Do environmental and occupational exposure to pyrethroids and organophosphates affect human semen parameters? Results of a systematic review and meta-analysis

Our purpose was to review and analyse the impact of pyrethroids and organophosphates exposure on human semen parameters. A comprehensive literature search was performed through MEDLINE via PubMed, Scopus and Webscience. Only cohort studies examining semen parameters in workers or general populations exposed to pyrethroids or organophosphates were included. Ejaculate volume, sperm count, concentration, motility, viability, normal morphology and seminal pH alterations were pooled using the Cochran–Mantel–Haenszel Method with the random effect model and expressed as weighted mean difference, risk ratios, 95% confidence intervals and p-values. Seven cross-sectional studies regarding pyrethroids were included. Four of them were eligible for meta-analysis. The only parameter affected by pyrethroid exposure was normal sperm morphology (WMD-7,61%, 95%CI –11,92 to −3,30;p = 0,0,005). Nine studies were selected to evaluate the impact of organophosphates on semen parameters with six of them eligible for meta-analysis. A significant reduction was detected for the following: ejaculate volume (WMD −0,47ml, 95%CI −0,69 to −0,25; p < 0,0001), sperm count (WMD-40,03, 95%CI −66,81 to −13,25;p = 0,003), concentration (WMD-13,69 x10⁶/mL, 95%CI −23, 27 to-4,12;p = 0,005) and motility (WMD −5,70%, 95%CI −12,89 to 1,50;p = 0,12). Despite the increase in sperm abnormality, it has been shown that pyrethroids are unrelated to reduced sperm quality. However, the negative association of organophosphates with spermatogenesis is noteworthy.     

In silico and in vitro evaluation of two novel oximes (K378 and K727) in comparison to K-27 and pralidoxime against paraoxon-ethyl intoxication

Organophosphate (OP) poisoning is a major global health issue; while compounds from this group have been used intensively over the last century, an effective antidote is still lacking. Oxime-type acetylcholinesterase (AChE) reactivators are used to reactivate the OP inhibited AChE. Pralidoxime is the only US Food and Drug Administration approved oxime for therapeutic use but its efficacy has been disappointing. Two novel oximes (K378 and K727) were investigated in silico and in vitro and compared with an experimental oxime (kamiloxime; K-27) and pralidoxime. In silico the molecular interactions between AChE and oximes were examined and binding energies were assessed. LogP (predicted log of the octanol/water partition coefficient) was estimated. In vitro the intrinsic ability of the oximes to inhibit AChE (IC₅₀) and their reactivation potency (R₅₀) when used in paraoxon inhibited human RBC-AChE was determined. Molecular docking revealed that K378 and K727 bind to the peripheral site(s) with high binding energies in contrast to the central binding of K-27 and pralidoxime. LogP values indicating that the novel compounds are significantly less hydrophilic than K-27 or pralidoxime. IC₅₀ of K378 and K727 were comparable (0.9 and 1?µM, respectively) but orders of magnitude lower than comparators. R₅₀ values revealed their inability to reactivate paraoxon inhibited AChE. It is concluded that the novel oximes K378 and K727 are unlikely to be clinically useful. The in silico and in vitro studies described allow avoidance of unnecessary in vivo animal work and contribute to the reduction of laboratory animal use.     

The effects of organophosphate pesticide exposure on Hispanic children's cognitive and behavioral functioning

OBJECTIVE: This study investigates the effects of Organophosphate (OP) pesticides exposure on the cognitive and behavioral functioning of Hispanic children living in an agricultural community. METHODS: Forty-eight children were administered a battery of cognitive measures, and their parents and teachers completed behavior rating scales. Children provided a urine sample for analysis of OP pesticides metabolites. RESULTS: All children had a detectable level of at least one OP pesticide metabolite. Higher OP pesticide metabolite concentration levels were significantly correlated with poorer performance on some subtests of the Wisconsin Card Sorting Test. However, the significance of this association was dependent upon the inclusion of two samples with noticeable higher OP pesticide metabolite concentration levels. CONCLUSIONS: Short-term OP pesticide exposure seems to have deleterious effects on children's speed of attention, sequencing, mental flexibility, visual search, concept formation, and conceptual flexibility. This study is among a relatively small number of studies investigating an extremely complex problem. Limitations and suggestions for future studies are discussed.     

