Perinatal exposure to diethyl-hexyl-phthalate induces obesity in mice

Abstract

The environmental obesogen hypothesis proposes that exposure to endocrine disruptors during developmental "window" contributes to adipogenesis and the development of obesity. Implication of environmental endocrine disruptor such as diethyl-hexyl-phthalate (DEHP) on adipose tissue development has been poorly investigated. Here, we evaluated the effects of DEHP on adipocyte differentiation in vitro and in vivo, and explored potential mechanism involved in its action. DEHP had no effect on adipocyte differentiation in the murine 3T3-L1 cell model, whereas DEHP induced the expression of transcriptional factors peroxisome proliferator-activated receptor (PPAR) gamma, CCAAT/enhancer-binding protein (C/EBP) alpha and sterol regulatory element binding factor 1 (Srebf1) as well as downstream target genes required for adipogenesis in vivo. Furthermore, perinatal exposure to DEHP had an impact on filial adipogenesis. Body weight, adipose tissue deposition, serum lipids and glucose levels were significantly elevated in offspring at postnatal day (PND) 60. Therefore, these results suggested that perinatal exposure to DEHP might be expected to increase the incidence of obesity in offspring and could act as a potential chemical stressor for obesity and obesity-related disorders.

In utero exposure to di-(2-ethylhexyl) phthalate induces metabolic disorder and increases fat accumulation in visceral depots of C57BL/6J mice offspring

“…These results indicate that excessive visceral fat storage due to in utero exposure to DEHP may be associated with a high risk of developing metabolic disorders. The present results agreed in part with two previous studies, which demonstrated that direct exposure to DEHP, through placenta and milk, increased body weight and adipose storage in offspring (13,14). However, in contrast to the effects of DEHP on body weight and visceral fat tissue in the F1 offspring observed in the present study, previous studies have detected no effect (3) or reductions (30) in body weight and white adipose tissue, suggesting that developmental exposure to DEHP is unlikely to cause metabolic disorders in adulthood (3).…”

“…The presence of DEHP metabolites in urine is associated with adiposity and insulin resistance in children (12). Previous studies have reported that perinatal exposure to DEHP may induce obesity and metabolic disorders in mice (13,14); however, the mechanisms underlying these associations are yet to be investigated.…”

Prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP) affects reproductive outcomes in female mice

“…A study by Hao et al . observed an increase in body weight in adult life following perinatal exposure to DEHP, and proposed that this occurred through PPAR-mediated pathways [39]. Our data showed a contrasting effect, but this could be explained by the difference in timing of exposure, as well as doses used in our study versus those used by Hao et al [39].…”

Urinary phthalate metabolite concentrations and maternal weight during early pregnancy

“…Phthalates interfere with the endocrine system through different pathways such as by activating peroxisome proliferator-activated receptors (PPARs), which can up-regulate adipogenesis (Desvergne et al 2009). Animal and non-pregnant population studies have suggested a potential association between obesity and specific phthalate metabolites such as mono-ethyl phthalate (MEP), mono-benzyl phthalate (MBzP), monoethylhexyl- phthalate (MEHP), and mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP) (Hao et al 2012; Hao et al 2013; Hatch et al 2008; Stahluht et al 2007), but have provided inconsistent results, which could in part be due to differences in outcome assessments and inclusion of covariates (Thayer et al 2012; Tang-Péronard et al 2011). On the other hand, in pregnant populations, the evidence of an association between phthalate exposure and maternal obesity are limited to a single study (James-Todd et al 2016).…”

“…Epidemiological studies focusing on phthalate exposure and obesity have applied standard statistical methods to report shifts in the mean of BMI as a function of phthalate metabolite concentrations (Hao et al 2012; Hao et al 2013; Hatch et al 2008; Stahluht et al 2007). Focusing on the mean alone, however, assumes that the exposure-outcome association is constant over the entire outcome distribution, and does not capture effects that primarily occur at the tails of the distribution (Beyerlein 2014).…”