Endocrine Disruptor Chemicals and Children's Health.

We are all exposed to endocrine-disrupting chemicals (EDCs) starting from embryonic life. The fetus and child set up crucial developmental processes allowing adaptation to the environment throughout life: they are extremely sensitive to very low doses of hormones and EDCs because they are developing organisms. Considering the developmental origin of well-being and diseases, every adult organism expresses consequences of the environment in which it developed. The molecular mechanisms through which the main EDCs manifest their effects and their potential association with endocrine disorders, such as diabetes, obesity, thyroid disease and alteration of adrenal hormones, will be reviewed here. Despite 40 years having passed since the first study on EDCs, little is yet known about them; therefore, our purpose is to take stock of the situation to establish a starting point for further studies. Since there is plenty of evidence showing that exposure to EDCs may adversely impact the health of adults and children through altered endocrine function-suggesting their link to endocrinopathies-it is essential in this context to bear in mind what is already known about endocrine disruptors and to deepen our knowledge to establish rules of conduct aimed at limiting exposure to EDCs' negative effects. Considering that during the COVID-19 pandemic an increase in endocrine disruptor effects has been reported, it will also be useful to address this new phenomenon for better understanding its basis and limiting its consequences.

Exposure to a mixture of per-and polyfluoroalkyl substances modulates pulmonary expression of ACE2 and circulating hormones and cytokines.

Genetic and environmental factors impact on the interindividual variability of susceptibility to communicable and non-communicable diseases. A class of ubiquitous chemicals, Per- and polyfluoroalkyl substances (PFAS) have been linked in epidemiological studies to immunosuppression and increased susceptibility to viral infections, but possible mechanisms are not well elucidated. To begin to gain insight into the role of PFAS in susceptibility to one such viral infection, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), male and female C57BL/6 J mice were exposed to control water or a mixture of 5 PFAS (PFOS, PFOA, PFNA, PFHxS, Genx) for 12 weeks and lungs were isolated for examination of expression of SARS-CoV-2-related receptors Angiotensin-Converting Enzyme 2 (ACE2) and others. Secondary analyses included circulating hormones and cytokines which have been shown to directly or indirectly impact on ACE2 expression and severity of viral infections. Changes in mRNA and protein expression were analyzed by RT-qPCR and western blotting and circulating hormones and cytokines were determined by ELISA and MESO QuickPlex. The PFAS mixture decreased Ace2 mRNA 2.5-fold in male mice (p < 0.0001), with no significant change observed in females. In addition, TMPRSS2, ANPEP, ENPEP and DPP4 (other genes implicated in COVID-19 infection) were modulated due to PFAS. Plasma testosterone, but not estrogen were strikingly decreased due to PFAS which corresponded to PFAS-mediated repression of 4 representative pulmonary AR target genes; hemoglobin, beta adult major chain (Hbb-b1), Ferrochelatase (Fech), Collagen Type XIV Alpha 1 Chain (Col14a1), 5'-Aminolevulinate Synthase 2 (Alas2). Finally, PFAS modulated circulating pro and anti-inflammatory mediators including IFN-γ (downregulated 3.0-fold in females; p = 0.0301, 2.1-fold in males; p = 0.0418) and IL-6 (upregulated 5.6-fold in males; p = 0.030, no change in females). In conclusion, our data indicate long term exposure to a PFAS mixture impacts mechanisms related to expression of ACE2 in the lung. This work provides a mechanistic rationale for important future studies of PFAS exposure and subsequent viral infection.

Significant changes in follicular fluid phthalate metabolite levels reflect the lifestyle changes brought about by the strict COVID-19 lockdown in India.

