Pesticide exposure and spontaneous abortion risk: A comprehensive systematic review and meta-analysis.

BACKGROUNDS AND AIM: Exposure to pesticides has been proposed as a potential contributor to adverse pregnancy outcomes, possibly through the induction of inflammation, oxidative stress, and disruption of endocrine functions. Nevertheless, the definitive link between prenatal pesticide exposure and the risk of Spontaneous Abortion (SAB) remains uncertain. The objective of this systematic review is to explore and analyze the existing evidence regarding the link between pesticide exposure and the risk of SAB. METHODS: A comprehensive systematic literature search was carried out on PubMed, Web of Science, and Scopus from their inception until February 2024 to identify relevant studies exploring the potential link between pesticide exposure and SAB. The frequency of SAB events and the total number of patients in each group were used to calculate the Relative Risk (RR) using the Mantel-Haenszel random-effects model. Heterogeneity among the studies was evaluated by visually inspecting the forest plot and performing the Chi-square test and I2 tests. We also used RevMan version 5.4 for Windows for the analysis. We also used the NIH tool to assess the quality of the included studies. RESULTS: The initial database search yielded 2121 results, with 1525 articles remaining after removing duplicates. After screening, 29 articles were eligible for full-text review, and 18 studies (Four case-control, eleven cohorts, three cross-sectional) were included in the meta-analysis, comprising 439,097 participants. All included studies evaluated the primary outcome, SAB. Most of the included studies were cross-sectional in design, and pesticide exposure was primarily assessed through questionnaires administered to patients. We found that most of our observational studies, precisely 12 out of the total, were deemed fair quality. Four studies were rated poor quality, while only two received a good quality rating. The analysis demonstrated a significant 41 % increase in SAB risk among pregnant women exposed to pesticides compared to pregnant women without exposure to pesticides (RR= 1.41, 95 % CI; [1.10, 1.80], P= 0.006). CONCLUSION: Our systematic review and meta-analysis revealed a significant 41 % increase in the risk of SAB among pregnant women exposed to pesticides. However, it is essential to acknowledge the limitations of the current evidence: potential publication bias and the inability to establish causality. Moving forward, future research should focus on longitudinal studies, mechanistic insights, and risk reduction strategies. In summary, our findings underscore the urgency of public health measures to protect maternal and fetal health in pesticide-exposed areas. Rigorous research and preventive strategies are crucial to mitigate adverse outcomes.

The simultaneous administration of microplastics and cadmium alters rat testicular activity and changes the expression of PTMA, DAAM1 and PREP.

This paper confirms the damaging effects produced by MP and Cd on testicular activity in the rat. Oral treatment with both chemicals resulted in testicular damage, documented by biomolecular and histological alterations, particularly by impaired morphometric parameters, increased apoptosis, reduced testosterone synthesis, and downregulation of the steroidogenic enzyme 3ß-HSD. We also demonstrated, for the first time, that both MP and Cd can affect the protein level of PTMA, a small peptide that regulates germ cell proliferation and differentiation. Interestingly, the cytoarchitecture of testicular cells was also altered by the treatments, as evidenced by the impaired expression and localization of DAAM1 and PREP, two proteins involved in actin- and microtubule-associated processes, respectively, during germ cells differentiation into spermatozoa, impairing normal spermatogenesis. Finally, we showed that the effect of simultaneous treatment with MP and Cd were more severe than those produced by MP alone and less harmful than those of Cd alone. This could be due to the different ways of exposure of the two substances to rats (in drinking water for Cd and in oral gavage for MP), since being the first contact in the animals' gastrointestinal tract, MP can adsorb Cd, reducing its bioavailability through the Trojan-horse effect.

From old pollutants to the regulation of bisphenol A: Lessons learned for health promotion and disease prevention.

