Multi- and Transgenerational Outcomes of an Exposure to a Mixture of Endocrine-Disrupting Chemicals (EDCs) on Puberty and Maternal Behavior in the Female Rat.

peer reviewedBACKGROUND: The effects of endocrine-disrupting chemicals (EDCs) on fertility and reproductive development represent a rising concern in modern societies. Although the neuroendocrine control of sexual maturation is a major target of EDCs, little is known about the potential role of the hypothalamus in puberty and ovulation disruption transmitted across generations. OBJECTIVES: We hypothesized that developmental exposure to an environmentally relevant dose of EDC mixture could induce multi- and/or transgenerational alterations of sexual maturation and maternal care in female rats through epigenetic reprograming of the hypothalamus. We investigated the transmission of a disrupted reproductive phenotype via the maternal germline or via nongenomic mechanisms involving maternal care. METHODS: Adult female Wistar rats were exposed prior to and during gestation and until the end of lactation to a mixture of the following 13 EDCs: di-n-butyl phthalate (DnBP), di(2-ethylhexyl) phthalate (DEHP), bisphenol A (BPA), vinclozolin, prochloraz, procymidone, linuron, epoxynaxole, dichlorodiphenyldichloroethylene, octyl methoxynimmate, 4-methylbenzylidene camphor (4-MBC), butylparaben, and acetaminophen. Perinatally exposed offspring (F1) were mated with unexposed males to generate germ cell (F2) and transgenerationally exposed (F3 and F4) females. Sexual maturation, maternal behavior, and hypothalamic targets of exposure were studied across generations. RESULTS: Germ cell (F2) and transgenerationally (F3) EDC-exposed females, but not F1, displayed delayed pubertal onset and altered folliculogenesis. We reported a transgenerational alteration of key hypothalamic genes controlling puberty and ovulation (Kiss1, Esr1, and Oxt), and we identified the hypothalamic polycomb group of epigenetic repressors as actors of this mechanism. Furthermore, we found a multigenerational reduction of maternal behavior (F1-F3) induced by a loss in hypothalamic dopaminergic signaling. Using a cross-fostering paradigm, we identified that the reduction in maternal phenotype was normalized in EDC-exposed pups raised by unexposed dams, but no reversal of the pubertal phenotype was achieved. DISCUSSION: Rats developmentally exposed to an EDC mixture exhibited multi- and transgenerational disruption of sexual maturation and maternal care via hypothalamic epigenetic reprogramming. These results raise concerns about the impact of EDC mixtures on future generations. https://doi.org/10.1289/EHP8795

Synthesis of hydrophilic CuInS2/ZnS quantum dots with different polymeric shells and study of their cytotoxicity and hemocompatibility

biomimedic

Induction of oxidative stress and alteration of synaptic gene expression in newborn hippocampal granule cells after developmental exposure to Aroclor 1254.

peer reviewedINTRODUCTION: Hippocampal newborn neurons integrate into functional circuits where they play an important role in learning and memory. We previously showed that perinatal exposure to Aroclor 1254, a commercial mixture of polychlorinated biphenyls (PCBs) associated with alterations of cognitive function in children, disrupted the normal maturation of excitatory synapses in the dentate gyrus. We hypothesized that hippocampal immature neurons underlie some of the cognitive effects of PCBs. METHODS: We used newly-generated neurons to examine the effects of PCBs in mice following maternal exposure. Newborn dentate granule cells were tagged with enhanced green fluorescent protein (EGFP) using a transgenic mouse line. The transcriptome of the newly generated granule cells was assessed using RNA sequencing. RESULTS: Gestational and lactational exposure to 6 mg/kg/day of Aroclor 1254 disrupted the mRNA expression of 1308 genes in newborn granule cells. Genes involved in mitochondrial functions were highly enriched with 154 genes significantly increased in exposed compared to control mice. The upregulation of genes involved in oxidative phosphorylation was accompanied by signs of endoplasmic reticulum stress and an increase in lipid peroxidation, a marker of oxidative stress, in the subgranular zone of the dentate gyrus but not in mature granule cells in the granular zone. Aroclor 1254 exposure also disrupted the expression of synaptic genes. Using laser-captured subgranular and granular zones, this effect was restricted to the subgranular zone, where newborn neurons are located. CONCLUSION: Our data suggest that gene expression in newborn granule cells is disrupted by Aroclor 1254 and provide clues to the effects of endocrine disrupting chemicals on the brain

Persistent vs Transient Alteration of Folliculogenesis and Estrous Cycle After Neonatal vs Adult Exposure to Bisphenol A.

Exposure to bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical (EDC), is known to produce variable effects on female puberty and ovulation. This variability of effects is possibly due to differences in dose and period of exposure. Little is known about the effects of adult exposure to environmentally relevant doses of this EDC and the differences in effect after neonatal exposure. This study sought to compare the effects of neonatal vs adult exposure to a very low dose or a high dose of BPA for 2 weeks on ovulation and folliculogenesis and to explore the hypothalamic mechanisms involved in such disruption by BPA. One-day-old and 90-day-old female rats received daily subcutaneous injections of corn oil (vehicle) or BPA (25 ng/kg/d or 5 mg/kg/d) for 15 days. Neonatal exposure to both BPA doses significantly disrupted the estrous cycle and induced a decrease in primordial follicles. Effects on estrous cyclicity and folliculogenesis persisted into adulthood, consistent with a disruption of organizational mechanisms. During adult exposure, both doses caused a reversible decrease in antral follicles and corpora lutea. A reversible disruption of the estrous cycle associated with a delay and a decrease in the amplitude of the LH surge was also observed. Alterations of the hypothalamic expression of the clock gene Per1 and the reproductive peptide phoenixin indicated a disruption of the hypothalamic control of the preovulatory LH surge by BPA

Chitosan-g-lactide copolymers for fabrication of 3D scaffolds for tissue engineering

peer reviewedBiomimedic

Synthesis of Hydrophilic CuInS₂/ZnS Quantum Dots with Different Polymeric Shells and Study of Their Cytotoxicity and Hemocompatibility

In this work, there is a detailed description of the whole process of biocompatible CIS/ZnS QDs production. Special attention was paid to the stability of QDs against photooxidation. It was shown that Cu/In ratio greatly affected not only nanocrystals PLQYs but photostability as well. CIS/ZnS QDs with Cu/In = 1:4 ratio showed high photostability under UV illumination both in toluene and aqueous solutions. Meanwhile, photoluminescence of CIS/ZnS QDs with Cu/In = 1:1 ratio was completely quenched after several hours under UV illumination, though their initial QY was as high as 40% with peak maximum at 740 nm. QDs were transferred to water by polymer encapsulation and were subsequently modified with polyethers Jeffamines, cheap analogues of PEG-derivatives. Three types of hydrophilic QDs differing in size, PEG content, and surface charge were obtained for further investigation and comparison of their cytotoxicity and hemocompatibility. It was shown that both leucocytes size distribution and coagulation activation change after introduction of polyethers into QDs polymeric shell, while red blood cells and platelets size distribution as well as hemolysis rate did not show any different results among different QDs and the polymer itself. All three types of QDs showed only slight cytotoxicity. Confocal microscopy proves penetration of hydrophilic CIS/ZnS QDs inside cells, so the low QDs cytotoxocity cannot be explained by low cellular uptake of the QDs and indicated low QDs toxicity in general