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PubMed2003

Biochemical markers of bone metabolism: application to understanding bone remodeling in children and adolescents.

Markers of bone remodeling have been developed that provide biochemical indices that reflect changes in the rates of bone formation, resorption, and mineralization. These processes are important determinants of bone metabolism, and indicators that correspond to these processes can provide clinically relevant information. Until recently, the best way to measure parameters of bone metabolism was to perform a bone biopsy after administration of two courses of tetracycline. Bone markers offer significant potential advantages over bone biopsy. Some of these markers are protein fragments that are generated during metabolism of type I collagen, the major structural protein of bone, and are formed as this collagen is synthesized or degraded. Other markers, such as osteocalcin and alkaline phosphatase, are released from osteoblasts during bone formation. Although these markers have found significant utility in the evaluation of adults with metabolic bone diseases, their application in children has been limited due to great variability in normal ranges that reflect the changes in skeletal metabolism induced by age, growth rate, gender, and pubertal state.

Adolescent↗
PubMed1994

Early modifications of biochemical markers of bone metabolism in spinal cord injury patients. A preliminary study.

Spinal cord injury is associated with the development of a rapid and severe osteoporosis which might reflect uncoupling between bone formation and resorption. A prospective study was made in 6 spinal cord injury patients followed up to 2-3 months after onset with various markers of a) bone formation: osteocalcin and C-terminal peptide of type I procollagen, b) bone resorption: pyridinolines and C-terminal telopeptide of type I collagen, c) connective tissue metabolism: amino-terminal propeptide of type III collagen (PIIINP). Preliminary results show that early after onset, bone formation was depressed as compared to dramatically increased bone resorption. Low bone formation rate lasted two weeks before it began to raise, while bone resorption showed a continuous tendency to increase. The dramatic increase in PIIINP levels might represent some attempt of bone to repair. This paper describes the evolution of various biochemical markers of bone and connective tissue metabolism after onset of paralysis and critically reviews the use of those markers in patients with spinal cord injury.

Adult↗
PubMed2005

Multicellular structures developing during maize microspore culture express endosperm and embryo-specific genes and show different embryogenic potentialities.

During maize pollen embryogenesis, a range of multicellular structures are formed. Using different approaches, the "nature" of these structures has been determined in terms of their embryogenic potential. In situ molecular identification techniques for gene transcripts and products, and a novel cell tracking system indicated the presence of embryogenic (embryo-like structures, ELS) and non-embryogenic (callus-like structures, CLS) structures that occurred for short periods within the cultures. Some multicellular structures with a compact appearance generated embryos. RT-PCR and fluorescence in situ hybridization (FISH) with confocal microscopy techniques using specific gene markers of the endosperm (ZmESR2, ZmAE3) and embryo (LTP2 and ZmOCL1, ZmOCL3) revealed "embryo" and "endosperm" potentialities in these various multicellular structures present in the cultures. The results presented here showed distinct and specific patterns of gene expression. Altogether, the results demonstrate the presence of different molecules on both embryonic and non-embryonic structures. Their possible roles are discussed in the context of a parallel between embryo/endosperm interactions in planta and embryonic and non-embryonic structure interrelations under in vitro conditions.

Biomarkers↗
PubMed1995

A comparison of the anabolic effects of parathyroid hormone at skeletal sites with moderate and severe osteopenia in aged ovariectomized rats.

Previous studies have shown that parathyroid hormone (PTH) stimulates bone formation and completely restores lost cancellous bone at skeletal sites with moderate osteopenia in relatively young ovariectomized (OVX) rats. The current study was designed to determine whether PTH has similar bone anabolic effects in aged OVX rats and to compare the bone restorative response to PTH at skeletal sites with moderate and severe osteopenia. Female Sprague-Dawley rats were subjected to sham surgery or bilateral ovariectomy at 3 months of age and maintained untreated for the first year after surgery to allow for the development of moderate vertebral osteopenia and severe tibial osteopenia in OVX rats. Groups of baseline control and OVX rats were sacrificed at the end of this pretreatment period. The remaining OVX rats were then treated for 10 weeks with vehicle, antiresorptive agents alone (estrogen, the bisphosphonate risedronate, or calcitonin) or PTH alone. Other groups of OVX rats were treated concurrently with PTH and each of the antiresorptive agents. As expected, the proximal tibia of baseline OVX rats exhibited severe cancellous osteopenia, whereas the first lumbar vertebral body was moderately osteopenic. Treatment of OVX rats with antiresorptive agents alone failed to restore cancellous bone at both skeletal sites, whereas treatment with PTH alone markedly stimulated bone formation and completely restored lost cancellous bone in the lumbar vertebra. PTH also stimulated bone formation and in the severely osteopenic proximal tibia of OVX rats but only marginally restored lost cancellous bone, possibly due to an inadequate number of bone spicules to serve as a foundation for new bone formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMedDate not supplied

Biomarkers of effect in toads and frogs.

