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译作分享|环境内分泌干扰物对青春期发育的影响（下）
2023年02月06日

译作分享


Effects of Environmental Endocrine Disruptors on Pubertal Development

环境内分泌干扰物对青春期发育的影响

Samim Özen1, fiükran Darcan2

1Pediatric Endocrinology Unit, Mersin Children Hospital, Mersin, Turkey

2Department of Pediatric Endocrinology and Metabolism, Ege University School of Medicine, Izmir, Turkey

接上文

Animal Studies/动物研究

EDs have first been noted in experimental studies and gained significance through evidence from animal experience. Following the accidental spill of high amounts of dichlorodiphenyltrichloroethane (DDT) and dicofol from a chemical company into Lake Apopka in Florida in 1980s, it has been noted that male alligators living in the lake had smaller phalluses, reduced serum testosterone levels and abnormal gonadal structures concurrently with high serum DDT levels (14). It was observed that administration of methoxychlor, a pesticide with potential estrogenic effects, in female rats during pregnancy and lactation periods, led to vaginal opening and appearance of puberty at a very early age in their female offspring (15). Similarly, accelerated and early vaginal opening was noted in female rats following subcutaneous injections of bisphenol A (BPA), genistein, resvetarol, zearalenone or DES in the prenatal period, findings confirming the estrogenic effects of these chemicals (16,17). Administration of methoxychlor or 17 beta-estradiol after the cessation of breastfeeding also resulted in early vaginal opening in female rats (15,17). In addition, Markey et al (18) showed that prenatal exposure to BPA caused early growth and proliferation of breast tissue as well as increased susceptibility to endogenous estrogen in female rats. Methoxychlor, an antiandrogenic and estrogenic agent, and also vinclozolin, an antiandrogenic agent, were shown to lead to delayed puberty in male rats and precocious puberty in female rats (19). 
EDs在一次实验性研究中被首次注意到，并在之后因动物研究获得的证据得到重视。1980年代，一家化学企业意外将大量二氯二苯基三氯乙烷（DDT）和三氯杀螨醇泄漏到佛罗里达州Apopka湖，人们注意到，生活在湖中的雄性鳄鱼的阴茎变小，血清睾丸水平降低，性腺结构异常，同时血清DDT水平较高（14）。据观察，对怀孕和哺乳期内的雌性大鼠施用具有潜在雌激素作用的杀虫剂甲氧氯，会导致雌性后代在很小的年龄就出现阴道开放和青春期（15）。同样，在产前期间皮下注射双酚A（BPA）、染料木黄酮、白藜芦醇、玉米赤霉烯酮或己烯雌酚（DES）后，雌性大鼠的阴道开放加速并提前，这些发现证实了以上化学物质的雌激素作用（16,17）。在停止母乳喂养后服用甲氧基氯或17β-雌二醇，也会导致雌性大鼠阴道开放提前（15,17）。此外，Markey等人（18）表明，产前接触BPA会导致雌性大鼠乳房组织的早期生长和增殖，以及雌性大鼠对内源性雌激素的敏感性增加。甲氧基氯（一种抗雄激素和雌激素）和长春唑啉（一种抗雄激素）已被证明会导致雄性大鼠的青春期延迟和雌性大鼠的性早熟（19）。

Dioxins are environmentally toxic chemicals. TCDD is a type of dioxin, which exerts its estrogenic or antiandrogenic effects by causing alterations in gene expression via binding to aryl hydrocarbon receptors. In utero, exposure of rodents to even low doses of this substance was found to result in reproductive system abnormalities and precocious puberty findings in the females and delayed puberty in the males (7,8,9,10,11,20,21,22). Other chemicals that can produce the same effects by binding to aryl hydrocarbon receptors include industrial products such as polychlorinated biphenyls (PCBs), polybrominated diphenyl ether and the pesticide methoprene (1,7,8,9,10,11).

