin alpha1. While laminin alpha1 expression in the lung is restricted to the embryonic period, laminin alpha 5 expression persists throughout embryogenesis and adulthood. Targeted mutation of the mouse laminin alpha 5 gene Lama5 causes embryonic lethality at E14-E17 associated with exencephaly, syndactyly, placentopathy, and kidney defects, all attributable to abnormal basement membranes. In this investigation, lung development in Lama5(-/-) mice up to E16.5 was examined. We observed normal lung branching morphogenesis and vasculogenesis, but incomplete lobar septation and absence of the visceral pleura basement membrane. Preservation of branching morphogenesis was associated with ectopic deposition of laminin alpha 4 in the airway basement membrane. Perturbation of pleural basement membrane formation and right lung septation correlated with absence of laminin alpha 5, which was found to be the only laminin alpha chain present in the normal visceral pleura basement membrane. Our finding of normal lung branching morphogenesis with abnormal lobar septation demonstrates that these processes are not obligatorily linked.

Animals↗
PubMed1996

Developmental phase specificity and dose-response effects of 2-methoxyethanol in rats.

Methoxyethanol (ME) produces embryotoxic effects in rodents, rabbits, and nonhuman primates. Mechanistic evaluations of ME dysmorphogenesis have focused mainly on developmental insults and chemical disposition in the mouse. These assessments in mice were based on developmental phase specificity (DPS) and dose-response relationship (DRR) of ME. DPS and DRR indicated treatments for selectively inducing defects to study ME disposition and expressed dysmorphogenesis. This study was conducted to establish DPS and DRR of ME in the rat. DPS was determined by injecting 500 mg ME/kg (6.6 mmol/kg) into the tail vein on Gestational Day (gd; sperm-positive day = gd 0) 10, 11, 12, 13, 14, or 15 (n = 6 dams/gd; saline controls on gd 12). On gd 20, embryolethality incidence was 100% after gd 10 dosing; at gd 11 through 15, it was 50, 32, 15, 2, and 5% respectively (control, 2%). Incidences of external defects in live fetuses exposed on gd 11-15 were 97, 98, 100, 44, and 0% and those of viscera were 100, 62, 44, 10, and 0%, respectively. The predominant anomalies observed were ectrodacyly and renal agenesis. DRR was determined on gd 13, when live embryos/litter and external malformations (ectro- and syndactyly, micromelia) were maximal. Dams (n = 8/dose group) were injected intravenously with 0, 100, 250, 350, or 500 mg ME/kg. On gd 20, fetal defect rates were 0, 0, 82.5, 83.0, and 100% at these concentrations, respectively. Based on these studies, appropriate ME doses, times of maternal exposure, and critical phases of development in the rat model are available for reproducing selective defects to investigate biochemical and pharmacokinetic determinants underlying their expression.

Animals↗
PubMed1999

The cloning and developmental expression of unconventional myosin IXA (MYO9A) a gene in the Bardet-Biedl syndrome (BBS4) region at chromosome 15q22-q23.

Bardet-Biedl Syndrome (BBS) is a heterogeneous, autosomal recessive disorder characterized by mental retardation, obesity, retinitis pigmentosa, syndactyly and/or polydactyly, short stature, and hypogenitalism and is caused by mutations at a number of distinct loci. Using a positional cloning approach for identifying the BBS4 (chromosome 15) gene, we identified and cloned an unconventional myosin gene, myosin IXA (HGMW-approved symbol MYO9A). Since mutations in unconventional myosins are known to cause several human diseases, and since mutations of unconventional myosin VIIa cause retinal degeneration, we evaluated myosin IXA as a candidate for BBS. We exploited PCR-based techniques to clone a 8473-nt cDNA for myosin IXA. A 7644-bp open reading frame predicts a protein with all the hallmarks of class IX unconventional myosins. Human Northern blot analysis and in situ hybridization of mouse embryos reveal that myosin IXA is expressed in many tissues consistent with BBS. Intron/exon boundaries were identified, and myosin IXA DNA and RNA from BBS4 patients were evaluated for mutation.

Amino Acid Sequence↗
PubMed2001

Tripedal knuckle-walking: a proposal for the evolution of human locomotion and handedness.

A comparative morphological analysis of human and non-human hominoids was conducted in an attempt to determine the mode of locomotion of the protohominid. Although the generalized hominoid anatomy permits variation of locomotion: brachiation, knuckle-walking, etc., minor variations in structure determine which behavior is favored. Arboreal arm swinging requires a flexible forelimb while terrestrial fist or knuckle-walking demands more rigidity of the hand and wrist. It is demonstrated that the large human thumb accompanied by the strong adduction of the thenar, hypothenar, and palmar interosseous muscles offer powerful rigidity to the hand, while fusion of the os centrale with the scaphoid during gestation permits the formation of an arch of carpals which imbue the wrist with the stability necessary for weight bearing. Fascialization of the contrahentes and dorsiepitrochlearis muscles in the human as well as depilation of the middle phalanges; the webbing (syndactyly) of the palm; the direction of the fibers of the interosseous membrane of the forearm; the shape of the puerile annular ligament, and the direction of the human glenoid fossa strongly suggest that the ancestor of man used a knuckle-walking form of locomotion prior to becoming bipedal. A model is presented that suggests that bipedalism was attained through an intermediate stage of tripedalism. The model is based on the fact that man's anatomy is much more asymmetric than that of the great apes. A presumption is made that due to the absence of trees for climbing in the transition from forest to open plain, the protohominid needed to carry tools (stones) at all times for protection. Stones could be carried for long distances on the posterior iliac crest since the weight would be shifted posteriorly over the legs. Pick up, medial rotation and adduction of the stone would employ a two-muscle chain of biceps brachii and latissimus dorsi. On the iliac crest, the stone is posterior to the coronal plane of the glenohumeral joint, and with the contraction of this two-muscle chain, the shoulder on one side is moved posteriorly effecting a semi-erect posture. It is proposed that tripedalism of the protohominid may be an explanation for the handedness unique to hominids.

Animals↗