Amphibians are good bioindicators of environmental pollution due to their susceptibility to chemicals during their freshwater cycles. The effects of environmental pollution, together with changes in human activity and climate, have contributed to the reduction in the amphibian population over recent decades. However, toxicological research on amphibians has been rather scarce compared with that on other vertebrates. In this article we review the biochemical alterations underlying xenobiotic action and/or the detoxifying responses described for anuran species, with the aim of establishing possible biomarkers of effect. During the embryonic development of anurans, morphological and behavioural alterations are the effects most frequently cited in connection with chemical exposures. However, such biomarkers have a low sensitivity and are unspecific compared with biochemical alterations. Some primary pesticide targets, in particular cholinesterases for organophosphates and carbamates, have been evaluated. Esterases change seasonally and with the stage of development, and their sensitivity to anticholinesterase agents varies between species. Thus their use as biomarkers in anurans must be carefully analysed. Enzymes and endogenous compounds related to oxidative metabolism may also be used as biomarkers of effect. Glutathione pool, glutathione-S-transferases and metallothioneins respond in different ways to pesticides and heavy metals in anuran embryos and tadpoles. Mixed-function oxidases, in turn, are less developed in amphibians, and show a reduced induction in response to pesticide exposures. Endogenous polyamine levels are also proposed as good age-related biomarkers of damage. Finally, molecular biomarkers related to receptor binding, signal transduction and genetic response have gained increasing relevance, as they have been implicated in the fertilisation process and the earliest events in anuran development. The identification of transcription factors associated with the exposure of amphibians to xenobiotics as well as other alterations in hormone signalling appears highly promising. However, these techniques are likely to complement other methods. In conclusion, the use of several biomarkers with multiple endpoints is needed to link exposure to response and to provide better predictive tools for the environmental protection of endangered anuran species.

Animals↗
PubMed2005

UVB radiation prevents skeleton growth and stimulates the expression of stress markers in sea urchin embryos.

Ozone depletion results in an increased flux of biologically damaging radiations reaching the earth. Although ultraviolet (UV) penetration is attenuated by the seawater, harmful effects can be still observed at low depths where sea urchin embryos are living. We have used Paracentrotus lividus embryos to study the impacts of UV radiation on their development. Blastula cultures were exposed to different doses of UVB (312 nm) radiations and the resulting endpoint effects were evaluated in terms of embryonic morphological abnormalities, variations in specific gene expression, and changes in the levels of stress proteins. We found that embryos were moderately sensitive to 50 J/m2 UVB radiation; an increase in the number of developmentally delayed and malformed embryos was detected when increasing doses, up to 1000 J/m2, were used. Major developmental defects, observed 24 and 48 h after exposure, consisted in the failure of skeleton elongation and patterning. Accordingly, we found a reduction in the number of primary mesenchyme cells that expressed Pl-SM30, a gene coding for one of the specific matrix proteins of the skeleton. The morphological effects observed 1, 24, and 48 h after exposure were correlated with a dose-dependent increase in the level and in the activation of two recognized stress markers, namely hsp70 and p38 MAPk, respectively, consistent with their role in mediating cellular response to stress and suggesting a function in embryo survival.

Abnormalities, Radiation-Induced↗
PubMed2000

Metallothionein isoform 3 as a potential biomarker for human bladder cancer.

