Maternal exposure to ambient black carbon particles and their presence in maternal and fetal circulation and organs : an analysis of two independent population-based observational studies

Funding European Research Council, Flemish Scientific Research Foundation, Kom op Tegen Kanker, UK Medical Research Council, and EU Horizon 2020. Acknowledgments The ENVIRONAGE birth cohort was initiated by the European Research Council (ERC-2012-StG 310898) and received additional funding from the Flemish Scientific Research Foundation and Kom op Tegen Kanker (KoTK). The detection equipment was funded by the METHUSALEM Program and the INCALO project (ERC-PoC). We acknowledge the Flemish Scientific Research Foundation (FWO; 1150920N to EB and G082317N). The SAFeR study was funded by the UK Medical Research Council (MR/L010011/1 and MR/P011535/1) and the EU's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie project PROTECTED (grant agreement number 722634) and FREIA project (grant agreement number 825100) as well as by NHS Grampian Endowments grants (16/11/056, 17/034, 18/14, 19/029, and 20/031) to PAF. We thank the midwives from the maternity ward of the East-Limburg Hospital in Genk, Belgium, for coordinating and supporting the study at the ward. We thank the Advanced Optical Microscopy Centre for the maintenance of the microscopic instruments. Moreover, we thank our colleagues from the Centre for Environmental Sciences for their hard work in collecting and processing the samples for the ENVIRONAGE birth cohort. Additionally, we thank the NHS Grampian Research Nurses and NHS Grampian R&D for their tireless recruitment work for the SAFeR study. We thank the past and present SAFeR team for their hard work with the fetuses and placentae. Finally, we thank the NHS Grampian Biorepository for their oversight role in SAFeR and assistance in processing and preparation of tissue sections.Peer reviewedPublisher PD

Acetaminophen (APAP, paracetamol) interferes with the first trimester human fetal ovary development in an ex vivo model

International audienceCONTEXT: Acetaminophen (APAP, paracetamol) is widely used by pregnant women. Although long considered safe, growing evidence indicates that APAP is an endocrine disruptor since in utero exposure may be associated with a higher risk of male genital tract abnormalities. In rodents, fetal exposure has long-term effects on the reproductive function of female offspring. Human studies have also suggested harmful APAP exposure effects. OBJECTIVE: Given that disruption of fetal ovarian development may impact women’s reproductive health, we investigated the effects of APAP on fetal human ovaries in culture. DESIGN AND SETTING: Human ovarian fragments from 284 fetuses aged 7 to 12 developmental weeks (DW) were cultivated ex vivo for 7 days in the presence of human-relevant concentrations of APAP (10 -8 to 10 -3 M) or vehicle control. MAIN OUTCOME MEASURES: Outcomes included examination of postculture tissue morphology, cell viability, apoptosis, and quantification of hormones, APAP and APAP metabolites in conditioned culture media. RESULTS: APAP reduced the total cell number specifically in 10-12 DW ovaries induced cell death and decreased KI67-positive cell density independently of fetal age. APAP targeted sub-populations of germ cells and disrupted human fetal ovarian steroidogenesis, without affecting prostaglandin or inhibin B production. Human fetal ovaries were able to metabolize APAP. CONCLUSIONS: Our data indicate that APAP can impact first trimester human fetal ovarian development, especially during a 10-12 DW window of heightened sensitivity. Overall, APAP behaves as an endocrine disruptor in the fetal human ovary

The profile of steroid hormones in human fetal and adult ovaries

International audienceBackground: Reproduction in women is at risk due to exposure to chemicals that can disrupt the endocrine system during different windows of sensitivity throughout life. Steroid hormone levels are fundamental for the normal development and function of the human reproductive system, including the ovary. This study aims to elucidate steroidogenesis at different life-stages in human ovaries.Methods: We have developed a sensitive and specific LC-MS/MS method for 21 important steroid hormones and measured them at different life stages: in media from cultures of human fetal ovaries collected from elective terminations of normally progressing pregnancy and in media from adult ovaries from Caesarean section patients, and follicular fluid from women undergoing infertility treatment. Statistically significant differences in steroid hormone levels and their ratios were calculated with parametric tests. Principal component analysis (PCA) was applied to explore clustering of the ovarian-derived steroidogenic profiles.Results: Comparison of the 21 steroid hormones revealed clear differences between the various ovarian-derived steroid profiles. Interestingly, we found biosynthesis of both canonical and \"backdoor\" pathway steroid hormones and corticosteroids in first and second trimester fetal and adult ovarian tissue cultures. 17α-estradiol, a less potent naturally occurring isomer of 17β-estradiol, was detected only in follicular fluid. PCA of the ovarian-derived profiles revealed clusters from: adult ovarian tissue cultures with relatively high levels of androgens; first trimester and second trimester fetal ovarian tissue cultures with relatively low estrogen levels; follicular fluid with the lowest androgens, but highest corticosteroid, progestogen and estradiol levels. Furthermore, ratios of specific steroid hormones showed higher estradiol/ testosterone and estrone/androstenedione (indicating higher CYP19A1 activity, p < 0.01) and higher 17-hydroxyprogesterone/progesterone and dehydroepiandrosterone /androstenedione (indicating higher CYP17A1 activity, p < 0.01) in fetal compared to adult ovarian tissue cultures.Conclusions: Human ovaries demonstrate de novo synthesis of non-canonical and \"backdoor\" pathway steroid hormones and corticosteroids. Elucidating the steroid profiles in human ovaries improves our understanding of physiological, life-stage dependent, steroidogenic capacity of ovaries and will inform mechanistic studies to identify endocrine disrupting chemicals that affect female reproduction

Exposure of human fetal kidneys to mild analgesics interferes with early nephrogenesis

International audienceAcetaminophen, aspirin, and ibuprofen are mild analgesics commonly used by pregnant women, the sole current recommendation being to avoid ibuprofen from the fifth month of gestation. The nephrotoxicity of these three analgesics is well documented in adults, as is their interference with prostaglandins biosynthesis. Here we investigated the effect of these analgesics on human first trimester kidneys ex vivo. We first evaluated prostaglandins biosynthesis functionality by performing a wide screening of prostaglandin expression patterns in first trimester human kidneys. We demonstrated that prostaglandins biosynthesis machinery is functional during early nephrogenesis. Human fetal kidney explants aged 7-12 developmental weeks were exposed ex vivo to ibuprofen, aspirin or acetaminophen for 7 days, and analyzed by histology, immunohistochemistry, and flow cytometry. This study has revealed that these analgesics induced a spectrum of abnormalities within early developing structures, ranging from cell death to a decline in differentiating glomeruli density. These results warrant caution for the use of these medicines during the first trimester of pregnancy