二恶英是具有环境毒性的化学品。TCDD是二恶英的一种，通过与芳烃受体结合导致基因表达的改变来发挥其雌激素或抗雄激素作用。研究发现。在子宫内暴露于该物质的啮齿动物，即使是低剂量的，也会导致生殖系统异常和雌性的性早熟，及雄性的青春期延迟（7,8,9,10,11,20,21,22）。其他可以通过与芳烃受体结合产生相同效果的化学品包括工业产品，如多氯联苯（PCB）、多溴二苯醚和杀虫剂烯虫酯（1,7,8,9,10,11）。

Some of the environmental chemicals may impair neuroendocrine functions through their effect on the central nervous system and the hypothalamic-hypophysealgonadal (HHG) axis. These include pesticides such as thiram, molinate, metam sodium, chlordimeform, amitraz, triazoles, dichloroacetic acid, atrazine, propazine, simazine, methanol and linuron (1). It has been shown in a study on rats that atrazine causes delayed puberty by suppressing luteinizing hormone (LH) and prolactin levels (23,24,25). In rats prenatally exposed to BPA, an increase in estrogen feedback as well as development of precocious puberty via inhibition of tyrosine hydroxylase activity in rostral preoptic periventricular neurons have been observed (26). Howdeshell et al (27)also noted precocious puberty in rats prenatally exposed to BPA.

一些环境化学物质可能会通过对中枢神经系统和下丘脑-垂体-性腺（HHG）轴的影响而损害神经内分泌功能，其中包括杀虫剂，如噻嗪酮、莫林酸盐、米亚钠、氯丁胺类、双甲脒、三唑类、二氯乙酸、阿特拉津、丙嗪、西马津、甲醇和利谷隆（1）。一项对大鼠的研究表明，阿特拉津通过抑制黄体生成素（LH）和催乳素水平导致青春期延迟（23,24,25）。在产前接触BPA的大鼠中，观察到雌激素反馈的增加，并通过抑制视前脑室周围神经元中的酪氨酸羟化酶活性而发展为性早熟（26）。Howdeshell等人（27）也注意到产前暴露于BPA的大鼠出现了性早熟。

Some of the EDs affect puberty by inhibiting the synthesis of endogenous hormones such as testosterone, 17 beta-estradiol and adrenal steroids via competitive inhibition of P450 steroidogenic enzymes (C17,20-lyase, aromatase) (1). Delayed puberty has been reported by exposure to imidazole group fungicides, ketoconazole and fadrozole in the peripubertal period (28). Another pesticide, prochloraz, suppresses estrogen and androgen synthesis via inhibition of aromatase and 17,20-lyase (29,30).

一些EDs通过竞争性抑制P450类固醇生成酶（C17,20-裂解酶、芳香酶）来抑制内源性激素的合成，如睾酮、17β-雌二醇和肾上腺类固醇等来影响青春期（1）。据报道，在青春期周围期间接触咪唑类杀真菌剂、酮康唑和法德罗唑会导致青春期延迟（28）。另一种杀虫剂咪鲜胺通过抑制芳香化酶和17,20-裂解酶来抑制雌激素和雄激素的合成（29,30）。

Human Studies/人类研究

Studies have shown that several environmental chemical pollutants including DDT/ dichlorodiphenyldichloroethylene (DDE), PCBs, polybrominated biphenyls (PBB), hexachlorobenzene, endosulfan, dioxins, heavy metals and phthalates affect puberty in humans (1,2,3,4,5,6,7,8,9,10,11).
研究表明，一些环境化学污染物，包括滴滴涕/二氯二苯二氯乙烯（DDE）、多氯联苯、多溴联苯（PBB）、六氯苯、硫丹、二恶英、重金属和邻苯二甲酸盐影响人类的青春期（1,2,3,4,5,6,7,8,9,10,11）。

Following the pollution of the environment by PBB as a result of an industrial accident in the state of Michigan in 2000, Blanck et al (31,32)investigated the serum PBB levels in pregnant women and compared ages of puberty onset and menarche in their daughters who were or were not breast-fed. When the girls with intrauterine exposure to high PBB concentrations (>7ppm) were compared with the girls who had no exposure (<1ppm), menarche was observed to occur one year earlier in those who were exposed to high concentrations. Among those exposed to high concentrations, breast-fed girls were observed to have pubarche one year earlier than the girls who were not breast-fed. No significant difference in terms of breast development was reported in this study. Gladen et al (33) found a relationship between intrauterine exposure to high doses of these pesticides and early thelarche and early pubarche in girls. 

