Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia.

Reduced fetal glucose supply, induced experimentally or as a result of placental insufficiency, produces an early activation of fetal glucose production. The mechanisms and substrates used to fuel this increased glucose production rate remain unknown. We hypothesized that in response to hypoglycemia, induced experimentally with maternal insulin infusion, the fetal liver would increase uptake of lactate and amino acids (AA), which would combine with hormonal signals to support hepatic glucose production. To test this hypothesis, metabolic studies were done in six late gestation fetal sheep to measure hepatic glucose and substrate flux before (basal) and after [days (d)1 and 4] the start of hypoglycemia. Maternal and fetal glucose concentrations decreased by 50% on d1 and d4 (P < 0.05). The liver transitioned from net glucose uptake (basal, 5.1 ± 1.5 µmol/min) to output by d4 (2.8 ± 1.4 µmol/min; P < 0.05 vs. basal). The [U-¹³C]glucose tracer molar percent excess ratio across the liver decreased over the same period (basal: 0.98 ± 0.01, vs. d4: 0.89 ± 0.01, P < 0.05). Total hepatic AA uptake, but not lactate or pyruvate uptake, increased by threefold on d1 (P < 0.05) and remained elevated throughout the study. This AA uptake was driven largely by decreased glutamate output and increased glycine uptake. Fetal plasma concentrations of insulin were 50% lower, while cortisol and glucagon concentrations increased 56 and 86% during hypoglycemia (P < 0.05 for basal vs. d4). Thus increased hepatic AA uptake, rather than pyruvate or lactate uptake, and decreased fetal plasma insulin and increased cortisol and glucagon concentrations occur simultaneously with increased fetal hepatic glucose output in response to fetal hypoglycemia.

Aetiology and pathogenesis of IUGR.

Intrauterine growth restriction (IUGR) is a major cause of perinatal mortality and morbidity. A complex and dynamic interaction of maternal, placental and fetal environment is involved in ensuring normal fetal growth. An imbalance or lack of coordination in this complex system may lead to IUGR. Animal studies have given us an insight into some aspects of the basic pathophysiology of IUGR, and recent technologies such as Doppler studies of maternal and fetal vessels have added further information. The aetiologies of IUGR are diverse, involving multiple complex mechanisms, which make understanding of the pathophysiology difficult. However, particular focus is placed on the mechanisms involved in uteroplacental insufficiency as a cause of IUGR, as (1) it is common, (2) outcome can be good if timing of delivery is optimal and (3) it may be amenable to therapy in the future. While the research into the pathophysiology of IUGR continues, there have been interesting discoveries related to the genetic contribution to IUGR and the intrauterine programming of adult-onset diseases attributed to IUGR.

Risk of hypospadias in relation to maternal occupational exposure to potential endocrine disrupting chemicals.

BACKGROUND: Reported rises in the prevalence of hypospadias and other abnormalities of the male reproductive system may be a result of exposure to endocrine disrupting chemicals. AIMS: To analyse the relation between risk of hypospadias and maternal occupation, particularly with regard to exposure to potential endocrine disrupting chemicals (EDCs). METHODS: Data (1980-96) from the National Congenital Anomaly System (NCAS) were used to analyse the proportion of all congenital anomaly cases (n = 35 962) which were notified with hypospadias (n = 3471) by occupational codes (348 individual job titles) and by categories of exposure to potential EDCs from a job exposure matrix. RESULTS: Five individual occupations (of 348) showed nominally statistically significant excesses, none of which had possible or probable exposure to potential EDCs. Odds ratios for "possible" or "probable" compared to "unlikely" exposure to potential EDCs did not show statistically significant increases in any of the EDC categories after adjustment for social class of the mother and father, nor was there evidence of an upward trend in risk with likelihood of exposure. In the 1992-96 time period odds ratios were increased for hairdressers (the largest group exposed to potential EDCs) and for probable exposure to phthalates (of which hairdressers form the largest group) before social class adjustment. CONCLUSIONS: There was little evidence for a relation between risk of hypospadias and maternal occupation or occupational exposure to potential EDCs, but as the exposure classification was necessarily crude, these findings should be interpreted with caution.

Postnatal endocrine dysfunction resulting from prenatal exposure to carbofuran, diazinon or chlordane.

Prenatal exposure to pesticides of three different classes initiated persistent postnatal endocrine dysfunction. Adrenal function and hepatic metabolism of corticosterone were studied in adult hybrid mice exposed during development to either an organophosphate (Diazinon), a carbamate (Carbofuran), or an organochlorine (Chlordane). Animals were exposed to relatively low levels of the toxins in utero and neonatally via the mothers' milk. Exposure to lower doses of the anticholinesterase compounds, Diazinon or Carbofuran, resulted in impairment of hepatic metabolism of corticosterone in vitro due to a loss in reductive capacity per unit liver weight. Plasma levels of corticosterone were also elevated in these animals, but without a concomitant increase in adrenal steroidogenesis in vitro. The effects of exposure to Chlordane were more complex. In male animals, exposure to lower doses of chlordane resulted in an increase in plasma corticosterone levels without an apparent increase in hepatic metabolism of corticosterone or adrenal steroidogenesis. In contrast, side-chain metabolism of corticosterone was decreased in female mice exposed to Chlordane. Similar effects on pituitary-adrenal function were not evident for the offspring of mice exposed to higher doses of the toxins. Possible mechanisms for this non-linear dose-response are discussed.

Ectopic apudocarcinomas and associated endocrine hyperplasias of the foregut.

Foregut endocrine polypeptide-secreting APUD cells (Amine-Precursor-Uptake and Decarboxylation), in their embryologic migration from neural crest to foregut may become "arrested" in the mesoderm or in other ectopic locations. They may become hyperplastic, adenomatous or malignant. Eight illustrative patients are reported. One patient had "pancreatic hyperparathyroidism" with hypercalcemic crises, pancreatic apudocarcinoma, normal parathyroids, biologically active parathormone, but inert immunochemically to the usual parathyroid antisera. Two had gastrin-secreting malignancies in the mesoderm. Remission after excision, but eventual recurrence of the syndrome due to islet cell hyperplasia required total gastrectomy. One patient had a gastric corpus apudocarcinoma found prospectively with hypergastrinemia which required excision of the tumor. One patient had acromegaly with hypergastrinemia and antral gastrinosis treated by pituitary irradiation, One patient had the antral or intermediary type of the Zollinger-Ellison syndrome with moderate hypergastrinemia, duodenal ulcer and antral gastrinosis, treated by vagotomy and antrectomy. One patient had hyperparathyroidism with antral gastrinosis, treated by parathyroidectomy. One patient had malignant Zollinger-Ellison syndrome and developed associated thyroid parafollicular cell hyperplasia and parathyroid chief cell hyperplasia, treated by total gastrectomy and multiple endocrine excisions. These investigative observations demonstrate ectopic loci and associated hyperplasias which support the concept of migration and bizarre potentiality of polypeptide-secreting cells of the foregut.