Applying the adverse outcome pathway concept for assessing non-monotonic dose responses: biphasic effect of bis(2-ethylhexyl) phthalate (DEHP) on testosterone levels

Astuto, Maria Chiara; Benford, Diane; Bodin, Laurent; Cattaneo, I.; Halldórsson, Thorhallur I.; Schlatter, Josef Rudolf; Sharpe, Richard M.; Tarazona, José; Younes, Maged

doi:10.1007/s00204-022-03409-9

Cited by 10 publications

(3 citation statements)

References 98 publications

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“…This could be studied explicitly in rodent models using sophisticated behavioral paradigms that have predictive validity for human sexual response [36,37]. In addition, there is evidence indicating that phthalates might exhibit non-monotonic effects [38,39], which was also noted in our study for MEP, MiBP, cx MiNP, oxo MiNP, McMHP, MnBP, OH-MiBP, OH-MnBP, cx-MEPP, oxo-MEHP and OH-MEHP (Fig. 3).…”

Section: Discussionsupporting

confidence: 72%

Endocrine effect of phthalate metabolites and a butterfly effect of prenatal exposure to androgens on qualitative aspects of female sexual response- an initial survey

Kolena,

Hlisníková,

Nagyová

et al. 2024

Int J Impot Res

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There is growing evidence that endocrine disruptive chemicals have deleterious effects on sexual and reproductive function. To examine subjective sexual functions in human females and their relationship to postnatal phthalate exposure and perinatal androgenization, a Sexuality Score (SS) was established from a first-stage survey questionnaire of subjective sexual function filled out by female university students (n = 68; average age 25.23 ± 5.17 years; rural 25.51 ± 6.74 vs. urban 25.85 ± 1.43 years). Seventeen phthalate metabolites in urine samples were analyzed by high‐performance liquid chromatography (HPLC) and tandem mass spectrometry (MS/MS). Females were also assessed for the 2D:4D digit ratio as an index of perinatal androgenization. The mean age of menarche was 12.82 ± 1.35 years (rural 12.59 ± 1.39 vs. urban 13.18 ± 1.27; p = 0.01). The mean age at first sexual intercourse was 14.88 ± 6.89 years (rural 14.62 ± 7.20 vs. urban 15.24 ± 6.55), and as the age of first sexual intercourse increases, the SS score tends to increase as well, albeit moderately (r = 0.25, p = 0.037). Mono‐iso‐butyl phthalate, mono(2‐ethyl‐5‐carboxypentyl) phthalate, mono(hydroxy‐n‐butyl) phthalate, mono(2‐ethyl‐5‐oxohexyl) phthalate (p ≤ 0.05) and mono(2-carboxymethylhexyl) phthalate (p ≤ 0.01) were negatively associated with SS. A compounding butterfly effect of prenatal exposure to androgens was observed with disruptive effects of mono(2‐ethyl‐5‐oxohexyl) phthalate and mono(2‐ethyl‐5‐carboxypentyl) phthalate on sexual function. Exposure to phthalates in adult females may lead to disruption of subjective sexual function, especially concerning sexual desire and sexual satisfaction, and perinatal androgenization could augment these effects.

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Section: Discussionsupporting

confidence: 72%

Endocrine effect of phthalate metabolites and a butterfly effect of prenatal exposure to androgens on qualitative aspects of female sexual response- an initial survey

Kolena,

Hlisníková,

Nagyová

et al. 2024

Int J Impot Res

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“…The evidence also indicates that phthalates lost their monotonicity, or the ability to consistently increase or decrease in response to a dose increase. According to similar findings, DEHP and DBP both have non-monotonic response patterns in general (Astuto et al, 2023), these characteristics make it exceedingly challenging to determine the acceptable exposure levels of phthalates.…”

Section: Discussionmentioning

confidence: 91%

Clastogenic, aneugenic, and tubulin polymerization properties of di-(2-ethylhexyl) phthalate and dibutyl phthalate