2000年密歇根州的一次工业事故导致环境被多溴联苯污染后，Blanck等人（31,32）调查了孕妇的血清多溴联苯水平，并比较了她们母乳喂养或未母乳喂养的女儿的青春期开始年龄和月经初潮。当宫内暴露于高浓度多溴联苯（>7ppm）的女孩与未暴露（<1ppm）的女孩进行比较时，观察到暴露于高浓度的女孩的月经初潮提前一年出现。在暴露于高浓度的女孩中，观察到母乳喂养的女孩比未母乳喂养的女孩提前一年出现青春期。这项研究没有报告乳房发育方面的明显差异。Gladen等人（33）发现，宫内暴露于高剂量的上述杀虫剂与女孩的乳房发育提前和阴毛初现提前之间存在关系。

Effects of DDT, with proven estrogenic effect, and its metabolite DDE on pubertal development have been investigated in several studies. After their detrimental effects had been explicated, DDT and its metabolites, formerly used widely as pesticides in agriculture, were banned in many countries. Its use has also been forbidden in Turkey since 1985. Vasiliu et al (34) reported that menarche occurred 1 year earlier in girls exposed to high amounts of DDT/DDE in the intrauterine period. Krstevska-Konstantinova et al (35) found that precocious puberty was 80 times more frequent and serum DDE levels significantly higher in daughters of immigrants compared to native Belgians. An association between serum DDT/DDE concentrations and early menarche was reported in a study conducted in Chinese textile workers (36).
有几项研究调查了已证明具有雌激素作用的DDT及其代谢物DDE对青春期发育的影响。在解释了它们的有害影响后，DDT及其代谢物（以前被广泛用作农业杀虫剂）在许多国家被禁止。自1985年以来，土耳其也禁止使用该物质。Vasiliu等人（34）的报告称，在宫内暴露于大量DDT/DDE的女孩，月经初潮提前1年出现。Krstevska-Konstantinova等人（35）发现，与比利时本土人相比，移民女儿出现性早熟的频率高80倍，其血清DDE水平明显更高。对中国纺织工人进行的一项研究中报告了血清DDT/DDE浓度与月经初潮提前之间的关联（36）。

Methoxychlor is an organochlorine widely used as a pesticide in agriculture. It was shown to impair reproductive behavior and functions in male rats due to its estrogenic effect (37). There are no human studies on the effects of this pesticide. Methoxychlor, which is a chlorinated hydrocarbon pesticide and has been introduced for use instead of DDT, accumulates in very little quantities in fat tissue. Although it has been reported to produce estrogenic effects similar to DDT and its metabolites in animal studies, there are no studies on the effects of this pesticide on precocious puberty in humans (15,38,39).

甲氧基氯是一种有机氯，在农业中广泛用作杀虫剂。由于其雌激素作用，甲氧基氯已被证明会损害雄性大鼠的生殖行为和功能（37）。目前还没有关于其对人类影响的研究。甲氧基氯是一种氯化碳氢化合物农药，已引入用于代替DDT，在脂肪组织中的积累量较少。虽然在动物研究中，有报告称其可产生类似于DDT及其代谢物的雌激素作用，但目前还没有关于甲氧基氯对人类性早熟影响的研究（15,38,39）。

Endosulfan and its derivatives are pesticides widely used in agriculture and are thought to have antiandrogenic and estrogenic effects (1,2,3,4,5,6,7,8,9,10,11). In animal studies, endosulfan was reported to have an estrogenic effect and to cause inhibition of follicle-stimulating hormone (FSH), LH and testosterone production (40,41). In an Indian study, LH was found to be increased and testosterone levels decreased in men exposed to endosulfan (41).

