DEHP, bis(2)-ethylhexyl phthalate, alters gene expression in human cells: possible correlation with initiation of fetal developmental abnormalities

Abstract

<jats:p> Diethylhexylphthalate (DEHP) is a widely distributed phthalate, to which humans are exposed to due to its variety of commercial and manufacturing uses. As a plasticiser, it is found in a wide number of products, and metabolites of DEHP have been detected in urine samples from a high percentage ofthe peoplescreened for phthalates. We utilised DNA microarray analysis to evaluate DEHP for gene expression disrupting activity using the human cell line MCF-7, and found that DEHP significantly dysregulated approximately 34% of the 2400 genes spotted on the NEN2400 chip we used. The results suggest that DEHP, a known estrogen agonist and probable androgen antagonist, alters the expression of a number of genes, many of which are critical for fetal development. Down-regulation of two genes, FGD1 and PAFAH1B1, related in that both are essential for fetal brain development, was corroborated using quantitative real time PCR. These studies show DEHP to be a highly effective human gene expression-altering chemical, and that, at appropriate concentrations, it has the possibility of altering fetal central nervous system development, resulting in the birth defects lissencephaly and/or faciodigitogenital dysplasia. </jats:p>

The effects of phthalate and nonylphenol exposure on body size and secondary sexual characteristics during puberty

“…Several human studies have suggested that DEHP has estrogenic effect (Cobellis et al, 2003;Hokanson et al, 2006). PAEs have a weak estrogenic potency compared with estradiol and other estrogenic substances (Jobling et al, 1995).…”

“…Recent literatures have suggested that either PAE or NP promotes adipocyte differentiation and induces obesity in mice (Hao et al, 2012a,b); furthermore, these chemicals may have estrogenic effects (Hokanson et al, 2006;Olsen et al, 2005). Muller et al conducted a toxicokinetics study regarding NP exposure in human.…”

Plasma Phthalate Levels in Pubertal Gynecomastia

“…38 However, recent studies in humans indicate a possible estrogenic effect. 17,19,20 The first study demonstrating a possible estrogenic effect for DEHP was reported by Colon et al 19 in Puerto Rico. They have shown that DEHP levels in 45 girls with premature thelarche were statistically significantly higher compared with the 35 control girls.…”

“…16 Although DEHP is considered to be an estrogen agonist and a testosterone antagonist, its mechanisms of toxicity are still not well understood, but are thought to be a function of the disruption of endocrine-regulated gene expression by interaction with estrogen receptor ␣. 17 Although there are some in vivo studies that show no estrogenic effect, 18 several articles have been recently published in which the authors reported a possible estrogenic effect of DEHP in humans, such as a probable role in premature thelarche, 19 endometriosis, 20 and precocious puberty. 21 As far as we know there is no report in which the authors investigated the relationship between DEHP/MEHP levels and pubertal gynecomastia, which develops as a result of an imbalance between androgenic and estrogenic activity.…”

Advanced Molecular Biologic Techniques in Toxicologic Disease

“…DEHP also inhibits connexin (gap junction) conduction in cardiomyocytes to produce arrhythmias in vitro [29]. Finally, DEHP has been implicated in neurologic defects in exposed developing fetuses [30]. Using the CTD approach to determine the role DEHP may play in these pathophysiologic events, numerous proteins had projected interactions with DEHP, including gamma-amino butyric acid (GABA) A receptors.…”