Prenatal exposure to anti-HIV drugs: Neurobehavioral effects of zidovudine (AZT) + lamivudine (3TC) treatment in mice
Section of Comparative Psychology, Laboratorio di Fisiopatologia O. S., Istituto Superiore di Sanità (I.S.S.), 00161 Rome, Italy. Teratology
01/2001; 63(1):26-37. DOI: 10.1002/1096-9926(200101)63:1<26::AID-TERA1005>3.0.CO;2-G
The new antiretroviral treatments that combine the zidovudine (AZT) regimen with lamivudine (3TC) appear as a cost-effective alternative to the current AZT monotherapy to prevent mother-to-fetus transmission of the HIV-1 virus. Recent evidence in uninfected children raised concern about the long-term effects of perinatal exposure to AZT and 3TC, especially when used in combination. Animal studies indicated behavioral changes in offspring exposed perinatally to both AZT and 3TC, whereas no animal data are available on the effects of the perinatal exposure to the AZT + 3TC combination on neurodevelopment.
Pregnant CD-1 mice received p.o. AZT + 3TC (160 and 500 mg/kg, respectively) or vehicle solution (NaCl 0.9%) twice daily from gestational day 10 to delivery. Maternal reproductive endpoints such as pregnancy length, abortion, litter size, sex ratio, and offspring viability were assessed. Pups were scored for different somatic and behavioral endpoints, including sensorimotor development, homing performance on postnatal day (PND) 10, passive-avoidance testing (PND 22-23), locomotor activity (PND 23), and social interaction (PND 35).
While no effects were observed on maternal reproductive endpoints, treated pups showed a long-lasting reduction of body weight and a slightly delayed maturation of placing and grasping reflexes and pole grasping. No effects on passive-avoidance or locomotor activity were found. AZT + 3TC-treated mice showed selective alterations in the social interaction test; the treated female offspring also displayed a significant reduction of affiliative interactions.
The combination of AZT and 3TC (1) induced small, but more marked, effects on somatic and sensorimotor development than either of these drugs administered separately; and (2) affected juvenile social behavior.
Available from: Gemma Calamandrei
- "Pups were then assessed for a number of measures currently used in the study of sensorimotor ontogeny in mice according to a slightly modified Fox battery [25,29,45]. The tests were conducted during the dark period between 09:00 and 14:00 hr under red light, each subject being tested at approximately the same time of the day. "
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ABSTRACT: Chlorpyrifos (CPF) is a non-persistent organophosphate (OP) largely used as pesticide. Studies from animal models indicate that CPF is a developmental neurotoxicant able to target immature central nervous system at dose levels well below the threshold of systemic toxicity. So far, few data are available on the potential short- and long-term adverse effects in children deriving from low-level exposures during prenatal life and infancy.
Late gestational exposure [gestational day (GD) 14-17] to CPF at the dose of 6 mg/kg was evaluated in CD-1 mice during early development, by assessment of somatic and sensorimotor maturation [reflex-battery on postnatal days (PNDs) 3, 6, 9, 12 and 15] and ultrasound emission after isolation from the mother and siblings (PNDs 4, 7 and 10). Pups' motor skills were assessed in a spontaneous activity test on PND 12. Maternal behavior of lactating dams in the home cage and in response to presentation of a pup previously removed from the nest was scored on PND 4, to verify potential alterations in maternal care directly induced by CPF administration.
As for the effects on the offspring, results indicated that on PND 10, CPF significantly decreased number and duration of ultrasonic calls while increasing latency to emit the first call after isolation. Prenatal CPF also reduced motor behavior on PND 12, while a tendency to hyporeflexia was observed in CPF pups by means of reflex-battery scoring. Dams administered during gestation with CPF showed baseline levels of maternal care comparable to those of controls, but higher levels of both pup-directed (licking) and explorative (wall rearing) responses.
Overall our results are consistent with previous epidemiological data on OP neurobehavioral toxicity, and also indicate ultrasonic vocalization as an early marker of CPF exposure during development in rodent studies, with potential translational value to human infants.
