Hypospadias in offspring is associated with chronic exposure of parents to organophosphate and organochlorine pesticides

Michalakis, Michalis; Tzatzarakis, Manolis; Kovatsi, Leda; Alegakis, Athanasios; Tsakalof, Andreas; Heretis, Ioannis; Tsatsakis, Aristidis

doi:10.1016/j.toxlet.2013.10.015

Cited by 61 publications

(33 citation statements)

References 41 publications

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“…It should be stressed that this CA category, apart from being more frequently investigated, it is also the only one extensively explored using biomarkers. This method of exposure assessment, as stated above, is the most reliable since it measures pesticides or metabolites directly in tissues/secretions such as maternal serum (Carmichael et al, 2010; Fernandez et al., 2007; Giordano et al, 2010; Longnecker et al, 2002; Pierik et al, 2007), breast milk (Brucker-Davis et al, 2008; Damgaard et al, 2006), hair (Michalakis et al, 2014), urine (Chevrier et al, 2011), cord blood (Brucker-Davis et al, 2008), and placenta (Fernandez et al, 2007). …”

Section: Urogenital Abnormalitiesmentioning

confidence: 99%

“…Studies assessing individual-level exposure using pesticide bio-markers (Bhatia et al, 2005; Brucker-Davis et al, 2008; Carmichael et al, 2010; Chevrier et al, 2011; Damgaard et al, 2006; Fernandez et al, 2007; Giordano et al, 2010; Longnecker et al, 2002; Michalakis et al, 2014; Pierik et al, 2007; Trabert et al, 2012) yielded conflicting results (Table 6). Most of them failed to detect an association (Bhatia et al., 2005; Brucker-Davis et al, 2008; Carmichael et al, 2010; Chevrier et al, 2011; Longnecker et al, 2002; Pierik et al, 2007; Toft et al, 2016; Trabert et al, 2012) while some of them directly linked UGAs risk with DDE and/or DDT (Bhatia et al, 2005; Brucker-Davis et al, 2008; Longnecker et al, 2002).…”

Section: Urogenital Abnormalitiesmentioning

confidence: 99%

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Association of pesticide exposure with human congenital abnormalities

Kalliora

Mamoulakis

Vasilopoulos

et al. 2018

Toxicology and Applied Pharmacology

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102

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Human pesticide exposure can occur both occupationally and environmentally during manufacture and after the application of indoor and outdoor pesticides, as well as through consumption via residues in food and water. There is evidence from experimental studies that numerous pesticides, either in isolation or in combination, act as endocrine disruptors, neurodevelopmental toxicants, immunotoxicants, and carcinogens. We reviewed the international literature on this subject for the years between 1990 and 2017. The studies were considered in this review through MEDLINE and WHO resources. Out of the n = 1817 studies identified, n = 94 were reviewed because they fulfilled criteria of validity and addressed associations of interest. Epidemiological studies have provided limited evidence linking pre- and post-natal exposure to pesticides with cancers in childhood, neurological deficits, fetal death, intrauterine growth restriction, preterm birth, and congenital abnormalities (CAs). In this review, the potential association between pesticide exposure and the appearance of some human CAs (including among others musculoskeletal abnormalities; neural tube defects; urogenital and cardiovascular abnormalities) was investigated. A trend towards a positive association between environmental or occupational exposure to some pesticides and some CAs was detected, but this association remains to be substantiated. Main limitations of the review include inadequate exposure assessment and limited sample size. Adequately powered studies with precise exposure assessments such as biomonitoring, are warranted to clarify with certainty the potential association between pesticide exposure and human CAs.

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Section: Urogenital Abnormalitiesmentioning

confidence: 99%

Section: Urogenital Abnormalitiesmentioning

confidence: 99%

Association of pesticide exposure with human congenital abnormalities

Kalliora

Mamoulakis

Vasilopoulos

et al. 2018

Toxicology and Applied Pharmacology

Self Cite

102

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“…To contemplate the above, hsp27 overexpression would eventually have ameliorative effect towards neuronal health by buffering the free radical generation against prolonged exposure of organisms to xenobiotics. Further, reports on free radical generation and oxidative stress-mediated adversities in humans after exposure to pesticides [62][63][64] constitute the relevance of the study towards human health. Considering the above, it is evident that hsp27 overexpression in flies that were exposed to DDVP for a prolonged period could rescue neuronal cell death (by increasing G6PD activity and GSH level and subsequently decreasing intracellular ROS level and oxidative stress) and improve life-and health-span of exposed Drosophila (Fig.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of hsp27 Rescued Neuronal Cell Death and Reduction in Life- and Health-Span in Drosophila melanogaster Against Prolonged Exposure to Dichlorvos

