Species-Specific Dibutyl Phthalate Fetal Testis Endocrine Disruption Correlates with Inhibition of SREBP2-Dependent Gene Expression Pathways

Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware 19803, USA.
Toxicological Sciences (Impact Factor: 3.85). 03/2011; 120(2):460-74. DOI: 10.1093/toxsci/kfr020
Source: PubMed


Fetal rat phthalate exposure produces a spectrum of male reproductive tract malformations downstream of reduced Leydig cell testosterone production, but the molecular mechanism of phthalate perturbation of Leydig cell function is not well understood. By bioinformatically examining fetal testis expression microarray data sets from susceptible (rat) and resistant (mouse) species after dibutyl phthalate (DBP) exposure, we identified decreased expression of several metabolic pathways in both species. However, lipid metabolism pathways transcriptionally regulated by sterol regulatory element-binding protein (SREBP) were inhibited in the rat but induced in the mouse, and this differential species response corresponded with repression of the steroidogenic pathway. In rats exposed to 100 or 500 mg/kg DBP from gestational days (GD) 16 to 20, a correlation was observed between GD20 testis steroidogenic inhibition and reductions of testis cholesterol synthesis endpoints including testis total cholesterol levels, Srebf2 gene expression, and cholesterol synthesis pathway gene expression. SREBP2 expression was detected in all fetal rat testis cells but was highest in Leydig cells. Quantification of SREBP2 immunostaining showed that 500 mg/kg DBP exposure significantly reduced SREBP2 expression in rat fetal Leydig cells but not in seminiferous cords. By Western analysis, total rat testis SREBP2 levels were not altered by DBP exposure. Together, these data suggest that phthalate-induced inhibition of fetal testis steroidogenesis is closely associated with reduced activity of several lipid metabolism pathways and SREBP2-dependent cholesterologenesis in Leydig cells.

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    • "Like many EDCs, also phthalate and their metabolites have been suggested to interfere with normal steroidogenesis, suppressing the expression of steroidogenic enzymes (Moody et al., 2013), disrupting the regulation of cholesterol and lipid homeostasis or insulin signaling (Barlow et al., 2003; Liu et al., 2005; Knez, 2013). Phthalate exposure reduces testis cholesterol and cholesterol-containing lipid droplets in rat FLCs (Barlow et al., 2003; Lehmann et al., 2004; Johnson et al., 2011, 2012). "
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    ABSTRACT: Endocrine disrupting chemicals (EDCs) are identified for their ability to perturb the homeostasis of endocrine system and hormonal balance. The male reproductive system is under close control of hormones and each change in their concentration and time of exposition and action can induce a deregulation of its physiology. In this review we summarize the most recent studies on two main categories of EDCs with different action: the estrogenic bisphenol A and alkylphenols and the anti-androgenic phthalates. This review describes the main effects of these substances on male reproductive system.
    02/2015; 3. DOI:10.3389/fenvs.2015.00003
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    • "Overall, the evidence indicates that steroidogenesis is aff ected by phthalate exposure although the cellular and molecular mechanisms remain uncertain. Studies have variously suggested a glucocorticoid-dependent mechanism, action through sterol-regulatory element-binding protein (SREBP2) or activation of peroxisome proliferator-activated receptor gamma (PPAR γ ; Gunnarsson et al. 2008, Johnson et al. 2011, Kobayashi et al. 2003, Xiao-feng et al. 2009). Studies examining gene expression after exposure to DBP recently identifi ed changes in the pathways responsible for cholesterol transport and metabolism as important (Liu et al. 2005, Plummer et al. 2007, Euling et al. 2013, Ovacik et al. 2013, Plummer et al. 2013). "
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    ABSTRACT: Phthalate diesters are a diverse group of chemicals used to make plastics flexible and are found in personal care products, medical equipment, and medication capsules. Ubiquitous in the environment, human exposure to phthalates is unavoidable; however, the clinical relevance of low concentrations in human tissues remains uncertain. The epidemiological literature was inadequate for prior reviews to conclusively evaluate the effects of phthalates on male reproductive tract development and function, but recent studies have expanded the literature. Therefore, we conducted a systematic review of the literature focused on the effects of phthalate exposure on the developing male reproductive tract, puberty, semen quality, fertility, and reproductive hormones. We conclude that although the epidemiological evidence for an association between phthalate exposure and most adverse outcomes in the reproductive system, at concentrations to which general human populations are exposed, is minimal to weak, the evidence for effects on semen quality is moderate. Results of animal studies reveal that, although DEHP was the most potent, different phthalates have similar effects and can adversely affect development of the male reproductive tract with semen quality being the most sensitive outcome. We also note that developmental exposure in humans was within an order of magnitude of the adverse effects documented in several animal studies. While the mechanisms underlying phthalate toxicity remain unclear, the animal literature suggests that mice are less sensitive than rats and potentially more relevant to estimating effects in humans. Potential for chemical interactions and effects across generations highlights the need for continued study.
    Critical Reviews in Toxicology 07/2014; 44(6):467-498. DOI:10.3109/10408444.2013.875983 · 5.10 Impact Factor
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    • "Evidence suggests that DBP is toxic throughout all phases of development.[815] DBP and its metabolites inhibit the synthesis of testosterone through the inhibition of cholesterol transport, and the synthesis of gene products related to testosterone synthesis.[1216] "
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    ABSTRACT: This study aimed to observe the possible protective effects of resveratrol (RSV) against damage induced by di-n-butylphthalate (DBP), on the ductus epididymis and deferens in rats. SIX GROUPS OF RATS WERE USED IN THE EXPERIMENT: Group 1: Control group; Group 2: Solvent (carboxymethylcellulose (CMC), 10ml/kg); Group 3: 500 mg/kg/day DBP; Group 4: 500 mg/kg/day DBP+20 mg/kg/day RSV; Group 5: 1000 mg/kg/day DBP; Group 6: 1000mg/kg/day DBP + 20 mg/kg/day RSV. Groups were treated by gavage for 30 days. Immunohistochemical, electronmicroscopic and histomorphometric examinations were carried out in the epididymis and deferens. In the ductus epididymis and deferens mitochondrial crystolysis, exfoliation of the stereocilia and openings in lateral surface increased with DBP dosage, but these structures were recovered with RSV. DBP reduced the epithelial height of epididymis and vas deferens. Lumen dilatation was observed in both tissues. These disorders may lead to dysfunction of epithelial absorption. In the TUNEL examinations in both tissues, there were no apoptotic cells or apoptotic bodies. In conclusion, DBP administration caused structural degeneration in the epididymis and deferens, parallel to dose evaluation and RSV can reverse these changes with its protective effects.
    Indian Journal of Pharmacology 03/2014; 46(1):51-6. DOI:10.4103/0253-7613.125167 · 0.69 Impact Factor
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