Citizens deserve regulatory changes and policies more sensitive to the current needs of humans, the climate, and nature. In this work we draw on prior experiences of preventable human suffering and economic losses caused by delayed regulation of legacy and emerging pollutants. Heightened awareness of environmental health problems is necessary among health professionals, the media, and citizens' organizations. Improved translation from research to the clinical world and to policy is critical to reduce the population burden of diseases caused by exposure to endocrine disruptors and other environmental chemicals. Numerous lessons can be learned from science-to-policy processes built for "old pollutants" (as persistent organic pollutants, heavy metals, tributyltin), as well as from current trends regarding the regulation of non-persistent chemicals, such as the prototypical endocrine disruptor bisphenol A. We end discussing relevant pieces of the puzzle to tackle the environmental and regulatory challenges faced by our societies.

Editorial: New mechanistic insight into perinatal origins of reproductive disorders caused by chemical exposures.

Introducing a Special Issue on mechanism of reproductive disorders in mammals originating from exposure to environmental chemicals during perinatal life.

Sex Differences between Urinary Phthalate Metabolites and Metabolic Syndrome in Adults: A Cross-Sectional Taiwan Biobank Study.

BACKGROUND: Phthalates are widely used in consumer products, food packaging, and personal care products, so exposure is widespread. Several studies have investigated the association of phthalate exposure with obesity, insulin resistance, and hypertension. However, little is known about the associations of phthalate exposure with sex, age, and menopausal status in metabolic syndrome (MetS). The purpose of this study was to investigate the association between 11 urinary phthalate metabolite concentrations and metabolic syndrome in adults. METHODS: We conducted a cross-sectional analysis of 1337 adults aged 30-70 years from the Taiwan Biobank 2016-2020. Prevalence odds ratios (POR) and 95% confidence intervals (CIs) were calculated using logistic regression and stratified by sex, age, and menopausal status. RESULTS: Participants with MetS comprised 16.38%. Higher concentrations of MEP metabolites were associated with more than two- to three-fold increased odds of MetS in males and males ≥ 50 years (adj. POR Q3 vs. Q1 = 2.13, 95% CI: 1.01, 4.50; p = 0.047 and adj. POR Q2 vs. Q1 = 3.11, 95% CI: 0.13, 8.63; p = 0.029). When assessed by menopausal status, postmenopausal females with higher ∑DEHP concentrations had more than nine-fold higher odds of MetS compared with postmenopausal females with the lowest ∑DEHP concentrations (adj. POR Q3 vs. Q1 = 9.58, 95% CI: 1.18, 77.75; p = 0.034). CONCLUSIONS: The findings suggest differential associations between certain phthalate metabolites and MetS by sex, age, and menopausal status.

A case-control study of polychlorinated biphenyl association with metabolic and hormonal outcomes in polycystic ovary syndrome.

Polychlorinated biphenyls (PCBs) are a class of environmental pollutants with a long half-life that sequester in fat. Women with polycystic ovarian syndrome (PCOS) may represent a sensitive subgroup to endogenous exposure to PCBs because of associated weight gain. Seven PCB congeners were compared in age, ethnicity, and BMI matched women with (n = 29) and without (n = 30) PCOS and related to metabolic outcomes, and steroid and thyroid hormone levels. PCB118, PCB138, PCB153, and PCB180 were detected in all serum samples but geometric mean did not differ between cases and controls. PCBs correlated with increasing concentrations of each other (p < .01), increasing age (p < .01) and decreasing lneGFR (p < .05). lnPCB118 correlated with increasing Free-T4 (p = .028). lnPCB158, lnPCB180, and ln∑PCB correlated with increasing lnSHBG (p = .044). In regression modeling, although not significant, PCB118 positively associated with lnSHBG in controls (p = .0504) but not in cases; estradiol inversely associated with PCB138 in controls (p = .055) and ∑PCB in cases (p = .051). No significant associations were observed between metabolic endpoints, and steroid and thyroid hormone levels. The results presented do not suggest the PCOS cases in this cohort are at adverse risk compared to age, ethnicity, and BMI matched controls.

