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Humoral signals (neurotransmitters and hormones) control cell division, migration, and differentiation processes which define the organization of brain pathways. Alterations in maternal, fetal, and neonatal biochemistry during critical periods of neurogenesis may irreparably alter the circuitry and, thus, postnatal behavior of young animals. Secalonic acid D (SAD), an ergochrome mycotoxin, causes behavioral and neurochemical deficits in developing mice following prenatal (transplacental) or early postnatal (transmammary) exposure. SAD-induced functional abnormalities include delays in reflex behaviors, integrated neuromuscular activity and strength, stress adaptation responses, and sensory discrimination. These behavioral changes are associated with reductions of brain monoamine neurotransmitter levels in both fetuses and neonates. SAD also alters concentrations of maternal plasma corticosteroids and fetal cyclic nucleotides during midgestation. SAD thus modulates several chemicals in pregnant mice and their fetuses which contribute to brain development, suggesting that this mycotoxin may pose a neuroteratogenic hazard to other immature mammals, including human infants.

MDMA is a hallucinogenic drug that is used by the general public as a recreational drug of abuse. The neurobehavioral consequences of prenatal MDMA exposure are unknown. Groups of pregnant rats were gavaged with 0, 2.5, or 10 mg/kg MDMA during gestation on alternate gestational days 6-18. Gestational duration, litter size, neonatal birth weights and physical appearance at birth were unaffected by MDMA treatments. Pregnancy weight gain was significantly reduced by MDMA treatment. Progeny growth, maturational parameters (eye opening and incisor eruption times), surface righting reflex, swimming performance, forelimb grip strength, milk-induced behaviors, passive avoidance behavior, figure-8 maze activity over 48 hours, the density of brain serotonin (5-HT) uptake sites, and brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels were unaffected by MDMA treatments. Olfactory discrimination on postnatal days (PND) 9-11 was enhanced in both male and female MDMA-treated progeny, while negative geotaxis (PND 7-10) was delayed in female pups. In contrast to progeny, MDMA caused dose-dependent decreases in 5-HT and 5-HIAA levels in discrete brain areas of the dam. It is concluded that prenatal exposure to MDMA at the levels used here produces only subtle behavioral alterations in developing rats. The dam is more at risk for MDMA-induced 5-HT depletion than is the conceptus.

Suckling mice exposed to secalonic acid D (SAD) mycotoxin postnatally (by gavaging dams with 0, 15 or 25 mg/kg on postgestational days 1 to 10) or prenatally (by gavaging with 25 mg/kg on gestational day 13 to produce a positive behavioral teratogenic control group) manifested subtle preweaning neurobehavioral, neurochemical and growth deficits. Gestational length, maternal weight gain, neonatal sex ratio and physical appearance of pups at birth were unaffected by treatment. Prenatal SAD (25 mg/kg) delayed (p less than 0.05) ontogeny of swimming on postnatal days (PND) 11 and 13 and reduced norepinephrine (NE) and dopamine (DA) levels in prosencephalon on PND 7 and in cerebellum-pons on PND 7-16. In the postnatal treatment groups, pup body weight gains were decreased from PND 9-22. Swimming was delayed in the 15 mg/kg postnatal exposure group on PND 11 and 13, while 25 mg/kg delayed swimming on PND 11-15. Postnatal exposure to 25 mg/kg also reduced NE and DA levels in prosencephalon and cerebellum-pons on PND 7-16. SAD thus caused concomitant ontogenetic delays in growth, swimming behavior and brain catecholamine levels following either prenatal (transplacental) or early postnatal (transmammary) exposure. These data indicate that both in utero and lactational exposures must be considered when assessing potential risks posed to developing mammals by environmental neurotoxicants.

The temporal interaction of an emulsifiable mixture of 2.3% dichlorvos and 10% crotoxyphos with phenothiazine anthelmintic was studied in 8 groups of 5 lambs each, free from or parasitized with Haemonchus and Trichostrongylus spp. Each lamb in 1 of 3 parasitized groups and 1 of 3 nonparasitized groups was treated with phenothiazine orally (12.5 g initially and 4 days later with 6.25 g every 3 days for 9 treatments) and/or the mixture of dichlorvos and crotoxyphos dermally (1,550 ml of 0.25% emulsion sprayed every 2 weeks for 3 applications). Two groups served as controls. Onset of clinical signs of toxicosis, lethality, and erythrocyte acetylcholinesterase (EACE) activity were monitored. After each dichlorvos-crotoxyphos mixture spray, clinical signs of toxicosis were seen within 40 minutes in parasitized and nonparasitized lambs regardless of concurrent phenothiazine treatment. Phenothiazine alone was not toxic and did not inhibit EACE activity. The EACE activities of dichlorvos-crotoxyphos mixture-sprayed lambs were significantly (P less than 0.05) depressed regardless of parasitism or concurrent phenothiazine treatments. The severity of inhibition increased with each dichlorvos-crotoxyphos mixture spray, but EACE activity recovered within 48 hours after each spray although base-line values were never attained. There was no apparent potentiation of the toxic effects of the dichlorvos-crotoxyphos mixture by phenothiazine.