OBJECTIVE: To assess if the unprecedented changes in lifestyle because of the lockdown initiated by the COVID-19 pandemic, which altered human behavior, and influenced purchase and consumption patterns, may have had an impact on the exposure to phthalates in Indian women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). To evaluate if the effects of the strict and lengthy lockdown in India, which promoted the new norms of stay-at-home and work-from-home, closure of beauty parlors, and restriction on public gatherings, may have contributed to a decrease in the exposure to phthalates like dibutyl phthalate and diethyl phthalate. These chemicals are found in many personal care products (PCPs) which include cosmetics and fragrances. To investigate if the extensive use of flexible single-use plastic in personal protective equipment like face masks/gloves and in plastic packaging used for online purchases, food takeaways, and home deliveries of essentials and groceries during the COVID-19 pandemic, in an attempt to provide a contact-free delivery system may have inadvertently led to an increase in exposure to phthalates like di(2-ethylhexyl) phthalate, di-isononyl phthalate, and di-isodecyl phthalate which are plasticizers used in manufacturing flexible plastic. DESIGN: A comparative study of the levels of six phthalate metabolites detected in follicular fluid (FF) of Indian women undergoing IVF/ICSI 1 year before and immediately after the lockdown initiated by the COVID-19 pandemic. SETTING: In vitro fertilization center in a large referral hospital in India. PATIENT(S): A total of 176 Indian women seeking treatment for infertility and undergoing oocyte retrieval were included after obtaining consent. Each woman contributed one FF sample to the study. Group A (n = 96) women (mean age, 34.0 [±3.9] years, and mean BMI, 25.4 [±4.8]) had their FF samples collected and screened between January 2019 and mid-March 2020, 1 year before the lockdown. Group B (n = 80) women (mean age, 33.9 [±4.1] years, and mean BMI, 25.0 [±4.4]) had their FF collected and screened post the lockdown between October 2020 and June 2021. Both groups were matched by age and BMI. INTERVENTION(S): The cryopreserved FF samples of 176 women were processed using enzymatic deconjugation as well as the solid-phase extraction technique, and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to detect the total levels of six phthalate metabolites. MAIN OUTCOME MEASURE(S): To evaluate the impact of the COVID-19 lockdown on the change in the phthalate metabolite levels in the FF of Indian women undergoing IVF/ICSI pre and post the lockdown. RESULT(S): The median levels of mono-n-butyl phthalate (1.64 ng/ml in group A vs. 0.93 ng/ml in group B; P<.001) and mono-ethyl phthalate (5.25 ng/ml in group A vs. 3.24 ng/ml in group B; P<.001) metabolites of dibutyl phthalate and diethyl phthalate found in PCPs including cosmetics and fragrances were significantly higher in the FF of 96 women (group A) compared with the levels seen in the FF of 80 women (group B). However, the median levels of mono-isononyl phthalate (0.11ng/ml in group A vs. 0.13 ng/ml in group B; P<.001), mono-isodecyl phthalate (0.11 ng/ml in group A vs. 0.14 ng/ml in group B; P<.001), and mono(2-ethyl-5-oxohexyl) phthalate (0.13 ng/ml in group A vs. 0.14 ng/ml in group B; P=.023) metabolites of di-isononyl phthalate, di-isodecyl phthalate, and di(2-ethylhexyl) phthalate used as plasticizers were significantly higher in the FF of women in group B compared with women in group A. CONCLUSION(S): The significant drop in mono-n-butyl phthalate and mono-ethyl phthalate levels, accumulated in the FF of 80 Indian women in group B reflects a decrease or absence of usage patterns of PCPs, including cosmetics and fragrances, thereby suggesting that these women may have deprioritized their use during the COVID-19 pandemic giving preference to personal hygiene and safety. Whereas the unprecedented increase in the use of flexible single-use plastic that became our first line of defense against the coronavirus during the COVID-19 pandemic might be responsible for the accumulation of significantly higher levels of mono-isononyl phthalate, mono-isodecyl phthalate, and mono(2-ethyl-5-oxohexyl) phthalate in FF of the same group.

Cytotoxic and apoptotic data of BPA and BPA alternatives TMBPF, BPAF, and BPS in female adult rat and human stem cells.