硫丹及其衍生物是广泛用于农业的农药，被认为具有抗雄激素和雌激素作用（1,2,3,4,5,6,7,8,9,10,11）。在动物研究中，据报道，硫丹具有雌激素作用，并导致抑制促卵泡激素（FSH）、LH和睾酮的产生（40,41）。在印度的一项研究中发现，接触硫丹的男性LH升高，睾酮水平下降（41）。

In a recent Danish study, as compared to the normal population, significantly earlier thelarche in girls and more frequent genital abnormalities such as hypospadias, micropenis in boys were noted in children of greenhouse owners, and it was suggested that these findings were due to pesticides. However, no pesticide analysis was conducted in this study (42). Antiandrogenic effect of vinclozolin has been shown in male animals (43). Although the estrogenic effect of this chemical used widely in agriculture is not known for sure, it has been reported that it might have an antiandrogenic effect and produce an estrogen-like effect through stimulation of estrogen receptor α (44).

在丹麦最近的一项研究中认为，与正常人群相比，温室主人的孩子中，女孩出现乳房发育时间明显提前，男孩生殖器异常发生更频繁，如尿道下裂、微阴茎等，是由于杀虫剂导致的。然而，这项研究中没有进行农药分析（42）。农利灵的抗雄激素作用已在雄性动物上表现出来（43）。虽然这种广泛用于农业的化学品的雌激素作用尚不清楚，但据报道，它可能具有抗雄激素作用，并通过刺激雌激素受体α产生类似雌激素的效果（44）。

The effects of PCB exposure on puberty have also been investigated by several authors. There are several sub-types of this group of substances that are thought to have estrogenic effects (1,2,3,4,5,6,7,8,9). While no relationship was detected between intrauterine and/or postnatal exposure to PCB and age of puberty or menarche in some studies, it was reported in others that menarche occurred significantly earlier in girls who were exposed to PCB 52, 70, 101, +90 and 187 sub-groups (45,46).

一些作者还研究了多氯联苯暴露对青春期的影响。这类物质有几种亚型被认为具有雌激素作用（1,2,3,4,5,6,7,8,9）。虽然在一些研究中没有发现宫内和/或产后接触多氯联苯与青春期或月经初潮年龄之间的关系，但在其他研究中报告称，暴露于多氯联苯52、70、101、+90和187亚组的女孩中，月经初潮明显提前（45,46）。

Chlorine is used as a whitener in many solutions used in daily life. Dioxins are formed as by-products of incomplete combustion of chlorinated waste products. Contact of plastic products with hot surfaces (serving hot liquids or food in plastic glasses or plates, microwave use) may also lead to production of dioxins. Exposure of humans to huge amounts of dioxin is only possible in industrial accidents. However, exposure to very small amounts may occur due to the contact of several daily used substances such as plastic glasses, plates, toys, cleaning substances or paper whitened by chlorine with hot surfaces. Dioxins can be taken by animals through ingestion of contaminated soil, vegetables and water, and due to long-term adipose tissue accumulation, they may be transferred to humans from animal meat or milk (1,2,3,4,5,6,7,8,9,10,11). There are two human studies investigating this toxic substance, which has been found to be associated with estrogenic effect and precocious puberty in animal studies. In a Belgian study, Den Hond et al (47) observed a reduction in testicular volume in boys exposed to a substance with dioxin-like activity, but failed to note a change in pubertal development. In this same study, the authors reported a delay in the breast development in girls, but no change in age of menarche or pubarche. In a study on Italian girls, Warner et al (48) found no change in age of menarche in girls exposed to TCDD postnatally before the age of 5 years. Mothers of these children were not exposed to this substance during pregnancy or before.

