Toshio Seto

Relationship between urinary cadmium and mortality among inhabitants living in a cadmium polluted area in Japan.

A 15 year follow-up study of 3119 inhabitants living in a cadmium polluted area was conducted to investigate the influence of environmental cadmium exposure on the mortality. The cumulative survival curves of the subjects with urinary cadmium concentration > or = 10 microg/g creatinine was lower than that of the subjects with < 10 microg/g creatinine in the men aged 50-59 and 60-69 years and in the women aged 60-69 and 70-79 years. In the men aged 50-69 years and the all aged women, the cumulative survival curves became lower in proportion to the increase of urinary cadmium concentration, when the subjects were divided into four groups according to the amount of urinary cadmium concentration (< 5, 5-9.9, 10.1-19.9, > or = 20 microg/g creatinine). These results suggested a dose response relationship between cadmium exposure and mortality.

Inhibitory effect of pregnancy on stress-induced immunosuppression through corticotropin releasing hormone (CRH) and dopaminergic systems

To clarify the involvement of pregnancy in the response of the neuroendocrine-immune system to stress, we examined splenic natural killer-cell-activity-(NKCA) and its relevant central and blood parameters in female virgin and pregnant rats (10 to 11 days gestation) exposed to forced water-immersion stress with durations of 90 min and 180 min. Decreases in splenic NKCA, corticotropin releasing hormone (CRH) in the hypothalamus, and increases in progesterone (P), beta-endorphin (beta EP), and dopamine (DA) metabolic ratios in the frontal cortex and nucleus accumbens produced by stress were recognized in the virgin rats, but not in the pregnant rats. Pregnancy reduced splenic NKCA in rats without stress, but elevated it in the rats exposed to stress with a duration of 180 min. These findings suggest inhibitory effects of pregnancy on stress-induced immunosuppression and neuroendocrine changes, thereby promoting homeostasis in the neuroendocrine-immune system against stress. Such enhanced homeostasis associated with pregnancy seemed to be mediated by the activation of placental P and placental or pituitary beta EP in cooperation with mesocortical and mesolimbic DA systems and hypothalamic CRH.

Effects of exposure to microwaves on cellular immunity and placental steroids in pregnant rats.

OBJECTIVES: Microwaves produce various detrimental changes based on actions of heat or non-specific stress, although the effects of microwaves on pregnant organisms has not been uniform. This study was designed to clarify the effect of exposure to microwaves during pregnancy on endocrine and immune functions. METHODS: Natural killer cell activity and natural killer cell subsets in the spleen were measured, as well as some endocrine indicators in blood--corticosterone and adrenocorticotrophic hormone (ACTH) as indices of the hypothalamic-pituitary-adrenal axis--beta-endorphin, oestradiol, and progesterone in six female virgin rats and six pregnant rats (nine to 11 days gestation) exposed to microwaves at 10 mW/cm2 incident power density at 2450 MHz for 90 minutes. The same measurements were performed in control rats (six virgin and six pregnant rats). RESULTS: Skin temperature in virgin and pregnant rats increased immediately after exposure to microwaves. Although splenic activity of natural killer cells and any of the subset populations identified by the monoclonal antibodies CD16 and CD57 did not differ in virgin rats with or without exposure to microwaves, pregnant rats exposed to microwaves showed a significant reduction of splenic activity of natural killer cells and CD16+CD57-. Although corticosterone and ACTH increased, and oestradiol decreased in exposed virgin and pregnant rats, microwaves produced significant increases in beta-endorphin and progesterone only in pregnant rats. CONCLUSIONS: Microwaves at the power of 10 mW/cm2 produced activation of the hypothalamic-pituitary-adrenal axis and increased oestradiol in both virgin and pregnant rats, suggesting that microwaves greatly stress pregnant organisms. These findings in pregnant rats suggest that--with exposure to microwaves--pregnancy induces immunosuppression, which could result in successful maintainance of pregnancy. This enhancement of adaptability to heat stress with pregnancy may be mediated by activation of placental progesterone and placental or pituitary beta-endorphin.