Available from: Hewlet McFarlane
- "The homing test was performed as previously described (Venerosi et al., 2001). On P11, the mice were tested inside a standard mouse cage in which 1/3 of the cage was evenly filled with shavings from the home cage and the remaining 2/3 of the cage with clean shavings. "
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ABSTRACT: Pharmacological studies indicate that vasoactive intestinal peptide (VIP) may be necessary for normal embryonic development in the mouse. For example, VIP antagonist treatment before embryonic day 11 resulted in developmental delays, growth restriction, modified adult brain chemistry and reduced social behavior. Here, developmental milestones, growth, and social behaviors of neonates of VIP-deficient mothers (VIP +/-) mated to VIP +/- males were compared with the offspring of wild type mothers (VIP +/+) mated to VIP +/+ and +/- males, to assess the contributions of both maternal and offspring VIP genotype. Regardless of their own genotype, all offsprings of VIP-deficient mothers exhibited developmental delays. No delays were seen in the offspring of wild type mothers, regardless of their own genotype. Body weights were significantly reduced in offspring of VIP-deficient mothers, with VIP null (-/-) the most affected. Regardless of genotype, all offspring of VIP-deficient mothers expressed reduced maternal affiliation compared with wild type offspring of wild type mothers; +/- offspring of wild type mothers did not differ in maternal affiliation from their wild type littermates. Play behavior was significantly reduced in all offsprings of VIP-deficient mothers. Maternal behavior did not differ between wild type and VIP-deficient mothers, and cross-fostering of litters did not change offspring development, indicating that offspring deficits were induced prenatally. This study illustrated that the VIP status of a pregnant mouse had a greater influence on the growth, development and behavior of her offspring than the VIP genotype of the offspring themselves. Deficiencies were apparent in +/+, +/- and -/- offspring born to VIP-deficient mothers; no deficiencies were apparent in +/- offspring born to normal mothers. These results underscore the significant contribution of the uterine environment to normal development and indicate a potential usefulness of the VIP knockout mouse in furthering the understanding of neurodevelopmental disorders with social behavior deficits such as autism.
Available from: Ernesto Antonio Figueiró-Filho
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ABSTRACT: A avaliação dos agentes anti-retrovirais utilizando modelos experimentais permite testar os efeitos farmacológicos e adversos destes fármacos sobre o organismo matemo e fetal. O objetivo do presente estudo foi avaliar experimentalmente os efeitos de drogas anti-retrovirais isoladas e em associação sobre as taxas de fertilidade em ratas prenhes expostas a estes fármacos, bem como o efeito perinatal nas crias. O estudo foi realizado no Biotério do Departamento de Clínica Médica da FMRP-USP, utilizando ratas fêmeas prenhes adultas da raça Wistar, pesando entre 200 e 230g. As drogas utilizadas nos experimentos foram a azidotimidina (AZT), lamivudina (3TC) e nelfinavir (NFV), com as dosagens respectivas de 25 mg, 12,5 mg e 97,5 mgidia, administradas isoladamente ou em associação. No total foram avaliados sete grupos, incluindo o controle. O inicio da experimentação foi o dia zero da prenhez de todos os animais, independente do grupo. A forma de sacrificio dos animais foi por decapitação após 7, 14 e 21 dias de prenhez, seguida das etapas experimentais descritas. A cesariana foi realizada imediatamente após a decapitação do animal. Uma vez aberto o útero, foram contados os fetos vivos e mortos, os quais foram retirados para anotação do sexo, pesagem dos fetos vivos e respectivas placentas. Em seguida, os cornos uterinos foram dissecados e, por observação direta, anotada a presença de reabsorções precoces e tardias (abortamentos). O número de sít. ... (continuação) 0,05. Conclusões: não houve alterações significativas nas taxas de perdas pré-implantação e da eficiência de implantação de ratas tratadas com anti-retrovirais isolados e em associação. Houve aumento significativo nas taxas de perda pós-implantação nos grupos de ratas tratadas com anti-retrovirais isolados e em associação. Observou-se também, redução significativa nas taxas de viabilidade fetal e número de fetos por ninhada nos animais que receberam as drogas isoladamente e associadas e houve redução do peso matemo e dos fetos nos grupos tratados com 3TC, AZT+3TC e AZT+3TC+NFV. Apesar de experimental, este estudo sinaliza para a necessidade de se pesquisar outros fármacos anti-retrovirais com menor potencial histotóxico e que possam, com segurança, serem utilizados por gestantes portadoras da infecção pelo vírus da imunodeficiência humana. Dissertação (Mestrado).
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