在日常生活中使用的许多溶液中，氯被用作增白剂。二恶英是氯化废物不完全燃烧的副产品。塑料产品与发热的表面接触（用可微波炉使用的塑料杯或塑料盘子中盛装热液体或食物）也可能导致二恶英的产生。人类只有在工业事故中才有可能暴露于大量的二恶英。然而，由于日常接触的常见物品，如塑料杯、塑料盘子、塑料玩具、清洁剂或表面被氯漂白的纸张等与热表面接触，可能会出现非常少量的二恶英暴露。二恶英可通过受污染的土壤、蔬菜和水被动物摄取吸收，由于动物长期的脂肪组织积累，二恶英还可能从动物肉类或牛奶中转移到人体内（1,2,3,4,5,6,7,8,9,10,11）。有两项人类研究正在调查该物质，在动物研究中发现该物质与雌激素效应和性早熟有关。在比利时的一项研究中，Den Hond等人（47）观察到，接触二恶英样活性物质的男孩的睾丸体积减少，但未记录青春期发育的变化。在同一项研究中，作者还报告了女孩乳房发育的延迟，但月经初潮或青春期的年龄没有变化。在一项关于意大利女孩的研究中，Warner等人（48）发现，在出生后5岁之前暴露于TCDD的女孩的月经初潮年龄没有变化。这些孩子的母亲在怀孕期间或之前都没有接触过该物质。

Colon et al (49)observed significantly higher levels of phthalate esters in 31 Puerto Rican girls with early thelarche compared to controls. Phthalates are used as plastic softeners and as preservatives in some cosmetic products and they may be found in plastic toys, hair sprays, deodorants, shampoo, nail polish and perfumes, and may easily enter the human body (1,2,3,4,5,6,7,8,9,10,11). The use of these substances, which possess estrogenic and antiandrogenic properties, has been prohibited in many European countries.

Colon等人（49）观察到，与对照组相比，31名月经初潮提早的波多黎各女孩的邻苯二甲酸酯水平明显更高。邻苯二甲酸盐在某些化妆品中用作塑料软化剂和防腐剂，可能存在于塑料玩具、发胶、除臭剂、洗发水、指甲油和香水中，并可能很容易进入人体（1,2,3,4,5,6,7,8,9,10,11）。许多欧洲国家禁止使用这些具有雌激素和抗雄激素特性的物质。

Lead, a heavy metal and one of the major environmental pollutants, has also been found to affect puberty. It was observed that menarche and pubarche were delayed in girls with high serum lead levels (50,51).

铅，重金属之一，也是主要的环境污染物之一，也被发现会影响青春期。据观察，血清铅含量高的女孩的月经初潮和青春期会推迟（50,51）。

In addition to its teratogenic and cancerogenic features, BPA, which is found in huge amounts in polycarbonate plastics (i.e. baby feeding bottles), has also been suggested to have estrogenic effects causing precocious puberty. Although BPA has been investigated thoroughly in many animal studies, human studies are lacking. It has been suggested in some studies that exposure to BPA at early ages is associated with an increased incidence of breast cancer (52).

除了致畸和致癌特征外，在聚碳酸酯塑料（即婴儿喂奶瓶）中大量存在的双酚A（BPA）还被认为具有雌激素作用，可导致性早熟。虽然BPA在许多动物研究中都进行了彻底的调查，但缺乏人类研究。一些研究表明，在早期接触BPA与乳腺癌发病率增加有关（52）。

Conclusion/总结

In conclusion, it is worth noting that for EDs, to cause impairment of endocrine functions, time of exposure is as important as dose, duration and age at exposure. Moreover, a single chemical substance may result in multiple endocrine system dysfunctions via several mechanisms. To date, various EDs have been shown to exert unwanted effects on pubertal development. It is possible that there are numerous other chemicals with potential harmful effects on pubertal development. Future population-based studies are warranted for further investigation.

总结，值得注意的是，对于EDs来说，要引起内分泌功能受损，暴露时间与暴露时的剂量、持续时间和年龄一样重要。此外，一种化学物质可能会通过多种机制导致多种内分泌系统功能失调。迄今为止，各类EDs已被证明对青春期发育产生了不利的影响。可能还有许多其他化学品对青春期发育有潜在的有害影响。未来基于人群的研究需要进一步调查。

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