Mechanism of Action of an Environmentally Relevant Organochlorine Mixture in Repressing Steroid Hormone Biosynthesis in Leydig Cells.

Within Leydig cells, steroidogenesis is induced by the pituitary luteinizing hormone (LH). The binding of LH to its receptor increases cAMP production, which then activates the expression of genes involved in testosterone biosynthesis. One of these genes codes for the steroidogenic acute regulatory (STAR) protein. STAR is part of a complex that shuttles cholesterol, the precursor of all steroid hormones, through the mitochondrial membrane where steroidogenesis is initiated. Organochlorine chemicals (OCs) are environmental persistent organic pollutants that are found at high concentrations in Arctic areas. OCs are known to affect male reproductive health by decreasing semen quality in different species, including humans. We previously showed that an environmentally relevant mixture of OCs found in Northern Quebec disrupts steroidogenesis by decreasing STAR protein levels without affecting the transcription of the gene. We hypothesized that OCs might affect STAR protein stability. To test this, MA-10 Leydig cell lines were incubated for 6 h with vehicle or the OCs mixture in the presence or absence of 8Br-cAMP with or without MG132, an inhibitor of protein degradation. We found that MG132 prevented the OC-mediated decrease in STAR protein levels following 8Br-cAMP stimulation. However, progesterone production was still decreased by the OC mixture, even in the presence of MG132. This suggested that proteins involved in steroid hormone production in addition to STAR are also affected by the OC mixture. To identify these proteins, a whole cell approach was used and total proteins from MA-10 Leydig cells exposed to the OC mixture with or without stimulation with 8Br-cAMP were analyzed by 2D SDS-PAGE and LC-MS/MS. Bioinformatics analyses revealed that several proteins involved in numerous biological processes are affected by the OC mixture, including proteins involved in mitochondrial transport, lipid metabolism, and steroidogenesis.

BPS and BPF are as Carcinogenic as BPA and are Not Viable Alternatives for its Replacement.

BACKGROUND: Plastic polymers are omnipresent, and life without them is virtually impossible. Despite the advantages provided by the material, conventional plastic also has harmful effects on the environment and human health. Plastics release microplastics and compounds, such as BPA, which is a xenoestrogen and once absorbed by the body, have an affinity for estrogen receptors α and ß, acting as an agonist on human cells, being an endocrine disrupter able to cause various diseases and acting as a potential neoplastic inducer. BPS and BPF are BPA's analogs, a proposed solution to solve its harmful effects. The analogs can be found in daily use products and are used in several industrial applications. OBJECTIVES: In the present work, the researchers aimed to conduct a revisional study on BPA's harmful effects on human health, focusing on its carcinogenic potential, discussing its mechanisms of action, as well as its analogs effects, and identifying if BPS and BPF are viable alternatives to BPA's substitution in plastic polymers' production. METHODS: In this review, articles published in the last 15 years related to the different aspects of conventional plastics and BPA were analyzed and revised with precision. The subjects ranged from conventional plastics and the problems related to their large-scale production, BPA, its negative aspects, and the feasibility of using its analogs (BPS and BPF) to replace the compound. The articles were extensively reviewed and concisely discussed. RESULTS: This study demonstrated that BPA has a high carcinogenic potential, with known mechanisms to trigger breast, ovarian, prostate, cervical, and lung cancers, thus elucidating that its analogs are also xenoestrogens, and they can exert similar effects to BPA and, therefore, cannot be considered viable alternatives for its replacement. CONCLUSION: .This study suggests that new research should be carried out to develop such alternatives, allowing the substitution of plastic materials containing BPA in their composition, such as developing economically viable and sustainable biodegradable bioplastics for socioenvironmental well-being.

Genome-wide gene-bisphenol A, F and triclosan interaction analyses on urinary oxidative stress markers.