Opioid peptides mediate heat stress-induced immunosuppression during pregnancy

To clarify the involvement of the opioid system in enhanced immunosuppression induced by heat stress during pregnancy, we examined the effects of heat exposure and intraperitoneal administration of opioid receptor antagonist naloxone on β-endorphin (β-EP) in blood, pituitary lobes, and placenta as well as splenic natural killer cell activity (NKCA) and placental steroids in pregnant rats at 15-16 days gestation. Two-way analysis of variance revealed significant increases in blood β-EP induced by heat and naloxone and a significant interaction between heat and naloxone on blood β-EP and progesterone (P). Whereas heat reduced NKCA, intraperitoneal administration of naloxone reversed it. Significant increases in blood and placental β-EP induced by both heat and naloxone administration and a significant interaction on blood and placental β-EP was observed. These results suggest that immunosuppression produced by heat stress during pregnancy is mediated by the opioid system. A positive correlation between β-EP in blood and placenta during heat and naloxone administration suggests that increased placental β-EP during heat results in hypersecretion of β-EP into blood. P increased by heat during pregnancy may be involved in the immunosuppression.To clarify the involvement of the opioid system in enhanced immunosuppression induced by heat stress during pregnancy, we examined the effects of heat exposure and intraperitoneal administration of opioid receptor antagonist naloxone on beta-endorphin (beta-EP) in blood, pituitary lobes, and placenta as well as splenic natural killer cell activity (NKCA) and placental steroids in pregnant rats at 15-16 days gestation. Two-way analysis of variance revealed significant increases in blood beta-EP induced by heat and naloxone and a significant interaction between heat and naloxone on blood beta-EP and progesterone (P). Whereas heat reduced NKCA, intraperitoneal administration of naloxone reversed it. Significant increases in blood and placental beta-EP induced by both heat and naloxone administration and a significant interaction on blood and placental beta-EP was observed. These results suggest that immunosuppression produced by heat stress during pregnancy is mediated by the opioid system. A positive correlation between beta-EP in blood and placenta during heat and naloxone administration suggests that increased placental beta-EP during heat results in hypersecretion of beta-EP into blood. P increased by heat during pregnancy may be involved in the immunosuppression.

Involvement of Central Neurotensin in Thermoregulatory and Neuroimmune Function in Pregnant Rats Exposed to Heat

To examine a functional relationship among pregnancy and central neurotensin and thermoregulatory and neuroimmune systems during heat stress, we monitored colonic temperature in six virgin female rats and six pregnant rats (9 to 11 days gestation) exposed to a microwave source. We also assayed splenic natural killer cell activity (NKCA), blood corticosterone (CS), and ACTH as indicators of the hypothalamic-pituitary-adrenal axis, beta-endorphin (beta-EP), and neurotensin (NT) in discrete brain regions. Additionally, we clarified the effects of intracerebroventricular (icv) administration of NT antiserum on these same responses in pregnant rats exposed to heat stress. Repeated-measures analysis of variance showed significant main effects of heat and pregnancy and a significant interactive effect on colonic temperature. Significant elevation in blood CS, ACTH, beta-EP, and NT in the hypothalamus and significant reductions in splenic NKCA and NT in the nucleus accumbens were produced by heat. In the experiment examining the effect of icv administration of NT antiserum, significant main effects of heat and administration and a significant interactive effect on colonic temperature were observed. Icv administration of NT antiserum increased splenic NKCA and decreased blood beta-EP. These results show that pregnancy enhances thermal homeostasis, suggesting central thermoregulatory mechanisms through NT in nucleus accumbens and hypothalamus in which placental or pituitary beta-EP may be involved. NT and beta-EP seem to play central roles simultaneously in heat-induced immunosuppression during pregnancy. Clarification for the effects of NT antiserum on beta-EP in virgin rats or manipulation of agents related to opioid system should be the focus of future work.

CENTRAL ADMINISTRATION OF INTERLEUKIN-1β REDUCES NATURAL KILLER CELL ACTIVITY IN NON-PREGNANT RATS, BUT NOT IN PREGNANT RATS

To examine responses of natural killer cell activity (NKCA) to interleukin-1 beta (IL-1 beta) during pregnancy, we determined splenic NKCA as well as blood and brain indicators in virgin and pregnant rats (14 or 21 days gestation) with intracerebroventricular (i.c.v.) administration of IL-1 beta. NKCA was reduced and blood beta-endorphin (beta EP) was increased with the progress of pregnancy. I.c.v. administration of IL-1 beta reduced NKCA and corticotropin-releasing hormone (CRH) in the median eminence (ME), and increased beta EP in virgin rats, but did not change any parameters in pregnant rats with 21 days gestation. These data suggest that the immunosuppressive effect of central administration of IL-1 beta is blocked by pregnancy. CRH in the ME and opioid system seem to be involved in the inhibitory effect of pregnancy on IL-1 beta-induced immunosuppression.