Developmental Exposure to Chlorpyrifos Induces Alterations in Thyroid and Thyroid Hormone Levels Without Other Toxicity Signs in Cd1 Mice (original) (raw)
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Environmental Health Perspectives, 2008
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.
Long-term effects on hypothalamic neuropeptides after developmental exposure to chlorpyrifos in mice
Environmental health …, 2009
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.
Environmental Health Perspectives, 2003
Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants routinely found in human and animal tissues. Developmental exposure to PCBs is associated with neuropsychologic deficits, which may be related to effects on thyroid hormone (TH) signaling in the developing brain. However, PCBs may interfere with TH signaling solely by reducing circulating levels of TH, or they may exert direct effects on TH receptors (TRs). Therefore, we tested whether maternal exposure to a commercial PCB mixture, Aroclor 1254 (A1254), exerts effects in the fetal brain by one or both of these mechanisms. Dams were dosed daily with 0, 1, or 4 mg/kg A1254 from gestational day 6 (GD6) until they were sacrificed on GD16. A1254 significantly reduced circulating levels of triiodothyronine (T 3 ) and thyroxine (T 4 ) in pregnant rats but increased the expression of several THresponsive genes in the fetal cortex, including neuroendocrine-specific protein A (NSP-A), RC3/neurogranin, and Oct-1. These findings are consistent with a direct action of PCBs on TRs. However, we did not identify parent PCB congeners or metabolites that bound to rat TRs isolated from hepatic nuclei. These findings indicate that PCBs can interfere with TH signaling in the fetal brain by direct actions on the fetus rather than by producing maternal hypothyroidism. Key words: brain development, endocrine disruption, NSP-A, NSP-C, Oct-1, PCBs, RC3/neurogranin, thyroid, thyroid hormone. Environ Health Perspect 112:516-523 (2004). doi:10.1289/ehp.6672 available via http://dx.doi.org/ [Online 22 December 2003]
Toxicology, 2011
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.
Neurotoxicology and Teratology, 2008
The developmental neurotoxicity of organophosphates such as chlorpyrifos (CPF) involve multiple mechanisms that ultimately compromise the function of specific neurotransmitter systems, notably acetylcholine (ACh) and serotonin (5-hydroxytryptamine, 5HT). Studies in mammalian models incorporate both direct effects on brain development and indirect effects mediated through maternal physiology and maternal/neonatal interactions. We examined the effects of CPF in an avian model, which does not share these potential confounds. Chick eggs were injected with CPF (10 or 20 mg/ kg) on incubation days 2 and 6 and markers of ACh and 5HT systems were examined at hatching. The higher dose caused a reduction in cholinesterase activity but there was no consistent downregulation of m 2-muscarinic ACh receptors as would have been expected from ACh hyperstimulation. Both doses evoked significant reductions in the presynaptic high-affinity choline transporter, the rate-limiting factor in ACh biosynthesis, as monitored by binding of hemicholinium-3. Choline acetyltransferase, a constitutive marker for ACh terminals, was unaffected. This suggests that CPF reduces ACh presynaptic activity rather than compromising the development of ACh projections per se. CPF exposure also reduced the expression of cerebrocortical 5HT 1A receptors. These effects in the chick model recapitulate many of the actions of early gestational CPF exposure in rats, and thus suggest that CPF exerts direct actions on the immature brain to compromise the development of ACh and 5HT pathways.
Reproductive Toxicology, 2009
Perfluorooctanesulfonate (PFOS), a persistent and accumulative compound, is widely distributed in humans and wildlife. Human exposure can occur early in development, as evidenced by the detection of PFOS in umbilical cord blood and breast milk. As part of a developmental neurotoxicology study for which developmental endpoints, including those related to the developing nervous system, have been reported separately, groups of 25 pregnant Sprague Dawley rats were given daily oral doses of either vehicle control or potassium PFOS (K + PFOS) at 0.1, 0.3, and 1.0 mg/kg-d from gestation day (GD) 0 (day positive for mating) through postnatal day (PND) 20. An additional 10 pregnant females per treatment group were treated through GD 19 and sacrificed on GD 20 in order to obtain maternal and fetal serum and tissue samples at the end of gestation. The present paper reports the results of samples of serum, liver, brain, and thyroid glands taken at various times to evaluate: (1) serum, liver, and brain PFOS concentrations by LC-MS/MS to establish the relationship between PFOS concentrations and study outcomes; (2) serum thyrotropin (TSH) concentrations by RIA; (3) thyroid follicular cell proliferation index by Ki-67 immunohistochemical staining; (4) thyroid follicle epithelial cell height and colloidal area by histomorphometric analysis; (5) selected liver mRNA transcripts by quantitative RT-PCR. PFOS concentrations in dam and pup serum, liver, and brain increased across treatment groups in approximate proportion to the proportional increases in maternal K + PFOS dose, and sex differences in PFOS concentrations were not apparent in pups on PND 21. In pups from K + PFOS maternal dose groups on PND 72, serum PFOS had decreased to about 3 and 11% of PND 21 concentrations in males and females, respectively, and liver PFOS had decreased to about 17% of PND 21 concentrations in both sexes. Liver PFOS concentrations were approximately 0.6-0.8 times serum PFOS in GD 20 fetuses, and increased to about 2-4 times serum concentrations on PND 4 and 21. GD 20 fetal and PND 4 pup brain PFOS concentrations were approximately 33% of the corresponding serum concentrations, dropping to approximately 10% by PND 21, in contrast to dam brain PFOS concentrations, which were approximately 4-9% of serum PFOS concentrations. Compared to controls, Cyp2b2 mRNA was increased (2.8-fold) in the 1.0 mg/kg-d treatment-group dams on GD 20. In male pups on PND 21, Cyp4A1, ACoA, and Cyp2b2 were increased 2.1-, 1.5-, and 1.8-fold, respectively, and Cyp7A1 was decreased 3.5-fold. Serum TSH and thyroid follicular morphology were not altered by K + PFOS treatment. The mean number of proliferating thyroid follicular cells was increased 2.1-fold over control in GD 20 female fetuses from 1.0 mg/kgd-treated dams, yet the highest individual count was similar to that of controls (116 versus 113 in controls).
