The teratogenicity and behavioral teratogenicity of di(2-ethylhexyl) phthalate (DEHP) and di-butyl Phthalate (DBP) in a chick model

Phthalates are industrial chemicals widely used in consumer products, plastics and children toys, and the risk of exposure to phthalates, especially prenatal exposure, is a growing concern justifying the development of an animal model to better understand their effect. The present study was designed to evaluate the suitability of a chick model for phthalate DEHP teratogenicity and neurobehavioral teratogenicity, a model which is simple and devoid of potential confounding factors such as maternal toxicity, maternal-fetal unit and maternalneonatal interactions; major findings were confirmed in the DBP study. Prehatch exposure to DEHP in doses ranging from 20 to 100 mg/kg, reduced the percent hatching from 80% in control eggs to 65%, and increased late hatchings from 12.5% in control eggs to 29.4%. In addition it induced developmental defects characterized by an opening or weakening of abdominal muscles allowing internal organs to protrude externally with or without a sac, omphalocele or gastroschisis, respectively. The effect was dose dependent ranging from 8% with DEHP (20 mg/kg) to 22% (100 mg/kg). Similar treatment with DBP 100 mg/kg has reduced percentage hatching to 57% and increased late hatching to 37.5%, with a 14% increase in gastroschisis. Biochemical evaluation revealed elevated levels of alkaline phosphatase, which reflects non-specific toxicity of DEHP at such a high dose. Behavioral evaluation using an imprinting test and locomotor activity on chicks pretreated with DEHP (100 mg/kg) has shown an abolishment of imprinting performance from the control (0.65) preference ratio. DNA damage measurements of the metabolite 8-hydroxydeoxyguanosine (8-OH-dG) in blood samples showed an increase of 39.7% after prehatch exposure to phthalates. This was statistically significant for DEHP and indicates genetic toxicity, since part of the teratogenic activity is associated with oxidative stress and DNA damage.This study was supported by a grant from the Al-Quds Nutrition & Health Research Institute. The authors would like to thank Mr. Rateb Hussein and Mr. Munther Metani for their technical assistance, and Dr. Tamer Essawi and Mr. Firas Hassan for their help in performing the biochemical measurements

C. elegans—An Emerging Model to Study Metal-Induced RAGE-Related Pathologies

The receptor for advanced glycation end products (RAGE), a multi-ligand receptor, is mostly associated with promoting inflammation and oxidative stress. In addition to advanced glycation end products (AGEs), its ligands include High mobility group box 1 protein (HMGB-1), S-100 proteins and beta-sheet fibrils. The effects of several metals and metalloids on RAGE expression and activation have been recently studied: in vivo and in vitro exposure to methylmercury, selenium, zinc, manganese, and arsenic was associated with a variety of RAGE-related alterations and behavioral impairments, which are mostly dependent upon the administration procedure (local vs. systemic) and age during exposure. Recently, C. elegans has been proposed as a potential novel model for studying RAGE-related pathologies; preliminary data regarding such model and its potential contribution to the study of metal-induced RAGE-related pathologies are discussed

C. elegans—An Emerging Model to Study Metal-Induced RAGE-Related Pathologies

The receptor for advanced glycation end products (RAGE), a multi-ligand receptor, is mostly associated with promoting inflammation and oxidative stress. In addition to advanced glycation end products (AGEs), its ligands include High mobility group box 1 protein (HMGB-1), S-100 proteins and beta-sheet fibrils. The effects of several metals and metalloids on RAGE expression and activation have been recently studied: in vivo and in vitro exposure to methylmercury, selenium, zinc, manganese, and arsenic was associated with a variety of RAGE-related alterations and behavioral impairments, which are mostly dependent upon the administration procedure (local vs. systemic) and age during exposure. Recently, C. elegans has been proposed as a potential novel model for studying RAGE-related pathologies; preliminary data regarding such model and its potential contribution to the study of metal-induced RAGE-related pathologies are discussed

Neurotoxic effect of active ingredients in sunscreen products, a contemporary review

