Prenatal exposure to methylmercury alters development of adrenergic receptor binding sites in peripheral sympathetic target tissues.

In order to assess the impact of prenatal exposure to methylmercury on sympathetic neurotransmission, effects on development of adrenergic receptor binding sites in peripheral tissues were evaluated. In the liver, methylmercury produced a dose-dependent increase in alpha 1-, alpha 2- and beta-receptor binding of radioligands throughout the first 5 weeks of postnatal life. Similarly, renal alpha-receptor subtypes showed increased binding capabilities, but binding to beta-receptor sites was reduced. At least some of the changes in receptors appear to be of functional significance, as physiological reactivity to adrenergic stimulation is altered in the same directions in these two tissues. The actions of methylmercury displayed tissue specificity in that the same receptor populations were largely unaffected in other tissues (lung, heart). These results suggest that methylmercury exposure in utero alters adrenergic responses through targeted effects on postsynaptic receptor populations in specific tissues.

Functional consequences of prenatal methylmercury exposure: effects on renal and hepatic responses to trophic stimuli and on renal excretory mechanisms.

The effects of prenatal exposure to methylmercury on the functional development of renal and hepatic response systems was examined in the developing rat. Methylmercury produced an elevation of basal activity of renal ornithine decarboxylase (ODC, an enzyme involved in regulation of cellular maturation) and an eventual relative hypertrophy; liver ODC was reduced and hypertrophy was not evident. In contrast, the reactivity of liver ODC to trophic stimulants (vasopressin, isoproterenol) was markedly enhanced by prenatal methylmercury exposure, whereas renal ODC responses were much less affected (vasopressin) or actually reduced (isoproterenol). Targeted actions of methylmercury on renal excretory function were also prominent, with increased fractional excretions of urea and electrolytes and an eventual reduction in glomerular filtration as assessed by creatinine clearance. In addition, the reactivity of the kidney to challenge with desmopressin was altered coincidentally with the appearance of the effects on basal clearance mechanisms. These studies show that doses of methylmercury ordinarily associated with selective actions on development of neurobehavioral patterns also influence the functional ontogeny of other organ systems; furthermore, the fact that the target tissues are different for prenatal vs. postnatal methylmercury exposure, indicates that the functional teratology of methylmercury exhibits critical periods of sensitivity.

Effects of neonatal methylmercury exposure on adrenergic receptor binding sites in peripheral tissues of the developing rat.

Neonatal exposure to methylmercury produces changes in patterns of tissue growth and function, in part, due to alterations in adrenergic neuronal input. To explore the mechanisms by which these changes come about, newborn rats were exposed to methylmercury (1 or 2.5 mg/kg per day) throughout the preweaning stage and the ontogeny of adrenergic receptor binding sites evaluated in liver, kidney, heart and lung, using [3H]prazosin (alpha 1-receptors), [3H]rauwolscine (alpha 2-receptors) and [125I]pindolol (beta-receptors). In the kidney, methylmercury caused decreases in beta- and alpha 1-receptor binding and increases in alpha 2-binding; previous work has shown that beta-receptor-mediated responses are generally enhanced in methylmercury-exposed pups, and the down-regulation of beta-receptor binding thus probably represents a compensatory action secondary to alterations in post-receptor coupling mechanisms. The effects of methylmercury on hepatic adrenergic receptors were different from those seen in the kidney, with substantial elevations in beta- and alpha 1-receptor binding apparent in the preweaning stage; this agrees also with the differences in effects of the mercurial on trophic reactivity and growth in the 2 tissues. Despite the fact that methylmercury causes activation of neonatal cardiac sympathetic nerves, beta-receptor binding sites in the heart were unaffected by methylmercury exposure; the failure to down-regulate cardiac postsynaptic receptors in the face of increased nerve activity again represents an anomaly of synaptic regulatory function. These results indicate that methylmercury alters adrenergic responsiveness, in part, through actions on the development of receptor binding sites, and further, that the organ-specificity and receptor subtype-selectivity are consistent with subsequent effects of the organomercurial on adrenergic participation in target organ growth; however, changes in receptor binding alone do not account for all of the effects of methylmercury on synaptic activity or trophic responses.

Effects of neonatal hypoxia on brain development in the rat: immediate and long-term biochemical alterations in discrete regions.

To evaluate the sensitivity of immature brain tissue to hypoxic insult, neonatal rats were exposed to 7% O2 for 2 h at critical stages of development (1, 8, 15, 23 days of postnatal age); the immediate and long-term impact of hypoxia was then assessed in cerebellum, cerebral cortex and midbrain through measurement of ornithine decarboxylase (ODC) activity, a biochemical determinant of cellular injury and subsequent maturation, and through measurements of protein synthesis, growth and synaptosomal uptake of norepinephrine (an index of noradrenergic synaptogenesis). In one-day-old rats, hypoxia caused stimulation of protein synthesis and short-term suppression of ODC activity which persisted for several hours after termination of low O2 exposure; over the ensuing days, there was a prolonged elevation of enzyme activity and a subsequent, regionally selective increase in synaptosomal uptake of norepinephrine without changes in brain growth. In contrast, hypoxia in 8-day-old rats produced signs of metabolic injury, with a short-term elevation of ODC throughout the brain and reduced protein synthetic rates, eventual shortfalls in brain regional growth and no net increase in synaptosomal uptake. The effects of hypoxia on brain regional growth in 8-day-old animals appeared to represent an age-specific effect, as low as O2 conditions in older animals did not affect growth (animals made hypoxic at 15 or 23 days), but did produce an eventual reduction in synaptosomal uptake (hypoxia at 15 days). Differences between one-day-old and 8-day-old rats were also apparent in cerebral responses simply to a 2-h separation from the dam under normoxic conditions. These results support the view that cellular development and synaptogenesis are compromised when neonatal brain tissue is exposed to hypoxic conditions, and that there are critical periods of sensitivity in which processes undergoing rapid maturational change are particularly vulnerable.