不同有机磷杀虫剂中毒家兔血胆汁游离毒质的分布

目的　探讨不同有机磷杀虫剂 (OP)在中毒家兔血浆、胆汁分布的过程及意义。方法　72只青紫蓝家兔分为 3组。敌百虫 (5 5 6 0mg/kg)、久效磷 (11 12mg/kg)、甲基对硫磷 (3 7 0 5mg/kg)。每组 2 4只。家兔中毒经皮下给药。中毒后 1、6、2 4、96h取血和胆汁 ,分离血细胞和血浆。用DTNB酶动力学法测乙酰胆碱酯酶 (AChE)活力 ,酶抑制法测游离有机磷毒质 (FOP)含量。结果　中毒后 1～ 96h ,血浆中FOP浓度与时间呈负相关 (敌百虫、久效磷、甲基对硫磷 ,r分别为 - 0 74,- 0 5 5 ,- 0 69,P值均 <0 0 1)。胆汁中敌百虫、久效磷FOP浓度与时间呈负相关 (敌百虫、久效磷r分别为 - 0 97,- 0 71,P值均 <0 0 1) ;甲基对硫磷无直线相关 (r=- 0 14,P >0 0 5 )。中毒后 96h ,血浆中无FOP残留时 ,胆汁中仍有高浓度的FOP ,敌百虫、久效磷、甲基对硫磷分别为 (3 0 0 3± 174 44、3 62 8± 13 6 62、10 1 0± 75 85 )IU/L。结论　胆囊中的胆汁是OP中毒动物FOP最重要的贮存库 ,FOP在胆汁中可存留96h以上 ;FOP在血、胆汁中的动态分布因理化性质不同而存在差异     

Lateral parabrachial lesions disrupt paraoxon-induced conditioned flavor avoidance.

Preliminary clinical evidence obtained in Gulf War veterans and patients suffering multiple chemical sensitivity points to the existence of a potential link between environmental exposure to organosphosphates (OPs) and the emergence of unspecific sickness syndromes in which associative Pavlovian conditioning might be partly involved. A laboratory animal model might be a useful tool for analyzing the involvement of conditioning in sickness syndromes potentially linked to OP poisoning. The first objective in the present study was to determine if paraoxon (PX), the neuroactive metabolite of the OP parathion, elicits a conditioned avoidance response to a novel stimulus (a taste-odor compound) in a conditioned flavor aversion procedure. Data obtained in Experiment 1 show conditioned flavor avoidance, demonstrative of the associative nature of the sickness properties of PX. The second objective was to characterize the nature of the specific physiological cue serving as the unconditioned stimulus in PX-induced conditioned avoidance. Despite PX administration did induce cholinergic hyperactivity, as measured by body hypothermia and increased jaw movements, lesions of the lateral parabrachial area (lPB) disrupted PX-elicited flavor avoidance responses, indicating that cholinergic signs were not sufficient as unconditioned stimuli supporting avoidance responses. Given that lPB neural integrity is necessary to process aversive interoceptive information, disruption of conditioned flavor avoidance as a result of lPB lesions is consistent with a central interruption of interoceptive processing in PX-poisoned animals. Data are discussed under the light of the hypothesis claiming the importance of associative processes and noncholinesterase targets in sickness syndromes potentially induced by OP exposure.     

An epidemiological study of the relations between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy and neuropsychological abnormalities in sheep farmers and dippers

OBJECTIVES—To investigate the hypothesis that chronic low level exposure to organophosphates (OPs) in sheep dips is related to clinically detectable measures of polyneuropathy.
METHODS—The design was a cross sectional exposure-response study of sheep dippers and other non-exposed groups. The study group consisted of 612 sheep dipping farmers, 53 farmers with no sheep dipping experience, and 107 ceramics workers. Retrospective exposure information was obtained by questionnaire based on stable and easily identifiable features of sheep dipping found during the first phase of the study; in particular, estimates of handling concentrate and splashing with dilute dip. Neurological assessments were based on a standard neuropathy symptoms questionnaire, and thermal and vibration quantitative sensory tests.
RESULTS—Adjusted for confounders there was a weak positive association between cumulative exposure to OPs and neurological symptoms, the significance of which was dependent on the inclusion of a few individual workers with extremely high exposure. There was no evidence of an association between cumulative exposure and the thermal or vibration sensory thresholds. However, separating the effects of exposure intensity and duration showed a higher prevalence of symptoms, primarily of a sensory type, among sheep dippers who handled the OP concentrate. There was also evidence that sensory and vibration thresholds were higher among concentrate handlers, the highest exposed group of dippers.
CONCLUSIONS—The findings showed a strong association between exposure to OP concentrate and neurological symptoms, but a less consistent association with sensory thresholds. There was only weak evidence of a chronic effect of low dose cumulative exposure to OPs. It is suggested that long term health effects may occur in at least some sheep dippers exposed to OPs over a working life, although the mechanisms are unclear.