et al. 2015

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Long-term exposure to dichlorvos (O,O-dimethyl-2,2-dichlorovinyl phosphate (DDVP), an organophosphate pesticide) is reported to exert neurotoxicity, i.e., generation of reactive oxygen species (ROS), oxidative damage, and neuronal cell death along with life- and health-span reduction in nontarget organisms including humans. However, studies on genetic modulation towards neuroprotection against prolonged DDVP exposure are elusive. Hsp27 (a small heat shock protein) is involved in various cellular processes and thus has attained emphasis as a therapeutic target. We aimed to examine the protective effect of hsp27 overexpression against prolonged DDVP exposure using an in vivo model Drosophila melanogaster. Flies were exposed to 15.0 ng/ml DDVP for a prolonged period to examine neuronal cell death, locomotor performance, and lifespan. After prolonged exposure, cell death, ROS level, glutathione depletion, nicotinamide adenine dinucleotide phosphate level (NADPH), glucose-6-phosphate dehydrogenase (G6PD), and thioredoxin reductase (TrxR) activities were examined in fly brain tissues at different days of age (days 10, 20, and 30). Flies with ubiquitous overexpression of hsp27 showed better resistance (improved lifespan and locomotor performance) in comparison to that targeted to motor neurons and nervous system. These flies also exhibited lesser intracellular ROS level and glutathione depletion by restoring G6PD activity, NADPH level, and TrxR activity in their brains thereby resisted neuronal cell death. Conversely, hsp27 knockdown flies exhibited reversal of the above endpoints. The study evidenced the neuroprotective efficacy of hsp27 overexpression against prolonged DDVP exposure and favored Hsp27 as a therapeutic target towards achieving better organismal (including human) health against long-term chemical exposure.

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“…Although most instances of hypospadias are idiopathic (Van der Zanden et al, 2012), molecular genetic analyses of affected individuals have revealed nucleotide variants (TannourLouet et al, 2010(TannourLouet et al, , 2014Geller et al, 2014), epigenetic anomalies (Vottero et al, 2011), protein modifications (Qiao et al, 2011), and mutations in known developmental genes (Beleza-Meireles et al, 2007;Carmichael et al, 2013). The results of genetic, toxicological, and epidemiological studies have led to the proposal that urethral tube defects are caused by the combinatorial effects of aberrant hormone activity, such as that caused by exposure to environmental endocrine-disrupting compounds (Michalakis et al, 2014;Winston et al, 2014), and underlying genetic susceptibility (Wang and Baskin, 2008;Kalfa et al, 2009Kalfa et al, , 2011Toppari et al, 2010;Yiee and Baskin, 2010;Van der Zanden et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Tissue-specific roles of Fgfr2 in development of the external genitalia

2015

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Congenital anomalies frequently occur in organs that undergo tubulogenesis. Hypospadias is a urethral tube defect defined by mislocalized, oversized, or multiple openings of the penile urethra. Deletion of Fgfr2 or its ligand Fgf10 results in severe hypospadias in mice, in which the entire urethral plate is open along the ventral side of the penis. In the genital tubercle, the embryonic precursor of the penis and clitoris, Fgfr2 is expressed in two epithelial populations: the endodermally derived urethral epithelium and the ectodermally derived surface epithelium. Here, we investigate the tissue-specific roles of Fgfr2 in external genital development by generating conditional deletions of Fgfr2 in each of these cell types. Conditional deletion of Fgfr2 results in two distinct phenotypes: endodermal Fgfr2 deletion causes mild hypospadias and inhibits maturation of a complex urethral epithelium, whereas loss of ectodermal Fgfr2 results in severe hypospadias and absence of the ventral prepuce. Although these cell type-specific mutants exhibit distinctive genital anomalies, cellular analysis reveals that Fgfr2 regulates epithelial maturation and cell cycle progression in the urethral endoderm and in the surface ectoderm. The unexpected finding that ectodermal deletion of Fgfr2 results in the most severe hypospadias highlights a major role for Fgfr2 in the developing genital surface epithelium, where epithelial maturation is required for maintenance of a closed urethral tube. These results demonstrate that urethral tubulogenesis, prepuce morphogenesis, and sexually dimorphic patterning of the lower urethra are controlled by discrete regions of Fgfr2 activity.

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Hypospadias in offspring is associated with chronic exposure of parents to organophosphate and organochlorine pesticides

Cited by 61 publications

References 41 publications

Association of pesticide exposure with human congenital abnormalities

Association of pesticide exposure with human congenital abnormalities

Overexpression of hsp27 Rescued Neuronal Cell Death and Reduction in Life- and Health-Span in Drosophila melanogaster Against Prolonged Exposure to Dichlorvos

Tissue-specific roles of Fgfr2 in development of the external genitalia

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