Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
Department of Animal Sciences, School of Environmental & Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
Endocrinology. 2020 Nov 1;161(11). doi: 10.1210/endocr/bqaa168.
Organophosphate flame retardants (OPFRs) are a class of chemicals that have become near ubiquitous in the modern environment. While OPFRs provide valuable protection against flammability of household items, they are increasingly implicated as an endocrine disrupting chemical (EDC). We previously reported that exposure to a mixture of OPFRs causes sex-dependent disruptions of energy homeostasis through alterations in ingestive behavior and activity in adult mice. Because feeding behavior and energy expenditure are largely coordinated by the hypothalamus, we hypothesized that OPFR disruption of energy homeostasis may occur through EDC action on melanocortin circuitry within the arcuate nucleus. To this end, we exposed male and female transgenic mice expressing green fluorescent protein in either neuropeptide Y (NPY) or proopiomelanocortin (POMC) neurons to a common mixture of OPFRs (triphenyl phosphate, tricresyl phosphate, and tris(1,3-dichloro-2-propyl)phosphate; each 1 mg/kg bodyweight/day) for 4 weeks. We then electrophysiologically examined neuronal properties using whole-cell patch clamp technique. OPFR exposure depolarized the resting membrane of NPY neurons and dampened a hyperpolarizing K+ current known as the M-current within the same neurons from female mice. These neurons were further demonstrated to have increased sensitivity to ghrelin excitation, which more potently reduced the M-current in OPFR-exposed females. POMC neurons from female mice exhibited elevated baseline excitability and are indicated in receiving greater excitatory synaptic input when exposed to OPFRs. Together, these data support a sex-selective effect of OPFRs to increase neuronal output from the melanocortin circuitry governing feeding behavior and energy expenditure, and give reason for further examination of OPFR impact on human health.
有机磷阻燃剂 (OPFRs) 是一类在现代环境中几乎无处不在的化学物质。虽然 OPFRs 为防止家庭用品易燃提供了有价值的保护，但它们越来越被认为是一种内分泌干扰化学物质 (EDC)。我们之前报道过，暴露于 OPFR 混合物中会导致成年雄性和雌性小鼠的摄食行为和活动发生性别依赖性的能量稳态紊乱。由于摄食行为和能量消耗主要由下丘脑协调，我们假设 OPFR 对能量稳态的破坏可能是通过 EDC 对弓状核中黑皮质素电路的作用发生的。为此，我们使表达绿色荧光蛋白的雄性和雌性转基因小鼠暴露于常见的 OPFR 混合物（磷酸三苯酯、磷酸三邻甲苯酯和磷酸三(1,3-二氯-2-丙基)酯；每种 1mg/kg 体重/天）4 周。然后，我们使用全细胞膜片钳技术电生理检查神经元特性。OPFR 暴露使 NPY 神经元的静息膜去极化，并使来自雌性小鼠的相同神经元中的一种超极化 K+电流（称为 M 电流）减弱。进一步证明这些神经元对 ghrelin 兴奋的敏感性增加，这更有效地减少了 OPFR 暴露雌性动物的 M 电流。来自雌性小鼠的 POMC 神经元表现出更高的基线兴奋性，并且在暴露于 OPFR 时被指示接收更大的兴奋性突触输入。总的来说，这些数据支持 OPFR 对调节摄食行为和能量消耗的黑皮质素电路中神经元输出的性别选择性影响，并为进一步研究 OPFR 对人类健康的影响提供了依据。