The goal of the present study was to determine if the expression of metallothionein isoform 3 (MT-3) might serve as a biomarker for human bladder cancer. To accomplish this goal, we defined the localization and expression of MT-3 protein and mRNA using fresh and archival biopsy specimens obtained from patients undergoing differential diagnosis for a variety of bladder disorders. We used immunohistochemistry, immunoblot, and RT-PCR analysis to define the localization and expression of MT-3 protein and mRNA. Immunohistochemical analysis disclosed no immunoreactivity for MT-3 in normal bladder cells. The absence of MT-3 expression in the normal bladder was further confirmed by demonstrating that MT-3 mRNA could not be detected using reverse transcriptase-polymerase chain reaction (RT-PCR) or MT-3 protein using immunoblot. Immunohistochemistry also disclosed no immunoreactivity for MT-3 in archival biopsy specimens from patients with interstitial cystitis and related disorders. Immunohistochemical analysis demonstrated that MT-3 was expressed in carcinoma in situ (CIS), high-grade bladder cancer, low-grade bladder cancer, and dysplastic lesions. MT-3 immunostaining was intense in both CIS and high-grade bladder cancer, and low to moderate in low-grade bladder cancer and dysplastic lesions. We determined MT-3 mRNA expression in a subset of these bladder cancer specimens; expression was elevated as compared to that of the housekeeping gene, ss-actin. The cDNA from the RT-PCR reaction primed for MT-3 contained a FokI restriction site, a site unique for MT-3 as compared to other MT family members. In conclusion, this study demonstrates that MT-3 is up-regulated in human bladder cancer and that this up-regulation increases with increasing tumor grade. The finding that MT-3 expression is minimal in normal bladder suggests that MT-3 might be developed into an effective biomarker for bladder cancer.

Adult↗
PubMedDate not supplied

A clinical flow cytometric biomarker strategy: validation of peripheral leukocyte phospholipidosis using Nile red.

Phospholipidosis, or intracellular accumulation of phospholipids, is caused by specific classes of xenobiotics. This phenomenon represents a challenge for risk assessment that could benefit from the use of biomarkers in the clinical development of new drug candidates. Flow cytometry, coupled with the lipophilic fluoroprobe Nile red, was correlated to histopathology, electron microscopy and inorganic phosphorus detection to validate the utility of this method for monitoring phospholipidosis in peripheral blood leukocytes. Replicate studies with model test compounds were conducted in which F344 rats were given 4 or 7 doses of either maprotiline hydrochloride, imipramine hydrochloride, tilorone dihydrochloride, amikacin hydrate or vehicle control. Transmission electron and light microscopy were used to examine peripheral blood smears and tissue samples for the presence of cytoplasmic vacuoles. Unstained and Nile red stained lysed peripheral blood samples were acquired for analysis using a FACScan flow cytometer. Inorganic phosphorus concentration in the liver was determined from extracted phospholipids and compared with flow cytometry and histological data. It was demonstrated that flow cytometric analysis of Nile red stained lysed whole blood can be used to detect drug-induced phospholipid accumulation in circulating peripheral leukocytes. Furthermore, clinically detectable leukocyte phospholipidosis may be a useful surrogate for coincident or premonitory detection of target organ phospholipidosis.

Animals↗
PubMed2006

Plasma proteome analysis reveals the geographical origin and liver tumor status of Dab (Limanda limanda) from UK marine waters.

The flatfish species dab (Limanda limanda) is the sentinel for offshore marine monitoring in the United Kingdom National Marine Monitoring Programme (NMMP). At certain sites in the North and Irish Seas, the prevalence of macroscopic liver tumors can exceed 10%. The plasma proteome of these fish potentially contains reporter proteins or "biomarkers" that may enable development of diagnostic tests for liver cancer and further our understanding of the disease. Following selection of sample groups by quality-assured histopathology ("phenotype anchoring"), we used surface-enhanced laser desorption/ionization (SELDI) time-of-flight mass spectrometry to produce proteomic profiles of plasma from 213 dab collected during the 2004 UK NMMP. The resulting protein profiles were compared between fish from the North and Irish Seas and between fish with liver neoplasia or nondiseased liver. Significant differences were found between the plasma proteomes of dab from the North Sea and Irish Sea, which in conjunction with artificial neural networks can correctly determine from which sea dab were captured in 85% of the cases. In addition, the presence of liver tumors is associated with significant changes in the plasma proteome. We conclude that SELDI-based plasma profiling is potentially of use in nonlethal marine monitoring using wild sentinels such as dab. Furthermore, accurate selection of sample groups is critical for avoiding effects of confounding factors such as age, gender, and geographic origin of samples.

Adenoma, Liver Cell↗
PubMed2003

Developmental cytokine response profiles and the clinical and immunologic expression of atopy during the first year of life.