Ain Shams journal of forensic medicine and clinical toxicology, 2013
Chlorpyrifos (CPF) is a broad spectrum organophosphorus (OP) insecticide used in the control of a wide variety of insects. Its wide use in agriculture raises a growing public concern about the accumulation of these insecticides in food products and water supplies. The aim of this work was to evaluate the toxicological effect of CPF on thyroid and suprarenal glands. Twenty adult male albino rats were used in this work and divided into two groups: control (group І) and CPF-treated (group ІІ). The treated group received CPF daily in a dose of 5.4 mg/kg orally for 28 days. Serum T3, T4, TSH, corticosterone and malondialdehyde (MDA) were determined. The thyroid and suprarenal glands were evaluated for oxidative stress and microscopically. Results showed that CPF induced a significant decrease of serum T3 and T4 and a significant increase of serum TSH. Serum corticosterone was increased but statistically insignificant. Serum and tissues MDA were significantly increased. Histological examination of thyroid gland revealed that most follicles appeared degenerated with empty lumen due to decrease colloid, obvious exfoliation of the follicular epithelial cells and vascular congestion. Adrenals showed increased vacuolations of zona granulosa cells. Thus, it was concluded that chlorpyrifos exposure for 28 days causes damage to thyroid and suprarenal glands.
Journal of Toxicology and Environmental Health, Part A, 2003
Exposure to some organophosphate (OP) compounds during pregnancy has been associated with adverse health consequence on both the mother and the offspring. The aim of the study was to evaluate the effect of exposure to chlorpyrifos (CPF) during gestation on implantation and on some neonatal parameters in mice. Twenty one virgin Swiss albino mice divided into 3 groups of 7 mice each served as subjects for this study. Mice in group 1 were dosed with corn oil (control), while those in groups 2 and 3 were exposed to CPF at a dose of 15.9 mg/kg (~15% LD 50 ) and 21.2 mg/kg (~20% LD 50 ), respectively. All the dams were dosed between gestation days (GD) 6 -15 and monitored for signs of toxicity and gestation length. At birth, the litter size and weight, and the anogenital distance of the pups were measured. The pups were evaluated for physical characteristics and death. The dams were sacrificed at postnatal day 22, and the uterine horns evaluated for number of implantation sites. The results showed a significant decrease in the litter size and weight, and anogenital distance in pups exposed to CPF in utero compared to the control. In addition, all the pups prenatally exposed to CPF were born weak and died few days postpartum. A dose-dependent increase in percentage postimplantation loss was observed in mice dosed with CPF. In conclusion, exposure of pregnant mice to CPF caused increased gestation length, and postimplantation loss, decreased litter size and weight, survivability and anogenital distance.
Toxicological Sciences, 2011
Perfluorooctane sulfonate (PFOS) and 2,2#,4,4#-tetrabromodiphenyl ether (BDE-47) are two persistent environmental contaminants that are toxic to developing nervous systems, particularly via their disruption of thyroid hormone (TH) function. To investigate whether an interaction existed between PFOS and BDE-47 on TH-mediated pathways, adult female Wistar rats were exposed to 3.2 and 32 mg/kg of PFOS or BDE-47 in their diet and co-exposed to a combination of each chemical (3.2 mg/kg) from gestational day 1 to postnatal day (PND) 14. Serum and brain tissues from both male and female neonates were collected on PNDs 1, 7, and 14 to examine TH-regulated gene and protein expression. The results revealed that (1) a significant accumulation difference occurred between the two chemicals; (2) On a equimolar basis, BDE-47 and PFOS affected serum total triiodothyronine and total thyroxine differently in adults and offspring; (3) there were region-specific and exposure-and timedependent alterations in TH concentrations and tested gene and protein expression levels; and (4) interaction for the combined chemicals was only observed for brain-derived neurotrophic factor (BDNF), which exhibited a synergistic effect on PND 1 in the cortex and an antagonistic effect on PND 14 in the hippocampus. Our results suggest a complex TH-mediated gene and protein response to BDE-47 and/or PFOS exposure that seems little related to TH homeostasis and that little combined interaction of co-exposures was observed except on BDNF. The underlying mechanisms remain uncertain but seem to involve more actions than just TH-regulated pathway.