Sunscreen application is the main strategy used to prevent the maladies inflicted by ultraviolet (UV) radiation. Despite the continuously increasing frequency of sunscreen use worldwide, the prevalence of certain sun exposure-related pathologies, mainly malignant melanoma, is also on the rise. In the past century, a variety of protective agents against UV exposure have been developed. Physical filters scatter and reflect UV rays and chemical filters absorb those rays. Alongside the evidence for increasing levels of these agents in the environment, which leads to indirect exposure of wildlife and humans, recent studies suggest a toxicological nature for some of these agents. Reviews on the role of these agents in developmental and endocrine impairments (both pathology and related mechanisms) are based on both animal and human studies, yet information regarding the potential neurotoxicity of these agents is scant. In this review, data regarding the neurotoxicity of several organic filters: octyl methoxycinnamate, benzophenone-3 and â4, 4-methylbenzylidene camphor, 3-benzylidene camphor and octocrylene, and two allowed inorganic filters: zinc oxide and titanium dioxide, is presented and discussed. Taken together, this review advocates revisiting the current safety and regulation of specific sunscreens and investing in alternative UV protection technologies. Keywords: Neurotoxicity, Sunscreen, Zinc oxide, Titanium dioxide, Octyl methoxycinnamate, Benzophenone-3, 4-Methylbenzylidene camphor, Octocrylen

Neurobehavioral teratogenicity of perfluorinated alkyls in an avian model

Perfluorinated alkyls are widely-used agents that accumulate in ecosystems and organisms because of their slow rate of degradation. There is increasing concern that these agents may be developmental neurotoxicants and the present study was designed to develop an avian model for the neurobehavioral teratogenicity of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Fertilized chicken eggs were injected with 5 or 10 mg/kg of either compound on incubation day 0. On the day of hatching, imprinting behavior was impaired by both compounds. We then explored underlying mechanisms involving the targeting of protein kinase C (PKC) isoforms (α, β, γ) in the intermedial part of the hyperstriatum ventrale, the region most closely associated with imprinting. With PFOA exposure, cytosolic PKC concentrations were significantly elevated for all three isoforms; despite the overall increase in PKC expression, membrane-associated PKC was unaffected, indicating a defect in PKC translocation. In contrast, PFOS exposure evoked a significant decrease in cytosolic PKC, primarily for the β and γ isoforms, but again without a corresponding change in membrane-associated enzyme; this likely partial, compensatory increases in translocation to offset the net PKC deficiency. Our studies indicate that perfluorinated alkyls are indeed developmental neurotoxicants that affect posthatch cognitive performance but that the underlying synaptic mechanisms may differ substantially among the various members of this class of compounds, setting the stage for disparate outcomes later in life.

Neurobehavioral teratogenicity of sarin in an avian model

Nerve gas organophosphates like sarin are likely to be used in urban terrorism, leading to widespread exposures of pregnant women and young children. Here, we established a model for sarin neurobehavioral teratogenicity in the developing chick so as to explore the consequences of apparently subtoxic sarin exposure and the mechanisms underlying synaptic and behavioral deficits. Chicken eggs were injected with sarin (2, 6 and 12 μg/kg) on incubation days 2 and 6, treatments that did not decrease hatching and did not evoke dysmorphology. After hatching the chicks were tested for filial imprinting and neurochemical markers known to be critical for imprinting. Imprinting was reduced at 2 and 6 μg/kg but not at the highest dose. Acetylcholinesterase and choline acetyltransferase were unaffected but sarin reduced the concentration of the high-affinity choline transporter, the rate-limiting factor in acetylcholine utilization. The concentration of PKC isoforms was assessed in the imprinting-related intermediate part of the medial hyperstriatum ventrale, the region most closely associated with cholinergic function in imprinting behavior. Sarin reduced the concentration of all isoforms (α, β, γ) with a similar, biphasic dose–response curve to that seen for behavioral performance, a relationship noted in previous work with organophosphate pesticides. Our results indicate that otherwise subtoxic exposures to sarin produce neurodevelopmental deficits; since we utilized a chick model, which is devoid of maternal confounds that are present in mammalian development, the adverse effects of sarin are mediated directly in the developing organism.