BACKGROUND: Allergic diseases have been linked to abnormal patterns of immune development, and this has stimulated efforts to define the precise patterns of cytokine dysregulation that are associated with specific atopic phenotypes. OBJECTIVE: Cytokine-response profiles were prospectively analyzed over the first year of life and compared with the clinical and immunologic expressions of atopy. METHODS: Umbilical cord and 1-year PBMCs were obtained from 285 subjects from allergic families. PHA-stimulated cytokine-response profiles (IL-5, IL-10, IL-13, and IFN-gamma) were compared with blood eosinophil counts and total and specific IgE levels (dust mites, cat, egg, Alternaria species, peanut, milk, and dog) at age 1 year and at the development of atopic dermatitis and food allergy. RESULTS: For the cohort as a whole, cytokine responses did not evolve according to a strict TH1 or TH2 polarization pattern. PHA-stimulated cord blood cells secreted low levels of IL-5 (2.1 pg/mL), moderate levels of IFN-gamma (57.4 pg/mL), and greater amounts of IL-13 (281.8 pg/mL). From birth to 1 year, IL-5 responses dramatically increased, whereas IL-13 and IFN-gamma responses significantly decreased. Reduced cord blood secretion of IL-10 and IFN-gamma was associated with subsequent sensitization to egg. In addition, there was evidence of TH2 polarization (increased IL-5 and IL-13 levels) associated with blood eosinophilia and increased total IgE levels by age 1 year. CONCLUSION: These findings demonstrate that cytokine responses change markedly during the first year of life and provide further evidence of a close relationship between TH2 skewing of immune responses and the incidence of atopic manifestations in children.

Aging↗
PubMed2006

Salivary diagnostics powered by nanotechnologies, proteomics and genomics.

BACKGROUND: The ability to monitor health status, disease onset and progression, and treatment outcome through noninvasive means is a highly desirable goal in health care promotion and delivery. Oral fluid is a perfect medium to be explored for health and disease surveillance. METHODS: Two prerequisites exist before the goal of salivary diagnostics can be achieved: identification of specific biomarkers associated with a health or disease state and the development of technologies that can discriminate between the biomarkers. A recent initiative of the National Institute of Dental and Craniofacial Research has created a roadmap to achieve these goals through the use of oral fluids as the diagnostic medium to scrutinize the health and/or disease status of patients. This is an ideal opportunity to optimize state-of-the-art saliva-based biosensors for salivary biomarkers that discriminate between diseases. RESULTS: Seven technology groups are developing point-of-care salivary diagnostic technologies. Three groups are working together toward deciphering the salivary proteome. CONCLUSION: These collective efforts and the convergence of salivary diagnostic technologies and the salivary proteome will present unparalleled opportunities to explore the diagnostic potential of saliva for oral and systemic diseases.

Biomarkers↗
PubMed1999

Kinetics of osteoprogenitor proliferation and osteoblast differentiation in vitro.

Fetal rat calvaria cells plated at very low density generate discrete colonies, some of which are bone colonies (nodules) from individual osteoprogenitors that divide and differentiate. We have analyzed the relationship between cell proliferation and acquisition of tissue-specific differentiation markers in bone colonies followed individually from the original single cell to the fully mineralized state. The size distribution of fully formed nodules is unimodal, suggesting that the coupling between proliferation and differentiation of osteoprogenitor cells is governed by a stochastic element, but distributed around an optimum, corresponding to the peak colony size/division potential. Kinetic analysis of colony growth showed that osteoprogenitors undergo 9-10 population doublings before the appearance of the first morphologically differentiated osteoblasts in the developing colony. Double immunolabeling showed that these proliferating cells express a gradient of bone markers, from proliferative alkaline phosphatase-negative cells at the periphery of colonies, to postmitotic, osteocalcin-producing osteoblasts at the centers. An inverse relationship exists between cell division and expression of osteocalcin, the latter being restricted to late-stage, BrdU-negative osteoblasts, while the expression of all other markers is acquired before the cessation of proliferation, but not concomitantly. Bone sialoprotein expression is biphasic, detectable in some of the early, alkaline phosphatase-negative cells, and again later in both late preosteoblast (BrdU-positive) and osteoblast (BrdU-negative, osteocalcin-positive) cells. In late-stage, heavily mineralized nodules, staining for osteocalcin and bone sialoprotein is not detectable in the oldest/most mature cells. Our observations support the view that the bone nodule "tissue-like" structure, originating from a single osteoprogenitor and finally encompassing mineralized matrix production, recapitulates successive stages of the osteoblast differentiation pathway, in a proliferation/maturation sequence. Understanding the complexity of the proliferation/differentiation kinetics that occurs within bone nodules will aid in the qualitative and/or quantitative interpretation of tissue-specific marker expression during osteoblastic differentiation.

