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Sabrina Tait,¹ Laura Ricceri,² Aldina Venerosi,² Francesca Maranghi,¹ Alberto Mantovani,¹ and Gemma Calamandrei²

¹ Section of Food and Veterinary Toxicology, Department of Food Safety and Veterinary Public Health, and ² Section of Neurotoxicology and Neuroendocrinology, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy

Abstract
Background: Increasing evidence from animal and human studies indicates that chlorpyrifos (CPF) , similar to other organophosphorus insecticides still widely used, is a developmental neurotoxicant. Developmental exposure to CPF in rodents induces sex-dimorphic behavioral changes at adulthood, including social and agonistic responses, which suggests that CPF may interfere with maturation of neuroendocrine mechanisms.

Objectives: We assessed the hypothesis that CPF affects the levels of neurohypophyseal hormones acting as modulators of social behavior in mammals, such as oxytocin (OT) , arginine vasopressin (AVP) , and prolactin (PRL) .

Methods: Pregnant female mice were orally administered with either vehicle (peanut oil) or 3 or 6 mg/kg CPF on gestational day (GD) 15 to GD18, and offspring were treated subcutaneously with either vehicle or 1 or 3 mg/kg CPF on postnatal days (PNDs) 11 to PND14. Dose levels were chosen to avoid systemic toxicity and inhibition of brain acetylcholinesterase. Offspring were sacrificed at 5 months of age, and expression of OT, AVP, and PRL was analyzed in the hypothalamus by Western blot or enzyme-linked immunosorbent assay (ELISA) analysis.

Results: Both male and female mice showed dose-related enhancement of OT expression, with males presenting the more intense effect. AVP expression was significantly reduced in male mice at the higher prenatal and postnatal dose. We observed no significant effect on PRL expression in either sex. Overall, outcomes were mainly attributable to fetal exposure, whereas postnatal doses appeared to potentiate the prenatal effects.

Conclusions: Our data indicate that developmental exposure to CPF may permanently interfere with specific key signaling proteins of the hypothalamic peptidergic system, with time-, dose-, and sex-related effects still evident at adulthood.

Key words: arginine vasopressin, developmental neurotoxicity, endocrine disruptors, organophosphorus insecticides, oxytocin, prolactin. Environ Health Perspect 117:112–116 (2009) . doi:10.1289/ehp.11696 available via http://dx.doi.org/ [Online 22 August 2008]

Address correspondence to G. Calamandrei, Section of Neurotoxicology and Neuroendocrinology, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Telephone: 39-06-4990-2106. Fax: 39-06-4957821. E-mail: gemma.calamandrei@iss.it

We thank C. La Rocca and V. Lagatta for their technical support.

This research was supported by the Networks of Excellence CASCADE contract FOOD-CT-2004-06319 and by Istituto Superiore di Sanità/National Institutes of Health project 0F14.

The authors declare they have no competing financial interests.

Received 13 May 2008 ; accepted 22 August 2008.