San Francisco, CA, USA. Atrazine, a common weedkiller in the U.S., already suspected of causing sexual abnormalities in frogs and fish, has now been found to alter hormonal signaling in human cells. The herbicide is the second most widely used weedkiller in the U.S., applied to corn and sorghum fields throughout the Midwest and also spread on suburban lawns and gardens. It was banned in Europe after studies linked the chemical to endocrine disruptions in fish and amphibians.

 

 

"These fish are very sensitive to endocrine disrupting chemicals, so one might think of them as 'sentinels' to potential developmental dangers in humans," said Holly Ingraham, PhD, senior author on the study and a UCSF Professor of Cellular and Molecular Pharmacology. "These atrazine- sensitive genes are central to normal reproduction and are found in steroid producing tissues. You have to wonder about the long-term effects of exposing the rapidly developing fetus to atrazine or other endocrine disruptors." The lead author of the study is Miyuki Suzawa, a postdoctoral fellow in Ingraham's lab.

 

Ingraham intends to determine precisely how atrazine affects human and other mammalian endocrine cells and why these cells are particularly sensitive to it. She notes that bisphenol A, a compound in many hard plastic consumer products, is also an endocrine disrupter and is now under increased study for its safety. In April, Canada announced a decision to ban sale of consumer products with bisphenol A.

 

UCSF researchers exposed sexually immature zebrafish to atrazine and other chemicals for different periods of time. They found that exposure to atrazine for 48 hours at concentrations that might be found in water containing agricultural runoff, produced twice as many female fish.

 

Through genetic analysis, they found that atrazine preferentially activates a class of receptors in the cell nucleus, including two known as SF-1 and LRH-1. SF-1 regulates production of enzymes involved in the synthesis of steroids in the body and development of many endocrine tissues. One of these enzymes, known as Aromatase, plays a role in determining whether lower vertebrates, such as fish will become male or female. Aromatase is known as a feminizing enzyme.

 

Europe banned atrazine following studies on endocrine disruptions in fish and amphibians.

In the human placental cell culture studies, the scientists found that a 24-hour exposure to atrazine activates a cluster of genes involved in hormone signaling and steroid synthesis. 

 

The researchers report that "Endocrine-related cell types with a capacity for steroid generation appear to be especially sensitive (to Atrazine), as demonstrated by the "exquisite" cellular specificity of the atrazine response."

 

The finding that a pervasive and persistent environmental chemical appears to significantly change hormone networks means that scientists must take a broader look at this herbicide's potential effect on human health, Ingraham said.

 

Up to now, much of the focus has been on breast cancer, but since proper development of the endocrine system is important for normal reproduction, stress responses and metabolism, early exposure to this chemical in a fetus or infant might alter normal physiology later in life, she said.

 

The research was supported by a postdoctoral fellowship Miyuki Suzawa from Susan B. Komen For The Cure and support for Holly A. Ingraham via an from RO1 grant from the U.S. National Institutes of Health (NIH).

 

The Herbicide Atrazine Activates Endocrine Gene Networks via Non-Steroidal NR5A Nuclear Receptors in Fish and Mammalian Cells. Suzawa M, Ingraham HA. PLoS ONE 3(5): e2117 doi: 10.1371 / journal.pone.0002117. [ Download PDF ]

Abstract. Atrazine (ATR) remains a widely used broadleaf herbicide in the United States despite the fact that this s-chlorotriazine has been linked to reproductive abnormalities in fish and amphibians. Here, using zebrafish we report that environmentally relevant ATR concentrations elevated zcyp19a1 expression encoding aromatase (2.2 µg/L), and increased the ratio of female to male fish (22 µg/L). ATR selectively increased zcyp19a1, a known gene target of the nuclear receptor SF-1 (NR5A1), whereas zcyp19a2, which is estrogen responsive, remained unchanged. Remarkably, in mammalian cells ATR functions in a cell-specific manner to upregulate SF-1 targets and other genes critical for steroid synthesis and reproduction, including Cyp19A1, StAR, Cyp11A1, hCG, FSTL3, LHß, INHα, αGSU, and 11ß-HSD2. Our data appear to eliminate the possibility that ATR directly affects SF-1 DNA- or ligand-binding. Instead, we suggest that the stimulatory effects of ATR on the NR5A receptor subfamily (SF-1, LRH-1, and zff1d) are likely mediated by receptor phosphorylation, amplification of cAMP and PI3K signaling, and possibly an increase in the cAMP-responsive cellular kinase SGK-1, which is known to be upregulated in infertile women. Taken together, we propose that this pervasive and persistent environmental chemical alters hormone networks via convergence of NR5A activity and cAMP signaling, to potentially disrupt normal endocrine development and function in lower and higher vertebrates.

Introduction (excerpt). Endocrine disrupting chemicals (EDCs) affect the reproductive health of fish and amphibious wild life, but their impact on mammals and particularly humans is less clear. Synthetic and natural endocrine disruptors fall into several chemical categories and include industrial chemicals, pesticides and herbicides. Some of these EDCs, such as the active chemical found in polycarbonate containers, bisphenol A, exhibit estrogenic effects in cultured cells by binding directly to the estrogen receptors ERα and ERβ. However, other EDCs fail to competitively bind ERs, including the widely used chlorotriazine herbicide atrazine (ATR).

The prevalent use of ATR as a broadleaf herbicide and its persistence in the environment underscores the importance of understanding the molecular impact of this EDC. Numerous studies in fish, amphibians, reptiles and mammals all suggest that ATR can alter normal endocrine, neuroendocrine and immune responses. For instance, in amphibians, low levels (0.1–25 µg/L) or short term exposure (48 hrs) to ATR, respectively, increases the number of intersex frogs, and impairs normal gonadal development. Consistent with these phenotypes, acute exposure to ATR lowers testosterone levels and impairs gonadal development in young fish, in the developing alligator, and in young peripubertal male rats. However, other studies suggest that reduced serum testosterone after ATR exposure results from a marked drop in body weight and food consumption. These latter effects are observed for both male and females rats and potentially reflect an unknown role of ATR in neuroendocrine signaling. Still others suggest that independent of body weight and hormone levels, ATR delays mammary gland development. Although there is ample literature documenting the effects of ATR in a variety of species, with the exception of aromatase (Cyp19A), other molecular targets of ATR remain poorly defined.

 

 

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