Foetal and neonatal exposure to chlorpyrifos: biochemical and metabolic alterations in the mouse liver at different developmental stages.
The mechanisms implicated in the age-related toxicity, including its neurobehavioral effects after subtoxic developmental exposure to chlorpyrifos (CPF), a widely used insecticide, have not been fully elucidated yet. With the aim of investigating whether metabolic differences during ontogeny could account for the age-related susceptibility to CPF, we examined the developmental time-course of hepatic metabolizing enzymes and CPF metabolism in a cohort of mice exposed either prenatally (gestational day 15-18) and/or postnatally (postnatal day (PND) 11-14) to CPF at doses which were previously reported to induce neurobehavioural alterations, in the absence of brain acetyl-cholinesterase inhibition. Testosterone hydroxylase activity, CPF ex vivo biotransformation, glutathione content, as well as aromatase activity were determined in the liver of control and treated male and female mice at PND0, 9, 15 and 150. In control mice most Cyp activities were detectable and progressively increased up to PND15. In newborn control mice CPF bioactivation was much higher than the Cyp-catalysed detoxication, negligible at birth, indicating a possible increased susceptibility to CPF-induced effects in newborn mice. Detoxication rapidly increased with age, so that Cyp-related metabolic features cannot explain the higher susceptibility of juvenile mice. The observed age-dependent metabolic picture was partially altered by CPF prenatal treatment. Following in utero exposure CPF detoxifying capability was enhanced at birth and reduced at PND15, when CPF-oxon formation was slightly increased. No effects were evident at adulthood. Prenatal dosing was more effective in causing metabolic alterations than CPF postnatal treatment; no potentiation was observed in mice experiencing pre- plus post-natal CPF administration. Both in utero and postnatal CPF exposure decreased aromatase activity by 50% at PND9 and 15; this effect together with the presence of higher levels of the sex-specific Cyp2c activity at adulthood in male mice may suggest the occurrence of long-lasting impairment in the expression of hepatic Cyps under hormonal regulation. Altogether, the alterations in CPF Cyp-mediated biotransformation caused by perinatal CPF exposure seem not sufficient per se to explain the reported vulnerability of developing central nervous system to this insecticide, which can be due also to the parent compound itself or to the activation of different toxicological pathways. The hypothesis that observed effects on aromatase and sex-specific Cyp activity may be associated with a possible interference with the long-term alterations in sex-specific behavioural pattern deserves further investigation.
Environment and Primary Prevention Department, Mechanisms of Toxicity Unit, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. franca.buratti@iss.it
Franca Maria
FM
Buratti
Giovanna
G
De Angelis
Laura
L
Ricceri
Aldina
A
Venerosi
Gemma
G
Calamandrei
Emanuela
E
Testai
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn / Q000196:embryology / Q000378:metabolism*; D004390:Chlorpyrifos / Q000633:toxicity*; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology
D004390:Chlorpyrifos