Javaji,

Mamilla,

Deshpande

et al. 2023

Toxicol Ind Health

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Phthalate compounds were found to disrupt the endocrine system and alter transcriptomes during human embryonic development. In our previous work, we have isolated and reported two such phthalates di-(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP) from Brevibacterium mcbrellneri bacteria and evaluated their bioactive properties. Naturally derived phthalates might be less toxic compared with synthesized molecules. We have investigated biologically isolated phthalates to understand the possible genotoxic effects in mice and further investigated in silico binding and polymerization of β-tubulin. Three sub-lethal concentrations of DEHP (150 μM, 175 μM, and 200 μM) and DBP (10 μM, 15 μM, and 30 μM) were studied. The results showed that the phthalates were found to be highly genotoxic in nature. However, the pattern of genotoxic effects was not found to be dose-dependent in the induction of chromosome aberrations (CA), micronuclei (MN), and changes in the mitotic index (MI) in cells. In silico studies of phthalates on polymerization of β-tubulin suggested that both DBP and DEHP were able to interact with the hydrogen bonds and make strong van der Waals interactions with β-tubulin thereby possibly causing destabilization of microtubule network. Our study suggests that these phthalates might be playing an important role in normal cell division thereby showing highly genotoxic effects.

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“…Furthermore, children's exposure to low doses of EDCs may cause harmful effect on the brain, affecting the quality of life, the ability to learn, memory, and neurobehavioral development [28]. On the basis of these observation, the European Food Safety Authority (EFSA) used the reduction in fetal testosterone to group some phthalates (i.e., DEHP, DBP and BBP), considering DEHP as the index compound for relative potency factors, and to set a group tolerable daily intake (TDI) of 50 µg kg −1 bw −1 , which was based on a no-observed-adverse-effect level (NOAEL) of 4.8 mg kg −1 bw −1 day −1 for anti-androgenic effects in a multigenerational reproductive study in male rats [29][30][31][32][33]. DEHP is the most commonly applied plasticizer in the manufacture of plastic products, especially PVC, and also in the production of lubricants, glues, paints, inks, pharmaceutics, cosmetics, perfumes, and pesticides.…”

Section: Introductionmentioning

confidence: 99%

Phthalates: The Main Issue in Quality Control in the Beverage Industry

Iannone,

Di Fiore,

Carriera

et al. 2024

Separations

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Phthalate esters (PAEs) are a group of chemicals used to improve the flexibility and durability of plastics. The chemical properties and the resistance to high temperatures promote their degradation and release into the environment. Food and beverages can be contaminated by PAEs through the migration from packaging material because they are not covalently bound to plastic and also via different kinds of environmental sources or during processing. For instance, alcoholic drinks in plastic containers are a particular risk, since the ethanol contained provides a good solubility for PAEs. According to its role as an endocrine disruptor compound and its adverse effects on the liver, kidney, and reproductive and respiratory systems, the International Agency on Research Cancer (IARC) classified di-(2-ethylhexyl) phthalate (DEHP) as a possible human carcinogen. For this reason, to control human exposure to PAEs, many countries prohibited their use in food as non-food substances. For example, in Europe, the Commission Regulation (EU) 2018/2005 restricts the use of DEHP, dibutyl phthalate (DBP), benzyl butyl phthalate (BBP), and diisobutyl phthalate (DiBP) to a concentration equal to or below 0.1 by weight in plasticizers in articles used by consumers or in indoor areas. There are reports from the US Food and Drug Administration (FDA) that some beverages (and food as well), particularly fruit juices, contain high levels of phthalates. In some cases, the deliberate adulteration of soft drinks with phthalate esters has been reported. This paper would like to show the difficulties of performing PAE analysis in beverage matrices, in particular alcoholic beverages, as well as the main solutions provided for quality control in the industrial branches.

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Applying the adverse outcome pathway concept for assessing non-monotonic dose responses: biphasic effect of bis(2-ethylhexyl) phthalate (DEHP) on testosterone levels

Cited by 10 publications

References 98 publications

Endocrine effect of phthalate metabolites and a butterfly effect of prenatal exposure to androgens on qualitative aspects of female sexual response- an initial survey

Endocrine effect of phthalate metabolites and a butterfly effect of prenatal exposure to androgens on qualitative aspects of female sexual response- an initial survey

Clastogenic, aneugenic, and tubulin polymerization properties of di-(2-ethylhexyl) phthalate and dibutyl phthalate

Phthalates: The Main Issue in Quality Control in the Beverage Industry

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