Keywords: organophosphates; sheep dippers; neuropathy     

Endocrine effects of organophosphate antidotal therapy

To determine the endocrine effects of the treatment of organophosphate poisoning, this prospective study was conducted in a university-based emergency department among patients with a history and clinical findings compatible with those of organophosphate poisoning. Thyrotrophin (TSH), free triiodothyronine (FT3), free thyroxine (FT4), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), progesterone (PRG), adrenocorticotropic hormone (ACTH), cortisol, and testosterone (TST) levels were analyzed before and after treatment with atropine and pralidoxime. The Wilcoxon’s sign rank sum (nonparametric) test was used to compare dependent variables before and after treatment. A total of 44 patients (19 male; mean age: 28.5±12.6 y) were enrolled in the study. Patients were hospitalized for 5.4±1.3 days. Posttreatment ACTH, cortisol, PRL, FT3, FSH, and PRG levels were significantly lower than pretreatment levels (P<.05). The decrease in TSH, LH, and TST levels did not reach statistical significance, while FT4 levels increased following the treatment (P<.05). Six patients were diagnosed on admission with sick euthyroid syndrome, and 11 patients who were euthyroid on admission developed sick euthyroid syndrome following treatment. ACTH, cortisol, PRL, FT3, FT4, FSH, and PRG levels are affected by acute organophosphate poisoning. The change in hormone levels may result from the effects of neurotransmitters, from the direct effect of the toxic agent, or from stress associated with events leading to the poisoning incident.     

Polyethylene glycosylation prolongs the stability of recombinant human paraoxonase-1

Paraoxonase-1 (PON1) is a native enzyme that is synthesized in the liver and is capable of hydrolyzing organophosphates (OPs). It is regarded as part of a promising approach for the pretreatment and therapy of OP poisoning. Previous experiments with purified rabbit serum PON1 have established that it can protect rats against many OP exposures. In the current paper, we described a preparation of active recombinant human PON1 (rHuPON1) by engineering an Escherichia coli expression system. Recombinant HuPON1 was purified by Ni-NTA affinity chromatography followed by DEAE sepharose fast-flow chromatography. After purification, rHuPON1 was chemically modified with polyethyleneglycol (PEG)-20K. Recombinant HuPON1 exhibited a mean residence time (MRT) of 8.9h, which was threefold shorter than that of native HuPON1 in rats. However, rHuPON1 chemically modified with PEG-20K displayed an MRT of 19.5h, suggesting that PEG modification can prolong the circulatory stability of rHuPON1. PEG-rHuPON1 had a catalytic efficiency sufficient in protecting rats against OP poisoning, as measured by acetylcholinesterase activity in tissues and signs after poisoning.     

19种有机磷农药对酵母D61.M菌株的诱变性

本文利用检测染色体丢失的酵母D61.M菌株对19种有机磷农药进行诱变性研究，并与本室过去利用其他两种诱变试验结果进行对比分析. 结果表明D61.M的检出率为89.5%(17/19)，即提示大多数有机磷农药可诱发非整倍体. 17种呈阳性的有机磷农药中有14种也能在体外微核试验中检出，它们可能单独引起非整倍体或兼能引起染色体断裂. 仅两种有机磷农药(乙硫磷，乙拌磷)单独在微核试验中检出而被D61.M漏检，提示只有少数有机磷农药单独具有断裂作用. 经进一步比较体内，体外微核试验及对甲基，乙基和其他有机磷农药的测试结果，提示D61.M对脱甲基以及“脱芳基”的能力最差.