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Behavioral Effects of Exposure to Phthalates in Female Rodents: Evidence for Endocrine Disruption?

ABSTRACT: Phthalates have been widely studied for their reprotoxic effects in male rodents and in particular on testosterone production, for which reference doses were established. The female rodent brain can also represent a target for exposure to these environmental endocrine disruptors. Indeed, a large range of behaviors including reproductive behaviors, mood-related behaviors, and learning and memory are regulated by sex steroid hormones. Here we review the experimental studies addressing the effects and mechanisms of phthalate exposure on these behaviors in female rodents, paying particular attention to the experimental conditions (period of exposure, doses, estrous stage of analyses etc.). The objective of this review is to provide a clear picture of the consistent effects that can occur in female rodents and the gaps that still need to be filled in terms of effects and mode(s) of action for a better risk assessment for human health.

SUBMITTER: Adam N

PROVIDER: S-EPMC8910129 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Behavioral Effects of Exposure to Phthalates in Female Rodents: Evidence for Endocrine Disruption?

Adam Nolwenn N Mhaouty-Kodja Sakina S

International journal of molecular sciences 20220225 5

Phthalates have been widely studied for their reprotoxic effects in male rodents and in particular on testosterone production, for which reference doses were established. The female rodent brain can also represent a target for exposure to these environmental endocrine disruptors. Indeed, a large range of behaviors including reproductive behaviors, mood-related behaviors, and learning and memory are regulated by sex steroid hormones. Here we review the experimental studies addressing the effects ...[more]

PMID: 35269705

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Project description:Background: Humans are consistently and increasingly exposed to phthalate products, but the effect of the combined exposure to phthalates on myocardial injury remains largely unexplored. The present study aimed to explore the effect of the combined exposure to phthalates on myocardial injury. Methods: A total of 1237 male adults (aged ≥20) without coronary artery disease (CAD) from the National Health and Nutrition Examination Survey (NHANES) in 1999-2004 were included in the current study. Multiple linear regression, Bayesian kernel machine regression (BKMR), and a weighted quantile sum (WQS) model were employed to examine the associations of urinary phthalate metabolites with two cardiac injury biomarkers, including troponin T (TNT) and troponin I, using four highly sensitive assays (Abbott, Chicago, IL, USA; Siemens, Erlangen, Germany; and Ortho, Raritan, NJ, USA) (TNIA, TNIS, TNIO). Results: According to the linear regression analysis, mono-(3-carboxypropyl) phthalate (MCPP, a metabolite of di-n-octyl phthalate) was found to be positively associated with serum TNT; a positive association was found between mono-isobutyl phthalate (MiBP, a metabolite of di-isobutyl phthalate) and TNIA, as well as MiBP and TNIS. Mono-benzyl phthalate (MBzP, a metabolite of butyl benzyl phthalate) and MCPP were positively associated with serum TNIO. The BKMR analyses showed a positive overall relationship of serum TNT, TNIA, TNIS, and TNIO with increased concentrations of phthalate metabolites. The WQS model showed MCPP and MBzP were the top two contributors to being an increased risk for elevated TNT levels. MCPP and mono-ethyl phthalate (MEP, a metabolite of diethyl phthalate) were identified as the leading contributors to increased TNIA and TNIS. MCPP and MBzP were the dominant contributors to elevated TNIO. Conclusions: As a combined mixture, phthalate metabolites were positively associated with serum TNT and TNI among adults without CAD, indicating the potential toxic effect of phthalate exposure on cardiac injury.

Project description:BackgroundThere is growing interest in evidence-based interventions, programs, and policies to mitigate exposures to bisphenols and phthalates and in using implementation science frameworks to evaluate hypotheses regarding the importance of specific approaches to individual or household behavior change or institutions adopting interventions.ObjectivesThis scoping review aimed to identify, categorize, and summarize the effects of behavioral, clinical, and policy interventions focused on exposure to the most widely used and studied bisphenols [bisphenol A (BPA), bisphenol S (BPS), and bisphenol F (BPF)] and phthalates with an implementation science lens.MethodsA comprehensive search of all individual behavior, clinical, and policy interventions to reduce exposure to bisphenols and phthalates was conducted using PubMed, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Google Scholar. We included studies published between January 2000 and November 2022. Two reviewers screened references in CADIMA, then extracted data (population characteristics, intervention design, chemicals assessed, and outcomes) for studies meeting inclusion criteria for the present review.ResultsA total of 58 interventions met the inclusion criteria. We classified interventions as dietary (n=27), clinical (n=13), policy (n=14), and those falling outside of these three categories as "other" (n=4). Most interventions (81%, 47/58) demonstrated a decrease in exposure to bisphenols and/or phthalates, with policy level interventions having the largest magnitude of effect.DiscussionStudies evaluating policy interventions that targeted the reduction of phthalates and BPA in goods and packaging showed widespread, long-term impact on decreasing exposure to bisphenols and phthalates. Clinical interventions removing bisphenol and phthalate materials from medical devices and equipment showed overall reductions in exposure biomarkers. Dietary interventions tended to lower exposure with the greatest magnitude of effect in trials where fresh foods were provided to participants. The lower exposure reductions observed in pragmatic nutrition education trials and the lack of diversity (sociodemographic backgrounds) present limitations for generalizability to all populations. https://doi.org/10.1289/EHP11760.

Project description:A prevailing challenge when testing chemicals for their potential to cause female reproductive toxicity is the lack of appropriate toxicological test methods. We hypothesized that starting a 28-day in vivo toxicity study already at weaning, instead of in adulthood, would increase the sensitivity to detect endocrine disruptors due to the possibility of including assessment of pubertal onset. We compared the sensitivity of two rat studies using pubertal or adult exposure. We exposed the rats to two well-known human endocrine disruptors, the estrogen diethylstilbestrol (DES; 0.003, 0.012, 0.048 mg/kg bw/day) and the steroid synthesis inhibitor ketoconazole (KTZ; 3, 12, 48 mg/kg bw/day). Specifically, we addressed the impact on established endocrine-sensitive endpoints including day of vaginal opening (VO), estrous cyclicity, weights of reproductive organs and ovarian histology. After 28 days of exposure, starting either at weaning or at 9 weeks of age, DES exposure altered estrous cyclicity, reduced ovary weight as well as number of antral follicles and corpora lutea. By starting exposure at weaning, we could detect advanced day of VO in DES-exposed animals despite a lower body weight. Some endpoints were affected mainly with adult exposure, as DES increased liver weights in adulthood only. For KTZ, no effects were seen on time of VO, but adrenal and liver weights were increased in both exposure scenarios, and adult KTZ exposure also stimulated ovarian follicle growth. At first glance, this would indicate that a pubertal exposure scenario would be preferrable as timing of VO may serve as sensitive indicator of endocrine disruption by estrogenic mode of action. However, a higher sensitivity for other endocrine targets may be seen starting exposure in adulthood. Overall, starting a 28-day study at weaning with inclusion of VO assessment would mainly be recommended for substances showing estrogenic potential e.g., in vitro, whereas for other substances an adult exposure scenario may be recommended.

Dataset Information

Behavioral Effects of Exposure to Phthalates in Female Rodents: Evidence for Endocrine Disruption?

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Behavioral Effects of Exposure to Phthalates in Female Rodents: Evidence for Endocrine Disruption?

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