BACKGROUND: Bisphenols and triclosan (TCS) are common endocrine disrupters (EDCs) that may induce oxidative stress. However, there is limited information as to whether these EDCs interact with genetic variants to modify the levels of oxidative stress on a genome-wide scale. METHODS: We first performed a genome-wide scan among a Chinese population and also measured three urinary EDCs, including bisphenol A (BPA), bisphenol F (BPF) and TCS, and three urinary oxidative stress markers [4-hydroxy-2-nonenal-mercapturic acid (HNE-MA), 8-iso-prostaglandin-F2α (8-isoPGF2α) and 8-hydroxy-deoxyguanosine (8-OHdG)]. Subsequently, we examined interactions between three urinary EDCs and nearly 4.6 million genetic variants for three urinary oxidative stress markers by the general linear model. RESULTS: Urinary BPA, BPF and TCS were positively associated with HNE-MA, 8-isoPGF2α and 8-OHdG. Significant rs6855040 (4p15.32/between SNORA75B and QDPR)-BPA, rs1112943 (4q35.1/SNX25)-TCS interactions were associated with the 8-isoPGF2α levels (all P < 5 × 10-8). In addition, rs4656116 (1p22.3/CACL1), rs16958760 (17p11.2/between USP43 and DHRS7C) and rs11651078 (17p11.2/LOC339260) showed significant gene-TCS interactions with 8-OHdG (all P < 5 × 10-8). The gene-level analysis found significant interaction between SNX25 and TCS for 8-isoPGF2α levels (P < 2.12 × 10-6). CONCLUSION: Our results identify several gene-EDCs interactions for oxidative stress, highlighting that EDCs may modify the effect of genetic variants on oxidative stress.

Female Reproductive Health and Exposure to Phthalates and Bisphenol A: A Cross Sectional Study.

The xenoestrogenicity of some plasticisers (phthalates and bisphenol A) is documented in the literature and may pose a risk to female reproductive health. The aim of this study was to assess exposure to six phthalates. This was achieved by measuring their respective metabolites (mono-ethylphthalate (MEP); mono-n-butylphthalate (MnBP); mono-n-ottylphthalate (MnOP); and monobenzylphthalate (MBzP)), as well as the sum of two of the diethyl-hexyl phthalate metabolites-(∑DEHP) and bisphenol A (BPA) in a female population with infertility problems, and by conducting a correlation analysis between infertility factors, work activities, and lifestyle habits, in order to formulate a causal hypothesis. A cross-sectional epidemiological study was carried out and women under 43 years of age were recruited from an assisted reproduction technology (ART) center; the sample of 186 women was given a specific questionnaire and a spot urine sample was collected. Phthalate metabolites and urinary BPA were analyzed by HPLC/MS/MS. The results showed significantly higher mean values for MEP in women with recurrent pregnancy loss (RPL) (820.5 ± 1929.5 µg/g of creatinine) and idiopathic infertility (230.0 ± 794.2 µg/g of creatinine) than in women with other infertility factors (76.9 ± 171.8 µg/g of creatinine). Similarly, for MnOP levels, women with idiopathic infertility (2.95 ± 3.44 µg/g of creatinine) showed significantly higher values than women with the other infertility factors taken together (1.35 ± 2.05 µg/g of creatinine). Women with tubal factors of infertility, RPL, and endocrine dysfunctions show higher values of DEHP (p = 0.032). Considering occupations, women working in commerce showed more than twice as much urinary BPA levels (1.10 ± 0.48 µg/g of creatinine) compared to women working in other industries (0.45 ± 0.35 µg/g of creatinine). The presence of significantly higher values of certain phthalates, DEHP in particular, especially in women with RPL and idiopathic infertility, suggests a possible involvement of these compounds as competing factors in reproductive issues. The study of sources of exposure suggested that the working activity in trade, as a casher in particular, represents a major one for BPA (p = 0.015).

Mechanisms of MEHP Inhibitory Action and Analysis of Potential Replacement Plasticizers on Leydig Cell Steroidogenesis.

