Comparative Developmental Neurotoxicity of Organophosphate Insecticides: Effects on Brain Development Are Separable from Systemic Toxicity

Abstract

A comparative approach to the differences between systemic toxicity and developmental neurotoxicity of organophosphates is critical to determine the degree to which multiple mechanisms of toxicity carry across different members of this class of insecticides. We contrasted neuritic outgrowth and cholinergic synaptic development in neonatal rats given different organophosphates (chlorpyrifos, diazinon, parathion) at doses spanning the threshold for impaired growth and viability. Animals were treated daily on postnatal days 1–4 by subcutaneous injection so as to bypass differences in first-pass activation to the oxon or catabolism to inactive products. Evaluations occurred on day 5. Parathion (maximum tolerated dose, 0.1 mg/kg) was far more systemically toxic than was chlorpyrifos or diazinon (maximum tolerated dose, 1–5 mg/kg). Below the maximum tolerated dose, diazinon impaired neuritic outgrowth in the forebrain and brainstem, evidenced by a deficit in the ratio of membrane protein to total protein. Diazinon also decreased choline acetyltransferase activity, a cholinergic neuronal marker, whereas it did not affect hemicholinium-3 binding to the presynaptic choline transporter, an index of cholinergic neuronal activity. There was no m2-muscarinic acetylcholine receptor down-regulation, as would have occurred with chronic cholinergic hyper-stimulation. The same pattern was found previously for chlorpyrifos. In contrast, parathion did not elicit any of these changes at its maximum tolerated dose. These results indicate a complete dichotomy between the systemic toxicity of organophosphates and their propensity to elicit developmental neurotoxicity. For parathion, the threshold for lethality lies below that necessary for adverse effects on brain development, whereas the opposite is true for chlorpyrifos and diazinon.

Comparative developmental neurotoxicity of organophosphates in vivo: Transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems

“…CPF and DZN (both from Chem Service, West Chester, PA) were dissolved in dimethylsulfoxide to provide consistent absorption [109] and were injected subcutaneously in a volume of 1 ml/kg once daily on postnatal days 1-4; control animals received equivalent injections of the dimethylsulfoxide vehicle. For both agents, we utilized doses below the threshold for growth retardation and systemic toxicity [16,91,109]: 1 mg/kg for CPF and 1 or 2 mg/kg for DZN. This CPF treatment and the higher dose of DZN produce neurotoxicity in developing rat brain while eliciting less than 20% cholinesterase inhibition, well below the 70% threshold necessary for symptoms of cholinergic hyperstimulation [20], whereas the lower dose of DZN produces no measurable inhibition in male neonates [86,87,97,100,109].…”

“…Thus, in addition to being informative about the underlying disparities in the regional expression of various gene families in the developing brain, the correspondence of these patterns to known maturational and anatomic differences serves as a validation for the overall approach taken here. The regional dissimilarities also interact with the effects of CPF and DZN, likely contributing to the ultimate differences in the regional targeting of neurotransmitter systems by these two organophosphates [50,86,87,89,91,97].…”

“…Accordingly, whereas all the organophosphates share cholinesterase as a target, they are likely to differ to a greater or lesser extent in their effects unrelated to that particular mechanism. Indeed, chlorpyrifos (CPF), the best-studied agent, affects brain development through diverse targets such as oxidative stress, cell signaling cascades, expression and function of nuclear transcription factors, and neuronal-glial cell interactions [42,73,86,87,89], mechanisms that may be shared in varying degrees by other organophosphates [1,67,73,75,86,87,91,110].…”

“…We recently compared the thresholds for cholinesterase inhibition, systemic toxicity and several developmental neurotoxicity endpoints for CPF, diazinon (DZN) and parathion [50,91,97] and found distinct disparities in both the sensitivity of various pathways involved in cell differentiation as well as in outcomes related to abnormal brain development. These findings point to the need to screen the various organophosphates for similarities and differences in their targeting of the key pathways that contribute to their ultimate neurodevelopmental consequences.…”

Probabilistic assessment of chlorpyrifos exposure to rice farmers in Viet Nam

“…Low-level exposure to chlorpyrifos has caused adverse developmental effects in human pregnancies, such as low birth weight and reduced head circumference. 7,8 Chlorpyrifos is also considered to be an endocrine disrupting compound, 9 and some recent studies have shown an association between chlorpyrifos exposure and both lung and prostate cancer. 10,11 Exposure assessment using probabilistic techniques have been shown to be an effective tool in environmental health risk assessment, in which the exposure values are presented in cumulative probability distributions rather than the traditional single-point exposure estimate.…”