Pregnant mice (dams) were gavaged once on gestational day 13 with 4 ml/kg of dimethylsulfoxide vehicle containing 0 (groups 15, 25 and negative control) or 25 (positive behavioral teratogenic control group) mg/kg of secalonic acid D (SAD). While nursing their offspring, dams were gavaged on postgestational days 1 to 10 with vehicle containing 0 (negative and positive control groups), 15 (group 15) or 25 (group 25) mg/kg/day of SAD. Gestational lengths, maternal pregnancy weights, litter sizes, neonatal sex ratios, neonatal physical appearance and female birth weights were unaffected by prenatal treatment, but male pups born to positive control dams weighed less (p less than 0.05) than negative control group. Compared to negative control, the positive control dams gained significantly more weight while nursing their offspring. Prenatal (positive control) and postnatal (15, 25) SAD exposure delayed ontogeny of surface righting, olfactory discrimination and hindlimb grip behaviors in males and females, and testes descent in males. Negative geotaxis in male and female offspring of group 25 and male offspring of positive control group, as well as times of incisor eruptions of both sexes in groups 15 and 25 were delayed. A significant dose-response effect in olfactory discrimination existed between the groups exposed to postnatal SAD. SAD was behaviorally teratogenic following both prenatal and early postnatal exposure.

Pregnant rats were gavaged with a 1:1 mixture of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) at 0 (G0), 50 (G 50) and 100 (G 100) mg/kg per day on gestational days 6-15. Treatment significantly (P less than 0.05) delayed ontogeny of dopamine (DA), but not norepinephrine (NE) levels, in the thalamus-hypothalamus on postnatal day 7; in the pons-medulla on days 7,9 and 15; and in the olfactory lobes on day 9. On day 25, serotonin (5-HT) levels were significantly decreased in the pons-medulla of G 100 rats, whereas 5-hydroxyindoleacetic acid (5-HIAA) levels decreased in the thalamus-hypothalamus and pons-medulla of G 50 and G 100 rats.

Mice were gavage-fed on day 13 of pregnancy with 0 (groups N, 15, 25) or 25 (group P) mg/kg of secalonic acid D (SAD) and again while nursing their offspring on postgestational days 1-10 with 0 (N,P), 15(15) or 25(25) mg/kg/day. SAD residues were present in the stomach of pups nursed by SAD-treated dams. Postnatal exposure to SAD decreased (P less than 0.05) body weight gains of offspring. Treatment decreased the developmental levels of norepinephrine and dopamine in the prosencephalon (forebrain) and cerebellum-pons of the offspring on postnatal days (PND) 7 and 7-16, respectively. On PND 7-16 serotonin and 5-hydroxyindoleacetic acid levels decreased in the prosencephalon and cerebellum-pons of offspring exposed prenatally (P) or postnatally (15,25) to SAD.

Various modifications and improvements of the electrometric method of Michel for measurement of blood cholinesterase activity in animals are reviewed. Reported normal values of blood cholinesterases activities for different animal species are tabulated. A modified electrometric method is described and recommended for the measurement of erythrocyte and plasma cholinesterase activities of sheep.

The effects of N-acetylcysteine (NAC) on the pharmacokinetic parameters of acetaminophen (AP) in adult female beagles were studied. Each of eight dogs received a single i.v. injection of 150 mg/kg of AP as a 5% solution in a vehicle of 40% aqueous propylene glycol at 0 h. Each of four AP-treated dogs (Group I) received an oral dose of 140 mg/kg NAC as a 20% aqueous solution at 0 h, and 70 mg/kg at 30 min and 1 h post-AP administration. Four dogs (Group II) served as controls and received isotonic saline orally. Mild signs of AP toxicosis seen in both groups within 2-3 h of AP administration including depression, weakness, recumbency and methaemoglobinaemia. Relative to Group II, treatment with NAC (Group I) enhanced the elimination of AP from the body as indicated by the decreased plasma half-life (t1/2 = 1.06 h for Group I v. 1.78 h for Group II) and a higher elimination rate constant (beta = 0.67/h for Group I v. 0.40/h for Group II). Changes in the area under plasma concentration curve data (AUC = 0.39 mg.h/ml for Group I v. 0.65 mg.h/ml for Group II) were associated with a 61% increase in total body clearance of AP in Group I. The apparent volume of drug distribution Vdarea was not affected.

Groups (G) of pregnant rats were gavaged with 1:1, 2,4-D/2, 4, 5-T mixture at 0 (GO), 50 (G50), 100 (G100) and 125 (G125) mg/day on gestational days 6 to 15. G100 and G125 dams gained significantly less weight during pregnancy and delivered fewer offspring than control. Gestational lengths, neonatal sex ratios, birth weights, and physical appearance at birth were unaffected by treatments. On postnatal day (PND) 1, G125 mortality was significantly increased. Except for a significant weight reduction in G125 on PND60, postnatal growth and maturation were unaffected by treatments. 2,4-D/2, 4, 5-T significantly delayed male and female surface righting (PND2-5), and negative geotaxis at 45 degrees angle (PND15-17) in all groups; olfactory discrimination (PND9-11), and negative geotaxis at 25 degrees (PND7-11) in G100 and G125. On PND9 negative geotaxis at 25 degrees were significantly delayed in G50 females. d-Amphetamine challenges significantly increased running wheel activity of G125 males on PND22 and 23. 2,4-D/2,4,5-T was behaviorally teratogenic at all dosage levels.

Rats exposed in utero on gestational days 6-15, to nonfetotoxic and grossly nonteratogenic mixtures (50 or 100 mg/kg) of 2,4-D/2,4,5-T as found in Agent Orange (but without significant contamination with 2,3,7,8 tetrachloro-p-dioxin) manifested subtle developmental neurotoxicity. Maturation of swimming behavior was significantly delayed on postnatal day 7 in both treatment groups. The concentration of norepinephrine (NE) in whole brain was significantly increased on postnatal day 15 in both treatment groups, whereas the concentration of dopamine (DA) was increased on postnatal day 15 at 100 mg/kg. The turnover and efflux rate constant of DA in whole brain were significantly reduced whereas the turnover time increased on postnatal day 3. The efflux rate constant for NE decreased and the turnover time increased significantly on postnatal day 15 at 100 mg/kg. These data indicate the value of ontogenic assessment following exposure to small doses, which result in functional alterations in the absence of overt toxic signs.