Steroid production in Leydig cells is stimulated mainly by the pituitary luteinizing hormone, which leads to increased expression of genes involved in steroidogenesis, including the gene encoding the steroidogenic acute regulatory (STAR) protein. Mono(2-ethylhexyl)phthalate (MEHP), the active metabolite of the widely used plasticizer DEHP, is known to disrupt Leydig steroidogenesis but its mechanisms of action remain poorly understood. We found that MEHP caused a significant reduction in hormone-induced steroid hormone production in two Leydig cell lines, MA-10 and MLTC-1. Consistent with disrupted cholesterol transport, we found that MEHP represses cAMP-induced Star promoter activity. MEHP responsiveness was mapped to the proximal Star promoter, which contains multiple binding sites for several transcription factors. In addition to STAR, we found that MEHP also reduced the levels of ferredoxin reductase, a protein essential for electron transport during steroidogenesis. Finally, we tested new plasticizers as alternatives to phthalates. Two plasticizers, dioctyl succinate and 1,6-hexanediol dibenzoate, had no significant effect on hormone-induced steroidogenesis. Our current findings reveal that MEHP represses steroidogenesis by affecting cholesterol transport and its conversion into pregnenolone. We also found that two novel molecules with desirable plasticizer properties have no impact on Leydig cell steroidogenesis and could be suitable phthalate replacements.

Review article: Emerging issues in pediatric skin of color, part 1.

Dermatology for the pediatric skin of color population is the application of dermatology to the genetically diverse and distinctive segment of the pediatric population that includes children of non-White racial and ethnic groups with increased pigmentation including individuals of Asian, LatinX, African, Native American, Pacific Island descent, Indigenous Peoples, among others, with overlap in particular individuals, and mixtures thereof. Treating children of color is a unique skill set within the field of pediatric dermatology, requiring knowledge and sensitivity. The discipline of pediatric skin of color can be challenging. Difficulty in diagnosis of common conditions stems from underlying pigmentation, variations in common hairstyling practices, and differences in demographics of cutaneous disease, whereas some conditions are more common in children of color, other conditions have nuances in clinical appearance and/or therapeutics with regard to skin color. This article is the first in a series of two articles looking at recently published skin-related issues of high concern in children of color. Conditions reviewed in Part 1 include (1) hairstyling hair-related concerns (traction alopecia, central centrifugal cicatricial alopecia, endocrine disruption), (2) autoimmune concerns (cutaneous lupus, vitiligo), and (3) infections (tinea capitis, progressive macular hypomelanosis).

Endocrine Disrupting Chemicals and Reproductive Health in Boys and Men.

Male reproductive health has declined as indicated by increasing rates of cryptorchidism, i.e., undescended testis, poor semen quality, low serum testosterone level, and testicular cancer. Exposure to endocrine disrupting chemicals (EDCs) has been proposed to have a role in this finding. In utero exposure to antiandrogenic EDCs, particularly at a sensitive period of fetal testicular development, the so-called 'masculinization programming window (MPW)', can disturb testicular development and function. Low androgen effect during the MPW can cause both short- and long-term reproductive disorders. A concurrent exposure to EDCs may also affect testicular function or damage testicular cells. Evidence from animal studies supports the role of endocrine disrupting chemicals in development of male reproductive disorders. However, evidence from epidemiological studies is relatively mixed. In this article, we review the current literature that evaluated relationship between prenatal EDC exposures and anogenital distance, cryptorchidism, and congenital penile abnormality called hypospadias. We review also studies on the association between early life and postnatal EDC exposure and semen quality, hypothalamic-pituitary-gonadal axis hormone levels and testicular cancer.

Evidence of melatonin ameliorative effects on the blood-testis barrier and sperm quality alterations induced by cadmium in the rat testis.