Alkaline Phosphatase↗
PubMed1997

Abnormal bone turnover in monoclonal gammopathy of undetermined significance: analyses of type I collagen telopeptide, osteocalcin, bone-specific alkaline phosphatase and propeptides of type I and type III procollagens.

The main difference between monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) is the presence of lytic bone destructions in the latter. About 20% of MGUS patients develop MM, and histomorphometric studies have shown disturbed bone turnover rates in some of these patients. This study was performed in order to evaluate whether serum analyses of the C-terminal telopeptide of type I collagen (ICTP), as a reflector of bone degradation, and of osteocalcin, bone-specific alkaline phosphatase (bAP) and the C-terminal propeptide of type I procollagen (PICP), as markers of bone formation, might give information on disturbances of bone metabolism in MGUS. Furthermore, serum N-terminal propeptide of procollagen III (PIIINP) might give information on disturbances in collagen III metabolism in the bone marrow. In the 35 patients examined, serum ICTP was elevated in 12 patients (34%), serum PIIINP elevated in 6 patients (17%), serum osteocalcin elevated in 11 patients (31%), serum bAP elevated in 6 patients (17%), and serum PICP elevated in 4 patients (11%). Serum ICTP correlated significantly with PIIINP (r = 0.72, p < 0.001), and with serum osteocalcin (r = 0.57, p < 0.001) and serum bAP (r = 0.51, p = 0.002). These findings indicate disturbances of bone turnover and affected collagen metabolism in some MGUS patients. Follow-up observation may reveal any prognostic value of these findings.

Aged↗
PubMed2006

Characterization of SEZ6L2 cell-surface protein as a novel prognostic marker for lung cancer.

To identify molecules that might serve as biomarkers or targets for development of novel molecular therapies, we have been screening genes encoding transmembrane/secretory proteins that are up-regulated in lung cancers, using cDNA microarrays coupled with purification of tumor cells by laser microdissection. A gene encoding seizure-related 6 homolog (mouse)-like 2 (SEZ6L2) protein, was chosen as a candidate for such molecule. Semi-quantitative RT-PCR and western-blot analyses documented increased expression of SEZ6L2 in the majority of primary lung cancers and lung-cancer cell lines examined. SEZ6L2 protein was proven to be present on the surface of lung-cancer cells by flow cytometrical analysis using anti-SEZ6L2 antibody. Immunohistochemical staining for tumor tissue microarray consisting of 440 archived lung-cancer specimens detected positive SEZ6L2 staining in 327 (78%) of 420 non-small cell lung cancers (NSCLCs) and 13 (65%) of 20 small-cell lung cancers (SCLCs) examined. Moreover, NSCLC patients whose tumors revealed a higher level of SEZ6L2 expression suffered shorter tumor-specific survival compared to those with no SEZ6L2 expression. These results indicate that SEZ6L2 should be a useful prognostic marker of lung cancers.

Biomarkers, Tumor↗
PubMed1998

Markers of bone remodelling in metabolic bone disease.

New specific markers of bone remodelling have been developed that allow the evaluation of bone formation (plasma levels of osteocalcin and bone alkaline phosphatases) or bone resorption (collagen crosslink levels in urine). These markers can be used to evaluate bone disease. Their best application is currently in renal osteodystrophy, where there is a broad spectrum of bone abnormalities. In patients with this disease, bone markers can obviate the need for bone biopsy. So far, bone alkaline phosphatase is the most sensitive and specific marker for predicting the type of bone disease and therefore for deciding treatment in dialysed patients, although it is not ideal. Bone markers have also allowed a dramatic improvement in the comprehensive approach to bone loss with aging in women. Monitoring of the marked increase in bone turnover, and its persistence, in older women after menopause may help in the design of treatment strategies for osteoporosis. There is some hope that the measurement of urinary levels of collagen crosslinks will help to predict the clinical outcome of osteoporosis with respect to fractures in postmenopausal women. Bone markers could, besides being a measurement of bone density, help to determine the optimal treatment of postmenopausal women. Bone markers could also be used to predict or ascertain the response to treatment of osteoporosis, but few data are currently available to judge the routine usefulness of these new applications.

Biomarkers↗
PubMed2004

Activation of the MDR1 upstream promoter in breast carcinoma as a surrogate for metastatic invasion.

