The effects of endocrine-disrupting chemicals on ovarian- and ovulation-related fertility outcomes.

Exposure to endocrine-disrupting chemicals (EDCs) is unavoidable, which represents a public health concern given the ability of EDCs to target the ovary. However, there is a large gap in the knowledge about the impact of EDCs on ovarian function, including the process of ovulation. Defects in ovulation are the leading cause of infertility in women, and EDC exposures are contributing to the prevalence of infertility. Thus, investigating the effects of EDCs on the ovary and ovulation is an emerging area for research and is the focus of this review. The effects of EDCs on gametogenesis, uterine function, embryonic development, and other aspects of fertility are not addressed to focus on ovarian- and ovulation-related fertility issues. Herein, findings from epidemiological and basic science studies are summarized for several EDCs, including phthalates, bisphenols, per- and poly-fluoroalkyl substances, flame retardants, parabens, and triclosan. Epidemiological literature suggests that exposure is associated with impaired fecundity and in vitro fertilization outcomes (decreased egg yield, pregnancies, and births), while basic science literature reports altered ovarian follicle and corpora lutea numbers, altered hormone levels, and impaired ovulatory processes. Future directions include identification of the mechanisms by which EDCs disrupt ovulation leading to infertility, especially in women.

Hippocampal Gαq/11 but not Gαo-coupled receptors are altered in aging.

Normal aging may limit the signaling efficacy of certain GPCRs by disturbing the function of specific Gα-subunits and leading to deficient modulation of intracellular functions that subserve synaptic plasticity, learning and memory. Evidence suggests that Gαq/11 is more sensitive to the effects of aging relative to other Gα-subunits, including Gαo. To test this hypothesis, the functionality of Gαq/11 and Gαo were compared in the hippocampus of young (6 months) and aged (24 months) F344 × BNF1 hybrid rats assessed for spatial learning ability. Basal GTPγS-binding to Gαq/11 was significantly elevated in aged rats relative to young and but not reliably associated with spatial learning. mAChR stimulation of Gαq/11 with oxotremorine-M produced equivocal GTPγS-binding between age groups although values tended to be lower in the aged hippocampus and were inversely related to basal activity. Downstream Gαq/11 function was measured in hippocampal subregion CA1 by determining changes in [Ca(2+)]i after mAChR and mGluR (DHPG) stimulation. mAChR-stimulated peak change in [Ca(2+)]i was lower in aged CA1 relative to young while mGluR-mediated integrated [Ca(2+)]i responses tended to be larger in aged. GPCR modulation of [Ca(2+)]i was observed to depend on intracellular stores to a greater degree in aged than young. In contrast, measures of Gαo-mediated GTPγS-binding were stable across age, including basal, mAChR-, GABABR (baclofen)-stimulated levels. Overall, the data indicate that aging selectively modulates the activity of Gαq/11 within the hippocampus leading to deficient modulation of [Ca(2+)]i following stimulation of mAChRs but these changes are not related to spatial learning.

Cannabinoid receptor activation modifies NMDA receptor mediated release of intracellular calcium: implications for endocannabinoid control of hippocampal neural plasticity.

Chronic activation or inhibition of cannabinoid receptors (CB1) leads to continuous suppression of neuronal plasticity in hippocampus and other brain regions, suggesting that endocannabinoids may have a functional role in synaptic processes that produce state-dependent transient modulation of hippocampal cell activity. In support of this, it has previously been shown in vitro that cannabinoid CB1 receptors modulate second messenger systems in hippocampal neurons that can regulate operation of intracellular processes including receptors which release calcium from intracellular stores. Here we demonstrate in hippocampal slices a similar endocannabinoid action on excitatory glutamatergic synapses via modulation of NMDA-receptor mediated intracellular calcium levels in confocal imaged neurons. Calcium entry through glutamatergic NMDA-mediated ion channels increases intracellular calcium concentrations by modifying release from ryanodine-sensitive channels in endoplasmic reticulum. The studies reported here show that NMDA-elicited increases in Calcium Green fluorescence are enhanced by CB1 receptor antagonists (i.e., Rimonabant), and inhibited by CB1 agonists (i.e., WIN 55,212-2). Suppression of endocannabinoid breakdown by either reuptake inhibition (AM404) or fatty-acid amide hydrolase inhibition (URB597) produced suppression of NMDA-elicited calcium increases comparable to WIN 55,212-2, while enhancement of calcium release provoked by endocannabinoid receptor antagonists (Rimonabant) was shown to depend on the blockade of CB1receptor mediated de-phosphorylation of Ryanodine receptors. Such CB1 receptor modulation of NMDA elicited increases in intracellular calcium may account for the respective disruption and enhancement by CB1 agents of trial-specific hippocampal neuron ensemble firing patterns during performance of a short-term memory task, reported previously from this laboratory.

Examination of murine tear film.

PURPOSE: To define spatially any free aqueous layer in murine tear film. METHOD: A pre-zeroed microelectrode was touched to the superficial corneal epithelium and then raised in steps of 1 micro m through the murine tear film into the air and then retraced along the same path. Other murine tear films were partially probed with a spatial resolution of 0.1 micro m. The reference microelectrode was placed in a fragment of 3% polyacrylamide gel equilibrated against 154 mM NaCl and located on the nasal quadrant of the scleral conjunctiva. Other murine corneas were quick frozen in melting isopentane and freeze substituted or pretreated with cetylpyridinium chloride and then examined by transmission electron microscopy. RESULTS: The recorded electrical profiles of the tear film were reproducible in each preparation and showed a relatively uniform positive electrical potential throughout their whole thickness, except within 0.5 micro m of the epithelial surface when the potential reversed to negative values. The thickness of mouse tear film averaged 7.4 +/- 0.8 micro m (mean +/- SD, n = 40). The electron microscope images showed the murine tear film to have a relatively uniform positive electron density throughout the thickness. CONCLUSIONS: Electrical profiles of the murine tear film presented no evidence of a separate free aqueous phase. The tear film is observed as an aqueous gel that includes anion-exchanging polyelectrolytes throughout most of its thickness, but within 0.5 micro m of the epithelial surface, it changes to cation-exchanging polyelectrolytes. Electron microscope images provide some supporting evidence.

The National Resident Matching Program and antitrust law.

In May 2002, a group of physicians filed a class action lawsuit alleging that the National Resident Matching Program (NRMP) violates antitrust laws. The plaintiffs contend that NRMP practices have stabilized lower-than-competitive wages and imposed exhausting working conditions on residents. They also maintain that NRMP procedures virtually force applicants for house officer positions to forfeit their right to negotiate for better wages and conditions. The plaintiffs also allege that the defendants have collectively fostered anticompetitive accreditation standards through the Accreditation Council for Graduate Medical Education. Jung v Association of American Medical Colleges could present antitrust law with some difficult challenges. Although the matching program on its face appears to limit competition in a manner that previous cases have found illegal, it operates in the context of important professional activities (medical education and quality improvement) that may generate some judicial deference. At this early stage, no confident prediction can be made about the outcome of the case if it goes to trial; however, the plaintiffs appear to have a plausible case under existing antitrust doctrine, and lengthy litigation is possible. Given the important questions that the litigation will not address, such as the potential costs of a finding of illegality to the government and other payers, and the impact of such a finding on the health care system as a whole, a legislative solution seems highly desirable.