Search

Toxic elements are present at low concentrations in the environment. This work was undertaken to investigate the age dependence of the liver content of selected elements in paediatric populations, as an index of internal exposure. Liver samples were collected at autopsy from 157 subjects, aged < 1 day to 6 years, as part of investigations on a possible role of Sb compounds in sudden infant death syndrome (SIDS). In addition to Sb, the concentrations of Ag, Cd and Pb were also determined by inductively coupled plasma mass spectrometry on the remaining digest. Comparison of 95% confidence intervals of the median concentrations of the four elements suggested that there were no differences between the two categories of cause of death, SIDS or those who had died of an identified disease. Cadmium, lead and antimony median concentrations were lower than corresponding values observed in adult populations. Silver concentrations were significantly higher at birth and decreased with age. Cadmium levels were almost negligible in neonates and infants, but increased in older children. The finding of non-negligible concentrations of both Ag and Pb in neonatal liver provides further direct evidence that these elements cross the human placental barrier. The reported data, by far the largest collection observed in subjects less than 1 year old, are the result of exposure, during pregnancy and in early childhood, to present levels of these elements in the environment. They can serve as a reference to compare post-mortem values from individuals or groups of subjects in this age range when an exposure risk is suspected and to highlight trends in human exposure.

A class of primitive progenitor cells with high proliferative potential in vitro (HPP-CFC), has been identified in fetal liver and adult bone marrow both in murine and human systems. The kinetic properties of HPP-CFC2 and the more mature granulocyte-macrophage colony forming units (CFU-GM) derived from murine fetal liver on d13, d15 and d19 of gestation, newborn liver and neonatal liver on d3 and d8 postpartum have been evaluated and compared with the kinetic properties of these progenitor cell populations derived from adult bone marrow. The frequency of HPP-CFC2 in fetal liver was found to be greatest on d15 of gestation then subsequently declined in newborn and neonatal liver. Similarly, the highest proportion of HPP-CFC2 engaged in DNA synthesis (53+/-3%) was detected in d15 fetal liver. This proportion decreased to 13+/-2% in the liver 1 wk after birth, which is comparable to the number of HPP-CFC2 derived from adult BM which were in S-phase (10+/-1%). Production of CFU-GM was found to be greater in adult bone marrow than in either fetal or newborn liver. While the proportion of CFU-GM in S-phase was high all 3 tissue samples, the greatest proportion of cycling CFU-GM (50+/-2%) was detected in d15 fetal liver. These results suggest that HPP-CFC2 derived from fetal liver are actively cycling while HPP-CFC2 derived from adult bone marrow are relatively quiescent. In contrast, a high proportion of CFU-GM derived from fetal, newborn liver and adult bone marrow are engaged in DNA synthesis.

The orderly transfer of haemopoiesis from the fetal liver to the medullary cavities during the ontogeny may result from a decrease in the capacity of the fetal liver to support haemopoiesis. Alternatively it could be facilitated by the preferential migration of primitive haemopoietic cells to the marrow. In this study we have compared the ability of high proliferative potential colony forming cells (HPP-CFC) derived from murine fetal liver (FL) on the 15th day of gestation and from murine adult bone marrow (BM) to adhere to either FL or BM derived stromal layers. Adhesion of FL HPP-CFC to bone marrow stromal layers was significantly greater than all other combinations tested. The remarkable affinity of HPP-CFC derived from FL for BM stromal layers is consistent with the preferential migration of haemopoietic cells from the fetal liver to the medullary cavities.

Only transient engraftment of infused fetal liver cells has been demonstrated in a small proportion of patients with hypoplastic bone marrow or patients undergoing treatment for acute leukemia. This presumably reflects the ability of the recipient to reject the infused cells, the infusion of too few viable stem cells or the availability of too few accessory cells; it is clear from the successful engraftment of infused fetal liver cells in a high proportion of infants and fetuses with severe immunodeficiency diseases that, under favorable circumstances, cells derived from human fetal liver are capable of establishing effective grafts and making a substantial contribution to hematopoiesis comparable to that of transplanted cells derived from the liver of the fetal mouse, rat, rabbit or dog. Significant clinical and hematological improvements have been described following infusions of fetal liver cells without evidence of engraftment. These improvements have been attributed to the ability of the infused cells to promote regeneration of autologous hematopoiesis and to inhibit the growth of tumor cells. These possibilities are worthy of evaluation in relation to the production of putative regulators of cellular proliferation in the liver. Meanwhile a suppressor of tumor growth is being used to purge bone marrow prior to autologous transplantation. The generation in vitro of cells which possess the properties of hematopoietic stem cells generated in the liver--from cells which can be maintained as permanent cell lines--would transform hematopoietic cell replacement therapy, and the possibility may not be too unrealistic to contemplate.

Haematopoietic stem cells in murine fetal liver are in a proliferative state unlike those in normal bone marrow which are quiescent. A regulatory activity is produced by cells in the fetal liver which will switch quiescent normal bone marrow haematopoietic stem cells into cell cycle in vitro. This regulator from Day 15 fetal liver cells is produced by adherent cells and by cells fractionated on a Percoll gradient in the 1.064 and 1.076 g per cm3 density bands but not in the 1.123 g per cm3 band. Colony-stimulating factor cannot be detected in the supernatants containing the stem cell regulatory activity. The stimulator can be detected in supernatants produced from cell suspensions of liver cells at Day 15 and Day 17 of gestation and 24 hours and 72 hours after birth. However by 1 week after birth the production of the stimulator decreases and is undetectable 3 and 10 weeks after birth. The total numbers of haematopoietic stem cells (CFU-S) in fetal liver decrease from Day 15 of gestation and only small numbers are present 1 week after birth. Thus the decline in the production of haematopoietic stem cell proliferation stimulator correlates with the decrease in haematopoietic stem cell numbers in the liver through gestation and after birth.

The proliferation of transplanted murine haematopoietic cells, derived from the femoral bone marrow of young adults and from the liver on the sixteenth day of gestation, has been compared under standardized conditions. Suspensions of bone marrow cells contained 9-6+/-0-9 CFU per 10(5) cells (sm) and suspensions of fetal liver cells contained 3-7+/-0-5 CFU per 10(5) cells (Sl).Sl/Sm = 0-4. The mean diameter of colonies established by cells derived from bone marrow was 1-3+/-0-3 mm (established mean volume, Vm = 1-2 mm3) and the mean diameter of colonies established by cells derived from fetal liver was 1-7+/-0-1 mm (estimated mean volume, Vl ;-6 mm3). Vl/Vm ;-2. The relationship between the weight of the spleen and the number of bone marrow cells injected into lethally irradiated recipients 10 days previously has been confirmed, and a similar relationship between the weight of the spleen and the number of fetal liver cells injected has been demonstrated. An arbitrarily defined difference of 50 mg between the weight of the spleen in untreated irradiated controls and the weight of the spleen in irradiated recipients of haematopoietic cells has been observed 10 days after the administration of 2-2 x 10(6) bone marrow cells (Dm) or 3-0 x 10(6) fetal liver cells (Dl). Dm/Dl = 0-7. The calculated values of Dm/Dl (relative proliferative capacity), Sl/Sm (relative stem cell content) and Vl/Vm (relative clone size) are in good agreement with the values estimated using the equation Dm/Dl = Sl/Sm x Vl/Vm.