Here, we used female adult rat adipose-derived stem cells (rASCs) and human adipose-derived stem cells (hASCs) to compare the toxicities and potencies of several widespread environmental toxins that may be endocrine-disrupting chemicals, including bisphenol A (BPA), and the newer BPA alternatives bisphenol S (BPS), bisphenol AF (BPAF), and tetramethyl bisphenol F (TMBPF). Adult stem cells were cultured to 80% confluency in vitro and then exposed to BPA (1 and 10 µM), 17ß-estradiol (E2; 10 µM), BPS (1 and 10 µM), BPAF (3 × 10-3-30 µM), TMBPF (0.01-50 µM), or control media alone (with 0.01% ethanol) for varying time intervals from 20 min to 5 hrs. Using several cellular assays, the levels of cell death, apoptosis, caspase-6 activation, and potencies were compared across chemical treatments and vehicle-treated controls. There was significantly decreased cell viability and increased apoptosis in rat and human stem cells treated with each BPA analog, as early as 20 min of exposure, and at low doses. With higher magnification, higher resolution imaging it was evident that in many of the BPA analog-treated cells, the Apopxin Deep Red dye indicative of apoptosis was localized to the cytoplasmic compartments of cells, while the nuclear green DCS1 dye indicative of late-stage apoptosis and necrosis was localized to the nuclei of cells. Notably, BPAF and TMBPF showed cytotoxicity in a dose-dependent manner (BPAF LC50 = 0.014 µM (rASCs) and 0.009 µM (hASCs); TMBPF LC50 = 0.88 µM (rASCs) and 0.06 µM (hASCs); lethal concentration with 50% survival). The rank order of potency was BPAF>TMBPF>BPA>BPS. The majority of cell death was due to apoptosis as indicated by high levels of activated caspase-6 in the cytoplasm of almost 100% of cells treated with the BPA analogs. This data allows for further confirmation of caspase-6-mediated apoptosis using higher magnification imaging that definitively demonstrate the cytotoxic and apoptotic effects of these BPA analogs. For a complete description, interpretation, and discussion of the data refer to the article in press [1].

Endocrine-Disrupting Chemicals and Infectious Diseases: From Endocrine Disruption to Immunosuppression.

Endocrine-disrupting chemicals (EDCs) are hormonally active compounds in the environment that interfere with the body's endocrine system and consequently produce adverse health effects. Despite persistent public health concerns, EDCs remain important components of common consumer products, thus representing ubiquitous contaminants to humans. While scientific evidence confirmed their contribution to the severity of Influenza A virus (H1N1) in the animal model, their roles in susceptibility and clinical outcome of the coronavirus disease (COVID-19) cannot be underestimated. Since its emergence in late 2019, clinical reports on COVID-19 have confirmed that severe disease and death occur in persons aged ≥65 years and those with underlying comorbidities. Major comorbidities of COVID-19 include diabetes, obesity, cardiovascular disease, hypertension, cancer, and kidney and liver diseases. Meanwhile, long-term exposure to EDCs contributes significantly to the onset and progression of these comorbid diseases. Besides, EDCs play vital roles in the disruption of the body's immune system. Here, we review the recent literature on the roles of EDCs in comorbidities contributing to COVID-19 mortality, impacts of EDCs on the immune system, and recent articles linking EDCs to COVID-19 risks. We also recommend methodologies that could be adopted to comprehensively study the role of EDCs in COVID-19 risk.

Association of urinary bisphenols during pregnancy with maternal, cord blood and childhood thyroid function.

BACKGROUND: Most pregnant women are exposed to bisphenols, a group of chemicals that can interfere with various components of the thyroid system. OBJECTIVES: To investigate the association of maternal urinary bisphenol concentrations during pregnancy with maternal, newborn and early childhood thyroid function. METHODS: This study was embedded in Generation R, a prospective, population-based birth cohort (Rotterdam, the Netherlands). Maternal urine samples were analyzed for eight bisphenols at early (<18), mid (18-25) and late (>25 weeks) pregnancy. Maternal serum thyroid stimulating hormone (TSH), free thyroxine (FT4) and total thyroxine (TT4) were measured in early pregnancy and child TSH and FT4 were measured in cord blood and childhood. RESULTS: The final study population comprised 1,267 mothers, 853 newborns and 882 children. Of the eight bisphenols measured, only bisphenol A (BPA) was detected in >50% of samples at all three time-points and bisphenol S (BPS) at the first time-point. There was no association of BPA or the bisphenol molar sum with maternal thyroid function. Higher BPS concentrations were associated with a higher maternal TT4 (ß [95% CI] per 1 (natural-log) unit increase: 0.97 [0.03 to 1.91]) but there was no association with TSH or FT4. Furthermore, higher BPS was associated with an attenuation of the association between maternal FT4 and TSH (Pinteraction = 0.001). There was no association of early or mid-pregnancy BPA or early pregnancy BPS with cord blood or childhood TSH and FT4. A higher late pregnancy maternal BPA exposure was associated with a higher TSH in female newborns (Pinteraction = 0.06) and a higher FT4 during childhood in males (Pinteraction = 0.08). DISCUSSION: Our findings show that exposure to bisphenols may interfere with the thyroid system during pregnancy. Furthermore, the potential developmental toxicity of exposure to bisphenols during pregnancy could affect the thyroid system in the offspring in a sex-specific manner.