Herein, we further document the protective action of melatonin (MLT) in mitigating cadmium (Cd) effects on adult rat testis. Cd treatment provoked testicular injury, that was documented by histological and biomolecular alterations, i.e., decrease of serum and testicular testosterone concentration and modified sperm parameters. Mainly, both the cytoarchitecture of the blood-testis barrier (BTB) and germ cell morphology were perturbed, as highlighted by impairment in structural (OCN, VANGL, Cx43) and regulative (Src and FAK) protein levels and/or activation. The study focused on the involvement of the autophagy pathway, that was enhanced especially in the Sertoli cells, probably in response to the disorganization of the BTB. Results obtained with the MLT co-treatment demonstrated that its administration decreased the level of oxidative damage caused by Cd, with reversal of all the observed changes. Moreover, the beneficial effects of MLT alone were evidenced by an increase of sperm quality, in term of motility and DNA integrity. The combined results, obtained in rat, strongly encourage to consider a role for MLT in improving also human testicular health, not only in men exposed to Cd, but also in those having fertility disorders, to ameliorate sperm quality and, consequently, reproductive success.

Comparison of Thyroid Hormone Levels between Women Farmers and Non-Farmers in Banten Indonesia.

Pesticides are suspected of being endocrine disruptors. This cross-sectional study measured serum samples for levels of thyroid hormones including thyroid stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), free T3 (FT3), and free T4 (FT4) among Indonesian female farmers (n = 127) and non-farmers (n = 127). A questionnaire was used to collect information on demographics and risk factors including work characteristics and frequency, and the use of home and agricultural pesticides. Results showed that there were no significant differences in the distribution of the clinical categories of thyroid levels between farmers and non-farmers except for FT3 and T4. However, in multivariable regression controlling for confounders, FT3 and T4 were significantly higher for farmers compared to non-farmers. In addition, 32% of farmers had clinically low iodine levels and 49% of non-farmers had clinically high iodine levels. We conclude that pesticide exposure may not be as important as iodine intake in explaining these findings. We recommend counseling by health workers about the importance of using iodized salt for farmers and counseling about high iodine foods that need to be avoided for non-farmers.

Altered Expression of DAAM1 and PREP Induced by Cadmium Toxicity Is Counteracted by Melatonin in the Rat Testis.

Cadmium (Cd) is one of the most toxic pollutants for health due to its accumulation in several tissues, including testis. This report confirms that Cd increased oxidative stress and apoptosis of germ and somatic cells and provoked testicular injury, as documented by biomolecular and histological alterations, i.e., CAT and SOD activity, the protein level of steroidogenic enzymes (StAR and 3ß-HSD), and morphometric parameters. Additionally, it further documents the melatonin (MLT) coadministration produces affects in mitigating Cd-induced toxicity on adult rat testis, as demonstrated by the reduction of oxidative stress and apoptosis, with reversal of the observed histological changes; moreover, a role of MLT in partially restoring steroidogenic enzymes expression was evidenced. Importantly, the cytoarchitecture of testicular cells was perturbed by Cd exposure, as highlighted by impairment of the expression and localization of two cytoskeleton-associated proteins DAAM1 and PREP, which are involved in the germ cells' differentiation into spermatozoa, altering the normal spermatogenesis. Here, for the first time, we found that the co-treatment with MLT attenuated the Cd-induced toxicity on the testicular DAAM1 and PREP expression. The combined findings provide additional clues about a protective effect of MLT against Cd-induced testicular toxicity by acting on DAAM1 and PREP expression, encouraging further studies to prove its effectiveness in human health.

In vitro and in silico investigations of endocrine disruption induced by metabolites of plasticizers through glucocorticoid receptor.