PURPOSE: Activation of the MDR1 upstream promoter (USP) has been described previously in four lymphoblastic leukemia patients, where it is the major MDR1 promoter associated with P-glycoprotein overexpression. We asked whether MDR1 USP-derived transcripts were also present in breast carcinoma and assessed their potential as a biomarker. EXPERIMENTAL DESIGN: We developed a sensitive method for detecting transcripts derived from the MDR1 USP and used it to identify MDR1 USP-derived transcripts in cell model systems, in 61 breast carcinoma biopsies of the primary tumor, and in isolated malignant epithelial cells both from the primary tumor and from the associated invaded lymph nodes. RESULTS: The MDR1 USP was not active in several independent leukemic and breast cancer cell lines or nucleated peripheral blood cells (n = 9). However, transcripts derived from the MDR1 USP were detected in some drug-resistant cell lines and a high proportion of primary breast tumors (71.6%; n = 61), whereas they were present at low frequency in normal breast tissue (10%; n = 10). Activation of MDR1 USP was not due to chromosomal amplifications or rearrangements at the MDR1 locus. Transcription from the MDR1 USP correlated with metastatic node invasion [N = 0-3 versus N > 3 (N = number of lymph nodes invaded); Fisher's exact test, P = 0.011] and was detected in malignant epithelial cells from the primary tumor and those that metastasized to the lymph nodes. CONCLUSIONS: MDR1 USP activation is a surrogate marker for breast carcinoma progression and can be used as a marker to study breast cancer susceptibility.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Development and evaluation of three immunofluorometric assays that measure different forms of osteocalcin in serum.

BACKGROUND: Circulating human osteocalcin (hOC) has been used as a marker of bone formation. Our aim was to validate three immunofluorometric assays (IFMAs), measuring different forms of hOC. METHODS: The two-site IFMAs were based on previously characterized monoclonal antibodies. Assay 2 recognized intact hOC, assays 4 and 9 measured the NH(2)-terminal mid-fragment and the intact hOC. In addition, assay 9 required hOC to be gamma-carboxylated. RESULTS: A 76-79% increase of serum immunoreactive hOC was found in the postmenopausal group compared with the premenopausal group with all IFMAs. With EDTA-plasma samples, the observed increases were lower (49-65%). The hOC concentration in the postmenopausal group receiving hormone replacement therapy was 42-44% lower than that in the postmenopausal control group in both serum and EDTA-plasma samples. The depressed carboxylation in warfarin-treated patients was accompanied by lower results in assay 9. The ratio of assay 9 to assay 4 totally discriminated the warfarin-treated patients from the controls. Assay 9 showed the smallest decreases in measured hOC after storage of serum or plasma for 4 weeks at 4 degrees C, followed by assay 4 and assay 2. Results from the last assay were <17% of their initial values after 4 weeks of storage. No diurnal variation was observed with assay 9 as opposed to the two other IFMAs. CONCLUSION: The three assays with their distinct specificity profiles (intact vs fragmented and carboxylated vs decarboxylated hOC) may provide valuable tools for investigating the significance of different hOC forms in various bone-related diseases.

Aged↗
PubMed1994

Aluminum effects on blood chemistry and long bone development in the chick embryo.

Body growth, blood chemistry, and long bone development of 10- to 16-day chick embryos (Gallus gallus) treated with aluminum (Al) citrate, sodium (Na) citrate, or sodium chloride (NaCl) were investigated. Two administration protocols were used. Acutely-treated embryos received 6.0 mumol Al citrate or Na citrate on day 8 of incubation. Chronically-treated embryos received a daily dose of 1.5 mumol Al citrate or Na citrate beginning on day 8 of incubation. For both protocols, Al citrate and Na citrate had no significant influence on viability or body weight. Al citrate-treated embryos had: (a) significantly shorter mean tibia lengths by day 16 of incubation, (b) a consistently lower ratio of tibia length: body weight on all days investigated, and (c) a persistent mid-diaphyseal malformation (angulation) of the femur and tibia. Spatially correlated with the malformation was a calcification defect detected by alizarin red S staining of intact tibias and the accumulation of aluminum as demonstrated by acid solochrome azurine staining of histological sections. Aluminum was localized at the mineralization front of the osteogenic collar surrounding the cartilage core of the tibia. Aluminum citrate or Na citrate had no significant effect on serum total calcium, inorganic phosphorus, total alkaline phosphatase activity, or creatinine, except for a transitory hypercalcemia (day 10) and phosphatemia (days 10 and 12) in Al citrate-treated embryos. The concomitant localization of Al and the early calcification defect in the region of tibial malformation implicate aluminum in the pathogenesis of the skeletal abnormality.

Alkaline Phosphatase↗