The endocrine disruptive capability of plasticizers to activate nuclear receptors has attracted great interest. This study is aimed to assess the potential glucocorticoid effects of metabolites of plasticizers. The effects of metabolites of plasticizers on the transcriptional activity of glucocorticoid receptor (GR) were investigated using reporter gene assays. All of them failed to exhibit agonistic/antagonistic effects on GR. However, a combination of dexamethasone and monobutyl phthalate (MBP) could synergistically activate GR. MBP combined with dexamethasone also enhanced GR nuclear translocation by Western blot, while mifepristone restrained GR cytoplasmic-to-nuclear translocation. MBP co-treated with dexamethasone resulted in synergistic induction of PEPCK and MKP-1 gene expression by real-time PCR and PEPCK protein level by Western blot. Furthermore, the carboxyl and ester groups of MBP have influences on the charge distribution of MBP, leading to change of electrostatic interactions between MBP and GR by calculations on electronic properties. Both hydrophobic and hydrogen bonding interactions play a crucial role in the stabilization between MBP and GR conducted by molecular docking and dynamics simulation. This work confirms that GR could remain stable upon binding to MBP. In conclusion, dexamethasone and MBP could synergistically activate GR, resulting in synergetic enhancement of subsequent GR-mediated endocrine disrupting effect.

Biomonitoring of occupational exposure to bisphenol A, bisphenol S and bisphenol F: A systematic review.

Bisphenol A (BPA) and its substitutes bisphenol S (BPS) and bisphenol F (BPF) are endocrine disrupting chemicals widely used in the production of polycarbonate plastics, epoxy resins and thermal papers. The aim of the review was to identify occupational studies using human biomonitoring (HBM) as a tool for bisphenol exposure assessment and to characterize research gaps on the topic as part of the HBM4EU project. Hence, a systematic literature search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology was conducted for articles published between 2000 and 27th March 2020 across three databases (PubMed, Scopus and Web of Science). Thirty studies on the occupational HBM of BPA met the inclusion criteria. Regarding BPS and BPF, only 4 and 2 publications were retrieved, respectively. Fifty-seven percent (57%) of the studies selected for BPA were conducted in Asia whereas half of BPS and BPF studies were undertaken in Europe. Studies on BPA in plastic and epoxy resin sectors were infrequent in Europe while Asian data showed higher exposure when the substance is employed as raw material. The main data on BPS were among cashiers while BPF data were available from incinerator workers. Several research gaps have been identified: (i) shortage of HBM studies on occupational exposure, especially to BPS and BPF; (ii) different methodological designs making suitable comparisons between studies difficult; and (iii) only few studies conducted on the industrial applications of bisphenols outside Asia. This review highlights the lack of recent occupational HBM studies on bisphenols and the need for a harmonized approach to acquire reliable data. Considering the increasing replacement of BPA by BPS and BPF, it is of relevance to evaluate the exposure to these substances and the impact of the available risk management measures on workers exposure and possible health risk.

Classical toxicity endpoints in female rats are insensitive to the human endocrine disruptors diethylstilbestrol and ketoconazole.

Developmental exposure to endocrine disrupting chemicals can have negative consequences for reproductive health in both men and women. Our knowledge about how chemicals can cause adverse health outcomes in females is, however, poorer than our knowledge in males. This is possibly due to lack of sensitive endpoints to evaluate endocrine disruption potential in toxicity studies. To address this shortcoming we carried out rat studies with two well-known human endocrine disruptors, diethylstilbestrol (DES) and ketoconazole (KTZ), and evaluated the sensitivity of a series of endocrine related endpoints. Sprague-Dawley rats were exposed orally from gestational day 7 until postnatal day 22. In a range-finding study, disruption of pregnancy-related endpoints was seen from 0.014 mg/kg bw/day for DES and 14 mg/kg bw/day for KTZ, so doses were adjusted to 0.003; 0.006; and 0.0012 mg/kg bw/day DES and 3; 6; or 12 mg/kg bw/day KTZ in the main study. We observed endocrine disrupting effects on sensitive endpoints in male offspring: both DES and KTZ shortened anogenital distance and increased nipple retention. In female offspring, 0.0012 mg/kg bw/day DES caused slightly longer anogenital distance. We did not see effects on puberty onset when comparing average day of vaginal opening; however, we saw a subtle delay after exposure to both chemicals using a time-curve analysis. No effects on estrous cycle were registered. Our study shows a need for more sensitive test methods to protect the reproductive health of girls and women from harmful chemicals.